WO2024192115A1 - Compositions and methods for the treatment of cancer - Google Patents

Abstract

Compositions and methods for the treatment of disorders associated with miR-21 dysregulation, particularly cancer, are disclosed.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER Cross-reference to related application This application claims priority to US Provisional Application No. 63/490,184 filed March 14, 2023, the entire contends being incorporated by reference herein as though set forth in full. Statement Regarding Federally Sponsored Research or Development This invention was made with government support under 1 R41 CA 235707-01A1 awarded by NIH. The government has certain rights in the invention. Incorporation-by-Reference of Material Submitted in Electronic Form The Contents of the electronic sequence listing (BDT-102.xml; Size: 23,436 bytes; and Date of February 14, 2023) is herein incorporated by reference in its entirety. Field of the Invention The present invention relates to the fields of oncology and medicinal chemistry. More specifically, compositions comprising complementary microRNA-21 (miR-21) oligonucleotide analogs that inhibit miR-21 and its isomiRs from binding to miR-21 binding sites in target mRNAs, including without limitation, mRNAs encoding tumor suppressor proteins, and other mRNAs encoding proteins involved in cellular proliferation, migration, metastasis, stress and inflammation are provided. The oligonucleotide analogs complementary to miR-21 are conjugated to ligands that direct cancer cell uptake. Methods for modulating of expression of such proteins, thereby, providing therapeutic benefit, are disclosed. Background of the Invention Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full. Triple negative breast cancer (TNBC) is an orphan disease that attacks 46,000 US women every year, primarily appearing in younger women with African, Asian, Hispanic, or BRCA1 mutant ancestry. TNBC cells lack human estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (Her2), the targets of many existing medicines. More recent treatment options that have been explored for TNBC include anti-angiogenic agents, poly(ADP-ribose) polymerase (PARP) inhibitors, checkpoint inhibitors, and antibody-drug conjugates. However, approval of the anti-angiogenic agent, bevacizumab, for breast cancer was revoked by the FDA due to poor clinical outcome and safety issues. Similarly, Roche voluntarily withdrew Tecentriq, an anti-PD-L1 antibody for TNBC due to poor outcome. Trodelvy, a recently approved antibody-drug conjugate, only increased TNBC overall survival by 3 months. Additionally, only a small subset of patients having BRCA1/2 mutations benefit from PARP inhibitors, while checkpoint inhibitors are only modestly effective in TNBC patients with elevated PD-L1. As such, despite being fraught with side effects and providing a median survival of 4 years, chemotherapy and radiation remain the standard of care. MicroRNAs (miRNAs) and their isomiRs are small non-coding RNA molecules, approximately 22 nucleotides in length that regulate gene translation through silencing or degradation of target mRNAs. They are involved in multiple biological processes, including differentiation and proliferation, metabolism, hemostasis, apoptosis or inflammation, and in the pathophysiology of many diseases. Numerous studies have suggested circulating miRNAs as promising diagnostic and prognostic biomarkers of many diseases. TNBC cells show high levels of oncogenic miRNAs, oncomiRs, which are non-protein-coding RNAs of 18–25 nucleotides (nt) that form base pairs with specific sequences in mRNAs. They inhibit translation of mRNAs sterically or by inducing mRNA degradation by Ago2. Biogenesis of all miRNAs initiates in the nucleus, where primary miRNAs are transcribed by either RNA polymerase II or RNA polymerase III. Primary miRNA transcripts are then processed by Drosha and its cofactor DGCR8 to produce shorter precursor miRNA hairpins of ~70 nt. Pre-miRNA hairpins are exported to the cytoplasm by exportin 5, then cleaved by Dicer to yield double-stranded miRNAs. The guide strand of the double-stranded miRNA is thought to exhibit weak hydrogen bonding at its 5’ end, favoring its binding to Ago2 in an RNA-induced silencing complex (RISC), allowing the guide strand to be active against complementary mRNAs. Therapeutically targeting such oncomiRs can bypass cancer heterogeneity, since a single miRNA can simultaneously regulate different targeted mRNA molecules and thereby regulate expression and function of multiple gene networks. Due to limited applicability and various drawbacks associated with existing treatment options, there remains a need in the art for compositions, methods, protocols and kits that provide greater efficacy, specificity, and safety for molecularly-targeted therapy of TNBC. The present invention addresses this need. Summary of the Invention The present invention provides compositions and methods for the treatment of triple negative breast cancer. In one embodiment, a miR-21 inhibitory nucleic acid-peptide analog having sequence complementarity to miRNA-21-5p which sequesters miR-21-5p and its isomiRs from binding to regulatory sites present in mRNAs is provided. In certain embodiments, the miR-21 inhibitory nucleic acid-peptide analog of comprises a modification selected from BNA, LNA, FANA, PNA, 2′-fluoro, 2’-O-alkyl, morpholino, piperazine, phosphorothioate, boranophosphate and boranophosphate mixed with phosphodiester linkages, phosphorodithioate or methylphosphonate linkages. In other embodiments, the miR-21 inhibitory nucleic acid-peptide analog comprises at least one inhibitory sequence shown in Figures 2B or 2C, e.g., SEQ ID NOS: 6-25 and the 9 mer and 8 mer sequences shown. In a preferred embodiment, the miR-21 inhibitory-peptide analog comprises SEQ ID NO: 5. In preferred embodiments, the inhibitory sequence comprises at least one, and preferably two, 5’ and 3’ BNA modifications as shown in Figure 15. In some embodiments, the antisense sequence includes a deoxyribonucleic acid (DNA) portion and at least one bridged nucleic acid (BNA) portion such as, but not limited to, the aminomethyl BNA 2’4’-BNA^NC. For example, in some embodiments, the antisense sequence is a gapmer having a BNA-DNA-BNA structure. In some embodiments, each of the BNA portions and the DNA portion include the same number of nucleotides. For example, in one embodiment, the antisense sequence includes 15 nucleotides with a 5-5-5 gapmer structure. In another embodiment, the gapmer comprises SEQ ID NO: 5. Alternatively, in some embodiments, the DNA portion includes a different number of nucleotides as compared to at least one of the BNA portions. For example, in one embodiment, the antisense sequence includes 13 nucleotides with a 4-5-4 gapmer structure. The miR-21 inhibitory-peptide analog can also comprise a cyclic peptide selected from CSKC, CRKC, CVKC, CGKC, CKGC, CFKC, CDKC, CHRC, CRVC, CGRC, CIRC, CQRC, CTRC, CRHC, CRGC, CRSC CRKC, CSRC, or CERC, in which all residues are D-amino acids, and a disulfide bond is formed between the N-terminal cysteine and the C-terminal cysteine. The miR-21 inhibitory-peptide analog can also comprise a peptide ligand for the insulin- like growth factor 1 receptor of SEQ ID NO: 26, CSKC. Also provided are methods for inhibiting binding of miR-21 to one or more binding sites in an mRNA encoding a protein that modulates cellular proliferation, migration, metastasis, stress, or inflammation. An exemplary method comprises contacting the miR-21-5p with the inhibitors described herein, wherein said inhibitor binds and sequesters said miR-21-5p and thereby prevents miR-21-5p binding to regulatory sites present in an mRNA encoding a protein that modulates malignant cell growth, and, or, metastasis. In preferred embodiments, methods for the treatment of triple negative breast cancer (TNBC) in a patient in need thereof is disclosed. An exemplary method comprises administering an effective amount of a miR-21 inhibitory- peptide analog as described above, wherein the analog causes TNBC stasis or cell death. In preferred embodiments, the analog is shown in Figure 15. The methods of the invention can also include administration of a chemotherapeutic agent selected from rituximab, bevacizumab, trastuzumab, imatinib, dinoxetine, cetuximab, nilotinib, sorafenib, bemcentinib, crizotinib, bosutinib, gilteritinib, amuvatinib, and Sunitinib, cabozantinib, foretinib, rebastinib, celastrol, dihydroartemisinin, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, cyclophosphamide, ifosfamide, thiotepa, methotrexate, mercaptopurine, fluorouracil and cytarabine, bleomycin, daunorubicin, actinomycin D, mitomycin, doxorubicin, mitoxantrone, vincristine, etoposide, teniposide, paclitaxel and docetaxel, cisplatin, carboplatin and oxaliplatin, euprolide, tamoxifen, flutamide and formestane, and arsenic trioxide. The invention also provides compositions and methods which effectively decreases or increases disease-driving protein levels (See Figure 1), to provide treated patients a therapeutic benefit. In other embodiments, the compositions and methods target expression of tumor suppressor proteins. In other embodiments, the tumor suppression gene is selected from PTEN and PDCD4. Brief Description of the Drawings Figures 1A-1J: Fig. 1A) A schematic diagram showing the many different signaling and disease pathways that provide targets for the miR-21 directed agents described below. Figs. 1B- 1J) Schematic diagram of different ligands for delivery of the complementary miR-21 oligonucleotide analogs described herein. Figures 2A-2D: (Fig. 1A) miR-21 pre-miRNA hairpin structure (SEQ ID NO: 1). (Fig. 2B – 2C) miR-21 oligonucleotide sequences are shown. The pre-miRNA hairpin structure contains miR-21-5p guide strand (upper magenta sequence), and a miR-21-3p passenger strand (lower magenta sequence). Most of the nucleotides in the miR-21-5p guide strand are complementary to the miR-21-3p passenger strand. Nucleosides to be excluded in the passenger strand seed sequence are shown in SEQ ID NO: 4 in blue. Either the guide strand or the passenger strand could be selected as the active miRNA in an RNA-inducing silencing complex (RISC). SEQ ID NOS: 5 to 25 and three 9 mers and three 8 mers provide additional anti-miR-21- 5p sequences ranging in length from 8 mers to 17 mers, which should hybridize efficiently to the target. SEQ ID NO: 5, a 15-mer, is shown in bold in Fig. 2B. (Fig. 2D) Schematic view of miR- 21 oligonucleotide-peptide blocker mechanism. miR-21 inhibitory nucleic acid binds to the mature miR-21-5p guide strand, preventing it from binding to its regulatory sites in the 3’UTR of target mRNAs. Figure 3: DNA/RNA analogs for increasing stability, binding affinity, and specificity. Schematics of DNA phosphorothioate (PS), methylphosphonate (MP), 2’-4’-locked nucleic acid (LNA), 2’-aminomethylene-bridged nucleic acid (NC-BNA), and polyamide nucleic acid (PNA). Figures 4A – 4B: (Fig. 4A) Structure of BND5412, a 15 nt miR-21 blocker BNA-DNA- BNA phosphorothioate. The short BNA sequence lacks the seed sequence of the corresponding miR-21 passenger strand, thus avoiding passenger strand mimicry. (Fig. 4B) IC₅₀ of miR-21 blocker BND5412 transfected into human MDA-MB-231 TNBC cells to induce de-repression of a Renilla luciferase reporter vector with a miR-21 binding site inserted into the 3’UTR of the luciferase gene. Error bars, s.d. Figures 5A – 5B: (Fig. 5A) Western blot analysis of protein expression ± s.d. following 50 nM miR-21 blocker BND5412 transfected into human MDA-MB-231 TNBC cells for 48 h (PDCD4) or 72 h (other proteins). (Fig. 5B) Western blot of immune checkpoint proteins in human HCC1806 TNBC cells 72 h post transfection with 50 nM miR-21 blocker BND5412. Figure 6: Cell Titer Glo assay ± s.e.m. following 50 nM miR-21 blocker BND5412 transfected into 7 different TNBC cell lines on day 0. Figure 7: A graph comparing FANA oligonucleotides with three BNA oligonucleotides of known sequence. FANA sequences 1 – 7 did not show significant inhibition compared to scrambled BNA or vehicle control. Cell viability was measured by Cell-Titer Glo assay. Error bars, s.d., n = 3. Figure 8: Correlation between cell proliferation IC₅₀ of miR-21 blocker BND5412 and miR-21 copies/cell in 7 human TNBC cell lines vs. a non-tumorigenic breast epithelial cell line transfected with concentration gradients of miR-21 blocker BND5412. Figure 9: LDH assay ± s.d. 72 h post 50 nM miR-21 blocker BND5412 transfection to test for apoptosis in human MDA-MB-231 TNBC cells. Figure 10: qPCR mRNA levels ± s.e.m. of PD-L1, PD-L2, CD47, and JAK2 mRNA, relative to GAPDH, extracted from human HCC1806 TNBC cells transfected with vehicle, 50 nM scrambled blocker (purple), or 50 nM miR-21 blocker BND5412 (blue), in 3 biological replicates, ± s.e.m. Relative expression levels were normalized to vehicle controls. [* = p<0.05, ** = p<0.01, vs. vehicle control by 1-way t-test]. Figures 11A-11B: (Fig. 11A) Cumulative frequency distribution of miR-21 target genes (red) and all other genes with significant differential expression (blue), in RNA-seq analysis from 6 biological replicates from human HCC1806 TNBC cells transfected with IC90 concentration of miR-21 blocker BND5412, [Kolmogorov-Smirnov test, p<0.0001]. (Fig. 11B) Top 3 enriched pathways of differentially expressed genes from miR-21 blocker treated samples. Figure 12: Design of miR-21 blocker conjugate of BNA-DNA-BNA gapmer with IGF1 peptide for endocytosis by cell surface IGF1R, highly expressed on TNBC cells. Figure 13: Structure of BND7673, AF647-labeled miR-21 blocker BNA-DNA-BNA phosphorothioate coupled to IGF1 peptide for IGF1R-mediated endocytosis. The short BNA sequence lacks the seed sequence of the corresponding miR-21 passenger strand, thus avoiding passenger strand mimicry. Figure 14: Confocal fluorescence images of live human HCC1806 TNBC cells after 4 h in 100 nM Cal560-miR-21 BNA-IGF1 peptide. Green: LysoTracker. Red: Cal560. Yellow: Cal560-LysoTracker overlap. Figure 15: Structure of BND6482, miR-21 blocker BNA-DNA-BNA phosphorothioate- IGF1 peptide for IGF1R-mediated endocytosis, without the fluorescent dye used for distribution. The short BNA sequence lacks the seed sequence of the corresponding miR-21 passenger strand, thus avoiding passenger strand mimicry. Figures 16A -16B: Dose dependent inhibition of miR-21 activity by 50 nM miR-21 blocker BND6482 without lipofection (blue) was measured in miR-21 luciferase reporter assay in comparison to miR-21 blocker BND6482 transfected at 50 nM (red) in high IGF1R expressing HCC1806 cells (Fig. 16A), and low IGF1R expressing MDA-MB-157 cells (Fig. 16B). Error bars, s.d. Figure 17: Distribution of fluorescent miR-21 blocker BND767 after a single IP injection at 5 mg/kg in orthotopic allografts in the mammary fat pads of immunocompetent female Balb/c mice generated with syngeneic mouse EMT6 TNBC cells over 2-96 hours. Figure 18: Imaging following IP injection of fluorescent anti-miR-21-peptide BND7673 in the TBC mouse model described in Figure 17 at 5 mg/kg once daily for 3 days inhibited tumor growth, as seen in white light images (left) or fluorescent images (right) of dissected tumors. Figure 19: IP injection of fluorescent anti-miR-21 blocker-peptide BND7673 at one daily dose of 5 mg/kg for 3 days inhibited tumor growth over 4 days in the TBC mouse model described in Figure 17. Individual tumor masses are shown with mean and S.E.M. Figure 20: miR-21 and PDCD4 mRNA levels in tumors from female Balb/c mice bearing syngeneic mouse EMT6 TNBC allografts after 3 daily doses of 5 mg/kg fluorescent miR-21 blocker-peptide BND7673. Error bars show S.E.M. Figure 21: Tumor volumes of mouse EMT6 TNBC orthotopic allografts stayed small after twice a week IP injection of 5 mg/kg of miR-21 blocker-peptide BND6482 over 13 days. Vehicle, scrambled drug and Trodelvy allowed continued growth. Error bars show mean with SEM. *p<0.05 by One-way ANOVA with Dunnett’s multiple comparison test. Figure 22: Tumor masses of mouse EMT6 TNBC orthotopic allografts were significantly reduced after twice a week IP injection of 5 mg/kg of miR-21 blocker-peptide BND6482 over 13 days. Error bars show mean with SEM. *p<0.05 by One-way ANOVA with Dunnett’s multiple comparison test. Figure 23: Toxicity markers in serum samples from treated tumor-bearing mice after twice a week IP injection of 5 mg/kg of miR-21 blocker-peptide BND6482 over 13 days or 3 IP injections of 6.25 mg/kg. Error bars show mean with SEM. *p<0.05 by One-way ANOVA with Dunnett’s multiple comparison test. Detailed Description of the Invention The design and synthesis of miR-21 directed therapeutic agents are described herein. miR-21, a 22 nt RNA single strand, is elevated in TNBC compared to adjacent normal tissues (Radojicic et al. 2011). Overexpression of miR-21 is universally observed in breast cancer cell lines and tissues (Ozgun et al. 2013), affecting cell proliferation, cell cycle check points, and metastasis (Anastasov et al. 2012). The expression of miR-21 in TNBC is also correlated with poor clinical outcome (Dong et al. 2014). The passenger strand miR-21-3p is up-regulated in TNBC, and has been associated with chemoresistance (Ouyang et al. 2014). Previously, a 19 mer anti-miR-21 nucleic acid analog with particular backbone modifications has been patented for use in the treatment of liver disease. Use for the treatment of breast cancer is not disclosed (Bhat and Marcusson 2015). Definitions Before further describing the inventions in general and in terms of various nonlimiting specific embodiments, certain terms used in the context of the describing the invention are set forth. Unless indicated otherwise, the following terms have the following meanings when used herein and in the appended claims. Those terms that are not defined below or elsewhere in the specification shall have their art-recognized meaning. As used herein, the term “pharmacological activity” refers to the inherent physical properties of a peptide or polypeptide. These properties include but are not limited to half-life, solubility, and stability and other pharmacokinetic properties. The terms “high,” “higher,” “increases,” “elevates,” or “elevation” refer to increases above basal levels, e.g., as compared to a control. The terms “low,” “lower,” “reduces,” or “reduction” refer to decreases below basal levels, e.g., as compared to a control. The term “modulate” as used herein refers to the ability of a compound to change an activity in some measurable way as compared to an appropriate control. As a result of the presence of compounds in the assays, activities can increase or decrease as compared to controls in the absence of these compounds. Preferably, an increase in activity is at least 25%, more preferably at least 50%, most preferably at least 100% compared to the level of activity in the absence of the compound. Similarly, a decrease in activity is preferably at least 25%, more preferably at least 50%, most preferably at least 100% compared to the level of activity in the absence of the compound. A compound that increases a known activity is an “agonist”. One that decreases, or prevents, a known activity is an “antagonist”. The term “inhibit” means to reduce or decrease in activity or expression. This can be a complete inhibition or activity or expression, or a partial inhibition. Inhibition can be compared to a control or to a standard level. Inhibition can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. The term “preventing” as used herein refers to administering a compound prior to the onset of clinical symptoms of a disease or conditions so as to prevent a physical manifestation of aberrations associated with the disease or condition. The term “in need of treatment” as used herein refers to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, or individual in the case of humans; veterinarian in the case of animals, including non-human mammals) that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a care giver's expertise, but that includes the knowledge that the subject is ill, or will be ill, as the result of a condition that is treatable by the disclosed compounds. By “treatment” and "treating" is meant the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. The effects of treatment can be measured or assessed as described herein and as known in the art as is suitable for cancer and its associated pathologies. A “cell” can be a cell from any organism including, but not limited to, a bacterium. A cell can be in vitro. Alternatively, a cell can be in vivo and can be found in a subject. By “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject along with the selected compound without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. “Percent (%) sequence identity” and “homology” with respect to a nucleic acid sequence, peptide, polypeptide or antibody sequence are defined as the percentage of nucleic acid or amino acid residues in a candidate sequence that are identical with the nucleic acid or amino acid residues in the specific nucleic acid or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. As used herein, the terms "component," "composition," "composition of compounds," "compound," "drug," "pharmacologically active agent," "active agent," "therapeutic," "therapy," "treatment," or "medicament" are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action. The terms "agent" and "test compound" denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. "Administering" or "administration" or "administer" means providing a material to a subject in a manner that is pharmacologically useful. The compounds of the invention may be administered via any acceptable route, e.g., via intravenous, intrapulmonary, orally, dermally, or systemically. As used herein, the term "combination therapy" is intended to define therapies which comprise the use of a combination of two or more compounds/agents (as defined above). Thus, references to "combination therapy", "combinations" and the use of materials/agents "in combination" in this application may refer to materials/agents that are administered as part of the same overall treatment regimen. As such, each of the two or more materials/agents may differ: each may be administered at the same time or at different times. It will, therefore, be appreciated that the materials/agents of the combination may be administered sequentially (e.g., before or after) or simultaneously, either in the same pharmaceutical formulation (i.e., together), or in different pharmaceutical formulations (i.e., separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary. “Concomitantly” means administering two or more materials/agents to a subject in a manner that is correlated in time, preferably sufficiently correlated in time so as to provide a modulation in a physiologic or immunologic response, and even more preferably the two or more materials/agents are administered in combination. In embodiments, concomitant administration may encompass administration of two or more materials/agents within a specified period of time, preferably within 1 month, more preferably within 1 week, still more preferably within 1 day, and even more preferably within 1 hour. In embodiments, the materials/agents may be repeatedly administered concomitantly, that is concomitant administration on more than one occasion, such as may be provided in the Examples. The phrase “disease driving protein levels” refers to the amount of a cellular protein that accelerates cell division, such as a receptor, kinase, transcription factor, or any member of a growth signal transduction pathway. The phrase “disease limiting protein levels” refers to the amount of a cellular protein that inhibits cell division, such as a receptor, phosphatase, protease, tumor suppressor, transcription repressor, or any member of a stasis or apoptotic signal transduction pathway. The phrase "effective amount" or "therapeutically effective amount" refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will provide an image for detection by any one of the imaging methods described herein. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried. “Pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmacologically inactive material used together with a pharmacologically active material to formulate the compositions. Pharmaceutically acceptable excipients comprise a variety of materials known in the art, including but not limited to saccharides (such as glucose, lactose, and the like), preservatives such as antimicrobial agents, reconstitution aids, colorants, saline (such as phosphate buffered saline), and buffers. The terms "subject," "individual," and "patient" are used interchangeably herein, and refer to an animal, for example a human, to whom treatment, including prophylactic treatment, with the pharmaceutical composition according to the present invention, is provided. The term "subject" as used herein refers to human and non-human animals. The terms "non-human animals" and "non-human mammals" are used interchangeably herein and include all vertebrates, e.g., mammals, such as non-human primates, (particularly higher primates), sheep, dog, rodent, (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses and non-mammals such as reptiles, amphibians, chickens, and turkeys. The terms "polynucleotide", "nucleotide sequence", "nucleic acid" and "oligonucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The term “microRNA (miRNA)” refers to small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in a wide variety of species, and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. An “isomiR” refers to a miRNA sequence having certain variations with respect to the reference miRNA sequence, but is able to bind Ago proteins and play a similar role in gene- expression regulation as it’s canonical miRNA. See for example, Kuchenbauer, et al. (2008) Genome Research 18:1787–1797. “Antisense oligonucleotides or strands” are oligonucleotides that are complementary to sense oligonucleotides, pre-mRNA, RNA or sense strands of particular genes and which bind to such genes and gene products by means of base pairing. Examples of base pairing nucleotides include but are not limited to, uracil, thymine, adenine, cytosine, guanine and hypoxanthine having their respective amino groups protected by acyl protecting groups, 2-fluorouracil, 2- fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pyrimidine analogs such as pseudoisocytosine and pseudouracil and other modified nucleobases such as 8- substituted purines, xanthines, or hypoxanthines. Further examples of base pairing nucleotides, include but are not limited to, expanded-size nucleobases in which one or more benzene rings has been added. When binding to a sense oligonucleotide, the antisense oligonucleotide need not base pair with every nucleotide in the sense oligonucleotide. “Tm” or melting temperature is the midpoint of the temperature range over which the oligonucleotide separates from the target nucleotide sequence. At this temperature, 50% helical (hybridized) versus coiled (unhybridized) forms are present. Tm is measured by using the UV absorbance spectrum to determine the formation and breakdown (melting) of hybridization. Tm can be determined using techniques that are well known in the art. There are also formulas available for estimating Tm on the basis of sequence and common chemical modifications if any. “Gene target” or “target gene” refers to a gene having an RNA transcript (processed or unprocessed) having a nucleic acid sequence that includes miR-21, and thus is capable of being bound by the miR-21 inhibitory RNA-peptide analogs described herein and modulate expression of the proteins encoded by the mRNAs containing miR-21 binding sites. As used herein, “modified nucleotides” refers to non-naturally occurring moieties that confer increased nuclease resistance or thermodynamic stability during hybridization as compared with a polynucleotide that differs from the inhibitory nucleic acid only by having a natural nucleotide in place of the modified nucleotide. In certain embodiments, the ribose moiety of a nucleotide is modified with an extra bridge connecting the 2′ oxygen and 4′ carbon. Numerous chemical modifications are commonly used for the synthesis of oligonucleotides for a variety of reasons. For example, to increase the phosphate backbone's stability, adjust duplex stability, change the oligonucleotide's conformation, or increase its ability to penetrate a lipid bilayer. Modified sugar moieties are also being incorporated into therapeutic oligonucleotides. Changing the sugar moiety generally increases nuclease resistance and binding affinity to a complementary target. “Bridged nucleic acid” (“BNA”) refers to 2′-O,4′-C-methylene-modified nucleic acids. “Locked nucleic acid nucleotide” (“LNA nucleotide”), as used herein, refers to a modified RNA nucleotide that provides the polynucleotide with greater thermodynamic stability during hybridization as compared with a polynucleotide that differs from the LNA only by having a natural ribonucleotide in place of the modified RNA nucleotide. As used herein the term "wild type" is a term of the art understood by skilled persons and means the typical form of an organism, strain, gene or characteristic as it occurs in nature as distinguished from mutant or variant forms. As used herein the term "variant" should be taken to mean the exhibition of qualities that have a pattern that deviates from the wild type or a comprises non naturally occurring components. The term “peptide” refers to a compound comprising a plurality of linked amino acids. Amino acids used in compounds provided herein (e.g. peptides and proteins) can be any one of the 20 genetically encoded amino acids, naturally occurring non-genetically encoded amino acids, or synthetic amino acids. Both L- and D-enantiomers of any of the above can be utilized in the compounds. In certain embodiments, all of the amino acids are D-enantiomers. The following abbreviations may be used herein for the following genetically encoded amino acids (and residues thereof): alanine (Ala, A); arginine (Arg, R); asparagine (Asn, N); aspartic acid (Asp, D); cysteine (Cys, C); glycine (Gly, G); glutamic acid (Glu, E); glutamine (Gln, Q); histidine (His, H); isoleucine (Ile, I); leucine (Leu, L); lysine (Lys, K); methionine (Met, M); phenylalanine (Phe, F); proline (Pro, P); serine (Ser, S); threonine (Thr, T); tryptophan (Trp, W); tyrosine (Tyr, Y); and valine (Val, V). In certain embodiments, the residues of the protein or peptide are sequential, without any non-genetically encoded amino acids, or synthetic amino acids interrupting the sequence of amino acid residues. In other embodiments, the sequence may comprise one or more non-genetically encoded or synthetic amino acid moieties. In particular embodiments, the sequence of residues of the peptide may be interrupted by one or more non- genetically encoded or synthetic amino acid moieties, including but not limited to those shown in Table 1. Table 1. Non-genetically Encoded or Synthetic Amino Acids Abbreviation Amino Acid

3.Hyp 3-Hydroxyproline 4Hyp 4-Hydroxyproline

Amino acids that are substitutable for each other generally reside within similar classes or subclasses. As known to one of skill in the art, amino acids can be placed into different classes depending primarily upon the chemical and physical properties of the amino acid side chain. For example, some amino acids are generally considered to be hydrophilic or polar amino acids and others are considered to be hydrophobic or nonpolar amino acids. Polar amino acids include amino acids having acidic, basic or hydrophilic side chains and nonpolar amino acids include amino acids having aromatic or hydrophobic side chains. Nonpolar amino acids may be further subdivided to include, among others, aliphatic amino acids. The definitions of the classes of amino acids as used herein are as follows: "Nonpolar Amino Acid" refers to an amino acid having a side chain that is uncharged at physiological pH, that is not polar and that is generally repelled by aqueous solution. Examples of genetically encoded hydrophobic amino acids include Ala, Ile, Leu, Met, Trp, Tyr, and Val. Examples of non-genetically encoded nonpolar amino acids include t-BuA, Cha, and Nle. "Aromatic Amino Acid" refers to a nonpolar amino acid having a side chain containing at least one ring having a conjugated n-electron system (aromatic group). The aromatic group may be further substituted with substituent groups such as alkyl, alkenyl, alkynyl, hydroxyl, sulfonyl, nitro, and amino groups, as well as others. Examples of genetically encoded aromatic amino acids include phenylalanine, tyrosine, and tryptophan. Commonly encountered non-genetically encoded aromatic amino acids include phenylglycine, 2-naphthylalanine, β-2-thienylalanine, 3- benzothiazol-2-yl-alanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 4- chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, and 4-fluorophenylalanine. “Aliphatic Amino Acid” refers to a nonpolar amino acid having a saturated or unsaturated straight chain, branched or cyclic hydrocarbon side chain. Examples of genetically encoded aliphatic amino acids include Ala, Leu, Val, and Ile. Examples of non-encoded aliphatic amino acids include Nle. “Polar Amino Acid" refers to a hydrophilic amino acid having a side chain that is charged or uncharged at physiological pH and that has a bond in which the pair of electrons shared in common by two atoms is held more closely by one of the atoms. Polar amino acids are generally hydrophilic, meaning that they have an amino acid having a side chain that is attracted by aqueous solution. Examples of genetically encoded polar amino acids include asparagine, cysteine, glutamine, lysine, and serine. Examples of non-genetically encoded polar amino acids include citrulline, homocysteine, N-acetyl lysine, and methionine sulfoxide. “Acidic Amino Acid” refers to a hydrophilic amino acid having a side chain pK value of less than 7. Acidic amino acids typically have negatively charged side chains at physiological pH due to loss of a hydrogen ion. Examples of genetically encoded acidic amino acids include aspartic acid (aspartate) and glutamic acid (glutamate). “Basic Amino Acid” refers to a hydrophilic amino acid having a side chain pK value of greater than 7. Basic amino acids typically have positively charged side chains at physiological pH due to association with hydronium ion. Examples of genetically encoded basic amino acids include arginine, lysine and histidine. Examples of non-genetically encoded basic amino acids include ornithine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, and homoarginine. “Ionizable Amino Acid” refers to an amino acid that can be charged at a physiological pH. Such ionizable amino acids include acidic and basic amino acids, for example, D-aspartic acid, D-glutamic acid, D-histidine, D-arginine, D-lysine, D-hydroxylysine, D-ornithine, L- aspartic acid, L-glutamic acid, L-histidine, L-arginine, L-lysine, L-hydroxylysine, or L-ornithine. As will be appreciated by those having skill in the art, the above classifications are not absolute. Several amino acids exhibit more than one characteristic property, and can therefore be included in more than one category. For example, tyrosine has both a nonpolar aromatic ring and a polar hydroxyl group. Thus, tyrosine has several characteristics that could be described as nonpolar, aromatic and polar. However, the nonpolar ring is dominant and so tyrosine is generally considered to be nonpolar. Similarly, in addition to being able to form disulfide linkages, cysteine also has nonpolar character. Thus, while not strictly classified as a hydrophobic or nonpolar amino acid, in many instances cysteine can be used to confer hydrophobicity or nonpolarity to a peptide. In some embodiments, polar amino acids contemplated by the present invention include, for example, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, homocysteine, lysine, hydroxylysine, ornithine, serine, threonine, and structurally related amino acids. In one embodiment the polar amino is an ionizable amino acid such as arginine, aspartic acid, glutamic acid, histidine, hydroxylysine, lysine, or ornithine. Examples of polar or nonpolar amino acid residues that can be utilized include, for example, alanine, valine, leucine, methionine, isoleucine, phenylalanine, tryptophan, tyrosine, and the like. The terms "non-naturally occurring" or "engineered" are used interchangeably and indicate the involvement of the hand of man. The terms, when referring to nucleic acid molecules or polypeptides mean that the nucleic acid molecule or the polypeptide is at least substantially free from at least one other component with which they are naturally associated in nature and as found in nature. Nucleic acid molecules that inhibit expression of a gene or nucleic acid can be referred to as “inhibitory nucleic acid” (referring to their composition). Inhibitory nucleic acid technologies are known in the art and include, but are not limited to, antisense oligonucleotides, catalytic nucleic acids such as ribozymes and deoxyribozymes, aptamers, triplex forming nucleic acids, external guide sequences, and RNA interference molecules (RNAi), particularly small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miR), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi). A “miR-21 inhibitory nucleic acid” or “miR-21 inhibitory nucleic acid analog” can hybridize to miR-21 or its isomiRs, blocking its activity, and thereby reduce expression of a protein encoded by an mRNA harboring miR-21 binding sites or a mRNA variant thereof, collectively. As used herein the term "analog(ues)" refers to chemical compounds that are structurally similar to another but which differ slightly in composition (as in the replacement of one atom by another or in the presence or absence of a particular functional group). As used herein, the term "bioavailability" refers to the degree to which or rate at which a drug or other substance is absorbed or becomes available at the site of biological activity after administration. This property is dependent upon a number of factors including the solubility of the compound, rate of absorption in the gut, the extent of protein binding and metabolism etc. Various tests for bioavailability that would be familiar to a person of skill in the art are described herein. The term "water solubility" as used in this application refers to solubility in aqueous media, e.g. phosphate buffered saline (PBS) at ~pH 7.4, 0.9% saline, or ~5% glucose. Tests for water solubility are given below in the Examples as "water solubility assay". Discussion Provided herein are miR-21 inhibitory nucleic acid-peptide analogs. In some embodiments, the inhibitor is an antisense oligonucleotide. An “antisense” nucleic acid sequence (antisense oligonucleotide) typically includes a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a regulatory RNA or a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to a target RNA. In such embodiments, the antisense inhibitory nucleic acid sequences bind to one or more binding sites present in target miR- 21. The inhibitory nucleic acid includes at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence complementarity with at least a part of miR-21. In some embodiments, the inhibitory nucleic acid does not include the section of nucleotides that mirrors the seed-region of the miR-21 passenger strand. In such embodiments, the complementarity of the inhibitory nucleic acid relates to any remaining part of the target miR-21 (i.e., the sense strand) corresponding to the section of the miR-21 passenger strand without the seed-region. For example, in one embodiment, the inhibitory nucleic acid has 100% sequence complementarity with at least a portion of the part of miR-21 corresponding to the section of the passenger strand without the seed-region. In other embodiments, the inhibitory nucleic acid has at least 70% sequence complementarity with at least a portion of the part of miR-21 corresponding to the section of the passenger strand without the seed-region. Suitable inhibitory nucleic acids include, but are not limited to, any of the sequences provided herein. As will be appreciated by those skilled in the art, sequence variations that might be expected due to genetic mutation, strain polymorphism, or evolutionary divergence can be tolerated by the inhibitory nucleic acids disclosed herein. In some embodiments, the inhibitory nucleic acid-peptide analog includes between 8 and 17 nucleotides, between 8 and 15 nucleotides, between 10 and 17 nucleotides, between 10 and 15 nucleotides, or any combination, sub-combination, range, or sub-range thereof. Additionally, or alternatively, in some embodiments, the inhibitory nucleic acid is a gapmer. The gapmer includes any suitable number of portions, with each portion including any suitable number of nucleotides according to the overall length of the inhibitory nucleic acid. In one embodiment, for example, the inhibitory nucleic acid includes a 15 nucleotide gapmer with a 5-5-5 structure. Other embodiments include any suitable variation in the number of nucleotides in any portion, each of which are explicitly covered herein. In some embodiments, the gapmer includes a deoxyribonucleic acid (DNA) portion and at least one bridged nucleic acid (BNA). In one embodiment, for example, the inhibitory nucleic acid includes a gapmer with three portions having a BNA-DNA-BNA structure. In another embodiment, the inhibitory nucleic acid includes an 8 nucleotide gapmer with a BNA-DNA- BNA portion including at least the sequence ATAAGC (Fig. 2C). In some embodiments, the sequence in the DNA portion is modified while retaining the ability to bind to the target miR-21. In some embodiments, the BNA portion includes the 2′ oxygen and 4′ carbon bridged by a methylene group. Other examples of BNA can include, but are not limited to, 2′,4′- BNA^NC[NH], 2′,4′-BNA^NC[NMe], and 2′,4′-BNA^NC[NBn]. In some embodiments, one or more portions of the gapmer include 2′-O,4′-C-ethylene-bridged nucleic acids (ENA), where the 2′ oxygen and 4′ carbon are bridged by an ethylene group. Additionally, or alternatively, in some embodiments, (s)-cEt (S-constrained Ethyl) and/or tcDNA (tricycloDNA) modifications can be used to constrain nucleotides. In certain embodiments, the ribose moiety of a modified RNA nucleotide is modified with an extra bridge connecting the 2′ oxygen and 4′ carbon. LNA nucleotides can comprise any type of extra bridge between the 2′-O and 4′-C of the RNA that increases the thermodynamic stability of the duplex between the LNA and its complement. Other 2′-O-modified nucleotides, such as 2′-O-Me, demonstrate greater stability, as well. In some embodiments, the inhibitory nucleic acid includes an oligonucleotide backbone configuration that demonstrates particularly high binding affinities to the target (measured by melting temperature or Tm) to implement the steric hindrance mechanism. BNA, Such backbones include, but are not limited to, LNA, FANA, 2′-fluoro, 2’-O-methoxyethyl (2’-MOE), 2’-NH2, 2’-F-RNA, morpholino, and piperazine containing backbones. Other modifications on the oligonucleotide ribose include, are not limited to, FHNA (Fluoro Hexitol Nucleic Acid), (s)-5’-C-methyl, UNA (Unlocked Nucleic Acid), 4’- thio-RNA, cyclohexene nucleic acid. Modified backbone linkages are sometimes used instead of phosphodiester linkage to minimize oligonucleotide degradation by nucleases. Some examples include, are not limited to, phosphorothioate, boranophosphonate, phosphoramidate, methyl phosphonate, (SC5’ Rp)-α,β- CNA (Dioxaphosphorinane-Constrained Nucleic Acid), PNA (Peptide Nucleic Acid), PMO (Phosphorodiamidate Morpholino Oligonucleotide), phosphoryl guanidine. 5’ modifications to increase phosphate stability include, are not limited to, E-VP ((E)-VinylPhosphonate), 5’ methyl phosphonate, 5’-phosphorothioate, (s)-5’-methyl with phosphate, 5’-methoxy. 3’ modifications to increase phosphate stability include, are not limited to, 2-hydroxyethylphosphate and 3’-ddc (dideoxyCytosine), 3’-amino. Base modifications to improve 3’ stability include, are not limited to, 2’-thio-dT. The generation of oligonucleotides with mixed linkages such as boranophosphate and phosphate linkages has been accomplished by several solid phase methods including one involving the use of bis(trimethylsiloxy)cyclododecyloxysilyl as the 5′-0-protecting group (Brummel and Caruthers, Tetrahedron Lett 43: 749, 2002). In another example the 5′-hydroxyl is initially protected with a benzhydroxybis-(trimethylsilyloxy)silyl group and then deblocked by Et₃N:HF before the next cycle (McCuen et al., J Am Chem Soc 128: 8138, 2006). This method can result in a 99% coupling yield and can be applied to the synthesis of oligos with pure boranophosphate linkages or boranophosphate mixed with phosphodiester, phosphorothioate, phosphorodithioate or methyl phosphonate linkages. In a further example, the boranophosphorylating reagent 2-(4-nitrophenyl)ethyl ester of boranophosphoramidate can be used to produce boranophosphate linked oligoribonucleotides This reagent readily reacts with a hydroxyl group on the nucleosides in the presence of 1H-tetrazole as a catalyst. The 2-(4- nitrophenyl)ethyl group can be removed by 1,4-diazabicyclo[5.4.0]undec-7-ene (DBU) through beta-elimination, producing the corresponding nucleoside boranomonophosphates (NMPB) in good yield. In some embodiments, the inhibitory nucleic acid sequence includes one or more nucleobase modifications to increase binding affinity. Suitable nucleobase modifications to increase binding affinity include, are not limited to, 5’-methylcytidine, 5-methyluridine (ribothymidine), abasic RNA. Despite having a reduced length (i.e., number of nucleotides), the antisense sequences disclosed herein bind strongly enough to miR-21 to specifically block the activation of mRNA translation. Additionally or alternatively, and without wishing to be bound by theory, it is believed that the BNA reduces or eliminates hybridization-dependent and hybridization- independent toxicity, while also providing improved hybridization affinity as compared to existing backbone modifications (e.g., locked nucleic acid (LNA)). Furthermore, and once again without wishing to be bound by theory, it is believed that the exclusion of the seed-region of the passenger strand reduces or eliminates passenger strand mimicry by the antisense sequence. Also provided herein, in some embodiments, are method of treating or ameliorating symptoms associated with cancer and/or other types of hyperproliferative disorders modulated by microRNA 21 activity. In some embodiments, the method includes administering one or more of the inhibitory nucleic acid sequences and analogs disclosed herein, and/or one or more sequences which are at least 80%, 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical thereto and retain the ability to treat or ameliorate symptoms associated with cancer, to a subject in need thereof. In one embodiment, for example, the method includes administering one or more of the sequences disclosed herein to a subject having cancer, such as, but not limited to, triple negative breast cancer (TNBC). Delivery methods useful for administration of inhibitory nucleic acids are known in the art. See for example, (Goodchild, Curr. Opin. Mol. Ther., 6(2):120-128 (2004); Clawson, et al., Gene Ther., 11(17):1331-1341 (2004) Durymanov M., et al. Front. Pharmacol. 9:971 (2018); Kulkarni et al., Nature Nanotechnology 16:630 (2021)) which are incorporated herein by reference in their entirety. An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides and, or, modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and 3’ and 5’ end modified or synthetic nucleotides can be used. Nucleic acid sequences provided herein, including, not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and /or DNA, including, but are not limited to such nucleic acids having modified nucleobases. In certain embodiments, oligonucleotides provided herein may comprise one or more modifications to a nucleobase, sugar, and/or internucleoside linkage, and as such is a modified oligonucleotide. The antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest. In a particularly preferred embodiment, the miR-21 inhibitory nucleic acid is operably linked to a peptide ligand of a receptor protein overexpressed on a cancer cell (e.g., IGF1R ligand) that facilitates endocytosis of the inhibitor into targeted cells. The peptide ligand can be covalently coupled to either the 5’ end or the 3’ end of the inhibitory nucleic acid. In certain embodiments, delivery of the miR-21 inhibitory nucleic acid can be enhanced by covalently conjugating the inhibitory nucleic acid to lipid molecules, including, not limited to cholesterol, α-tocopherol, or long-chain fatty acids. In another embodiment, delivery of the miR- 21 inhibitory nucleic acid can be enhanced by covalently conjugating the inhibitory nucleic acid to GalNAc. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by covalently conjugating the inhibitory nucleic acid to an antibody. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by covalently conjugating the inhibitory nucleic acid to an aptamer. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by covalently conjugating the inhibitory nucleic acid to protein or peptide, including, not limited to polybasic amino acids, cell-penetrating peptides, cell-targeting peptides, or receptor-binding proteins. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by associating the inhibitory nucleic acid to another cell-penetrating molecule through noncovalent interactions. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by packaging the inhibitory nucleic acid in nanocarriers. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by packaging the inhibitory nucleic acid inside liposomes, including, not limited to functionalized lipid nanoparticles with PEGylated lipids, or other ligands associated with the lipid nanoparticles for cell-targeted delivery. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by loading the inhibitory nucleic acid inside exosomes. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by chemically linking the inhibitory nucleic acid on surfaces of spherical nanoparticles. In another embodiment, delivery of the miR-21 inhibitory nucleic acid can be enhanced by incorporating the inhibitory nucleic acid in stimuli-sensitive nanostructures, including, not limited to DNA origami, scaffold molecules conjugated with multiple delivery moieties. In some forms, the miR-21 inhibitory nucleic acid-peptide analog can comprise an external guide sequence (EGS). EGSs are molecules that bind a target nucleic acid molecule forming a complex, and this complex is recognized by RNase P, which cleaves the target molecule. EGSs can be designed to specifically target a RNA molecule of choice. RNAse P aids in processing transfer RNA (tRNA) within a cell. Bacterial RNAse P can be recruited to cleave virtually any RNA sequence by using an EGS that causes the target RNA:EGS complex to mimic the natural tRNA substrate. Similarly, eukaryotic EGS/RNAse P-directed cleavage of RNA can be utilized to cleave desired targets within eukaryotic cells. Examples of how to make and use EGS molecules to facilitate cleavage of a variety of different target molecules are known in the art. The practice of the present invention employs, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. In some embodiments, a vector is capable of driving expression of one or more sequences in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187- 195). When used in mammalian cells, the expression vector's control functions are typically provided by one or more regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, simian virus 40, and others disclosed herein and known in the art. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. The pharmaceutically acceptable salts of compounds of the invention include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Hydrochloric acid salts are of particular interest. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. Formulations The novel miR-21 inhibitory nucleic acid-peptide analogs described herein can be formulated for enteral, parenteral, topical, or pulmonary administration. The compounds can be combined with one or more pharmaceutically acceptable carriers and/or excipients that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. See, e.g., Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, PA, which discloses typical carriers and conventional methods of preparing pharmaceutical compositions that can be used in conjunction with the preparation of formulations of the compounds described herein and which is incorporated by reference herein. These most typically would be standard carriers for administration of compositions to humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Other compounds will be administered according to standard procedures used by those skilled in the art. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Parenteral Formulations The compounds described herein can be formulated for parenteral administration. For example, parenteral administration may include administration to a patient intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intravitreally, intratumorally, intramuscularly, subcutaneously, subconjunctivally, intravesicularly, intrapericardially, intraumbilically, by injection, and by infusion. Parenteral formulations can be prepared as aqueous compositions using techniques known in the art. Typically, such compositions can be prepared as injectable formulations, for example, solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection; emulsions, such as water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes. If for intravenous administration, the compositions are packaged in solutions of sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent. The components of the composition are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or concentrated solution in a hermetically sealed container such as an ampoule or sachet indicating the amount of active agent. If the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water or saline can be provided so that the ingredients may be mixed prior to injection. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Solutions and dispersions of the active compounds as the free acid or base or pharmacologically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, viscosity modifying agents, and combination thereof. Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β- iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine. The formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent degradation of the active agent(s). The formulation is typically buffered to a pH of 3-8 for parenteral administration upon reconstitution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers. Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol. Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art. Controlled Release Formulations The parenteral formulations described herein can be formulated for controlled release including immediate release, delayed release, extended release, pulsatile release, and combinations thereof. Nano- and microparticles For parenteral administration, the one or more compounds, and optional one or more additional active agents, can be incorporated into microparticles, nanoparticles, or combinations thereof that provide controlled release of the compounds and/or one or more additional active agents. In forms wherein the formulations contains two or more drugs, the drugs can be formulated for the same type of controlled release (e.g., delayed, extended, immediate, or pulsatile) or the drugs can be independently formulated for different types of release (e.g., immediate and delayed, immediate and extended, delayed and extended, delayed and pulsatile, etc.). For example, the compounds and/or one or more additional active agents can be incorporated into polymeric microparticles, which provide controlled release of the drug(s). Release of the drug(s) is controlled by diffusion of the drug(s) out of the microparticles and/or degradation of the polymeric particles by hydrolysis and/or enzymatic degradation. Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives. Polymers, which are slowly soluble and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide, can also be suitable as materials for drug containing microparticles. Other polymers include, but are not limited to, polyanhydrides, poly(ester anhydrides), polyhydroxy acids, such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybutyrate (PHB) and copolymers thereof, poly-4-hydroxybutyrate (P4HB) and copolymers thereof, polycaprolactone and copolymers thereof, and combinations thereof. Alternatively, the drug(s) can be incorporated into microparticles prepared from materials that are insoluble in aqueous solution or slowly soluble in aqueous solution, but are capable of degrading within the GI tract by means including enzymatic degradation, surfactant action of bile acids, and/or mechanical erosion. As used herein, the term “slowly soluble in water” refers to materials that are not dissolved in water within a period of 30 minutes. Preferred examples include fats, fatty substances, waxes, wax-like substances and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol), fatty acids and derivatives, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides), and hydrogenated fats. Specific examples include, but are not limited to hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oils available under the trade name Sterotex®, stearic acid, cocoa butter, and stearyl alcohol. Suitable waxes and wax-like materials include natural or synthetic waxes, hydrocarbons, and normal waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, paraffins and candelilla wax. As used herein, a wax-like material is defined as any material, which is normally solid at room temperature and has a melting point of from about 30°C to 300ºC. In some cases, it may be desirable to alter the rate of water penetration into the microparticles. To this end, rate-controlling (wicking) agents can be formulated along with the fats or waxes listed above. Examples of rate-controlling materials include certain starch derivatives (e.g., waxy maltodextrin and drum dried corn starch), cellulose derivatives (e.g., hydroxypropylmethyl-cellulose, hydroxypropylcellulose, methylcellulose, and carboxymethyl- cellulose), alginic acid, lactose and talc. Additionally, a pharmaceutically acceptable surfactant (for example, lecithin) may be added to facilitate the degradation of such microparticles. Proteins, which are water insoluble can also be used as materials for the formation of drug containing microparticles. Additionally, proteins, polysaccharides and combinations thereof, which are water-soluble, can be formulated with drug into microparticles and subsequently cross-linked to form an insoluble network. For example, cyclodextrins can be complexed with individual drug molecules and subsequently cross-linked. Method of making Nano- and Microparticles Encapsulation or incorporation of the miR-21 inhibitory nucleic acid-peptide analogs described herein can be incorporated into carrier materials to produce therapeutic microparticles can be achieved through known pharmaceutical formulation techniques. In the case of formulation in fats, waxes or wax-like materials, including in some cases the peptide ligand itself conjugated to a hydrophobic tail, the carrier material is typically heated above its melting temperature and the mimetic or drug is added to form a mixture comprising drug particles suspended in the carrier material, drug dissolved in the carrier material, or a mixture thereof. Microparticles can be subsequently formulated through several methods including, but not limited to, the processes of congealing, extrusion, spray chilling or aqueous dispersion. In a preferred process, wax is heated above its melting temperature, drug is added, and the molten wax-drug mixture is congealed under constant stirring as the mixture cools. Alternatively, the molten wax-drug mixture can be extruded and spheronized to form pellets or beads. These processes are known in the art. For some carrier materials, it may be desirable to use a solvent evaporation technique to produce drug-containing microparticles. In this case drug and carrier material, including in some cases the peptide ligand itself conjugated to a hydrophobic tail, are co-dissolved in a mutual solvent and microparticles can subsequently be produced by several techniques including, but not limited to, forming an emulsion in water or other appropriate media, spray drying or by evaporating off the solvent from the bulk solution and milling the resulting material. In some forms, drug in a particulate form is homogeneously dispersed in a water- insoluble or slowly water-soluble material. To minimize the size of the drug particles within the composition, the drug powder itself may be milled to generate fine particles prior to formulation. The process of jet milling, known in the pharmaceutical art, can be used for this purpose. In some forms, drug in a particulate form is homogeneously dispersed in a wax or wax like substance, including in some cases the peptide ligand itself conjugated to a hydrophobic tail, by heating the wax or wax like substance above its melting point and adding the drug particles while stirring the mixture. In this case a pharmaceutically acceptable surfactant may be added to the mixture to facilitate the dispersion of the drug particles. The particles can also be coated with one or more modified release coatings. Solid esters of fatty acids, which are hydrolyzed by lipases, can be spray coated onto microparticles or drug particles. Naturally water-insoluble proteins can be coated onto drug containing microparticles or drug particles by spray coating or by wet granulation techniques. In addition to naturally water- insoluble materials, some substrates of digestive enzymes can be treated with cross-linking procedures, resulting in the formation of non-soluble networks. Many methods of cross-linking proteins, initiated by both chemical and physical means, have been reported. One of the most common methods to obtain cross-linking is the use of chemical cross-linking agents. Examples of chemical cross-linking agents include aldehydes (glutaraldehyde and formaldehyde), epoxy compounds, carbodiimides, and genipin. In addition to these cross-linking agents, oxidized and native sugars have been used to cross-link gelatin. Cross-linking can also be accomplished using enzymatic means; for example, transglutaminase has been approved as a GRAS substance for cross-linking seafood products. Finally, cross-linking can be initiated by physical means such as thermal treatment, UV irradiation and gamma irradiation. To produce a coating layer of cross-linked protein surrounding drug containing microparticles or drug particles, a water-soluble protein can be spray-coated onto the microparticles and subsequently cross-linked by the one of the methods described above. Alternatively, drug-containing microparticles can be microencapsulated within protein by coacervation-phase separation (for example, by the addition of salts) and subsequently cross- linked. Some suitable proteins for this purpose include gelatin, albumin, casein, and gluten. Polysaccharides can also be cross-linked to form a water-insoluble network. For many polysaccharides, this can be accomplished by reaction with calcium salts or multivalent cations, which cross-link the main polymer chains. Pectin, alginate, dextran, amylose and guar gum are subject to cross-linking in the presence of multivalent cations. Complexes between oppositely charged polysaccharides can also be formed; pectin and chitosan, for example, can be complexed via electrostatic interactions. Injectable/Implantable formulations The miR-21 inhibitory nucleic acid-peptide analogs described herein can be incorporated into injectable/implantable solid or semi-solid implants, such as polymeric implants. In some forms, the compounds are incorporated into a polymer that is a liquid or paste at room temperature, but upon contact with aqueous medium, such as physiological fluids, exhibits an increase in viscosity to form a semi-solid or solid material. Exemplary polymers include, but are not limited to, hydroxyalkanoic acid polyesters derived from the copolymerization of at least one unsaturated hydroxy fatty acid copolymerized with hydroxyalkanoic acids. The polymer can be melted, mixed with the active substance and cast or injection molded into a device. Such melt fabrication requires polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive. The device can also be prepared by solvent casting where the polymer is dissolved in a solvent and the drug dissolved or dispersed in the polymer solution and the solvent is then evaporated. Solvent processes require that the polymer be soluble in organic solvents. Another method is compression molding of a mixed powder of the polymer and the drug or polymer particles loaded with the active agent. Alternatively, the compounds can be incorporated into a polymer matrix and molded, compressed, or extruded into a device that is a solid at room temperature. For example, the compounds can be incorporated into a biodegradable polymer, such as polyanhydrides, polyhydroalkanoic acids (PHAs), PLA, PGA, PLGA, polycaprolactone, polyesters, polyamides, polyorthoesters, polyphosphazenes, proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin, and combinations thereof and compressed into solid device, such as disks, or extruded into a device, such as rods. The release of the one or more compounds from the implant can be varied by selection of the polymer, the molecular weight of the polymer, and/or modification of the polymer to increase degradation, such as the formation of pores and/or incorporation of hydrolyzable linkages. Methods for modifying the properties of biodegradable polymers to vary the release profile of the compounds from the implant are well known in the art. Enteral Formulations Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, sodium saccharine, starch, magnesium stearate, cellulose, magnesium carbonate, etc. Such compositions will contain a therapeutically effective amount of the compound and/or antibiotic together with a suitable amount of carrier so as to provide the proper form to the patient based on the mode of administration to be used. Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups, and lozenges. Tablets can be made using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can prepared as hard or soft capsule shells, which can encapsulate liquid, solid, and semi-solid fill materials, using techniques well known in the art. Formulations may be prepared using a pharmaceutically acceptable carrier. As generally used herein “carrier” includes, but is not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof. Carrier also includes all components of the coating composition, which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides. Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants. “Diluents”, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. “Binders” are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone. “Lubricants” are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. “Disintegrants” are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone® XL from GAF Chemical Corp). “Stabilizers” are used to inhibit or retard drug decomposition reactions, which include, by way of example, oxidative reactions. Suitable stabilizers include, but are not limited to, antioxidants, butylated hydroxytoluene (BHT); ascorbic acid, its salts and esters; Vitamin E, tocopherol and its salts; sulfites such as sodium metabisulphite; cysteine and its derivatives; citric acid; propyl gallate, and butylated hydroxyanisole (BHA). Controlled Release Enteral Formulations Oral dosage forms, such as capsules, tablets, solutions, and suspensions, can for formulated for controlled release. For example, the one or more compounds and optional one or more additional active agents can be formulated into nanoparticles, microparticles, and combinations thereof, and encapsulated in a soft or hard gelatin or non-gelatin capsule or dispersed in a dispersing medium to form an oral suspension or syrup. The particles can be formed of the drug and a controlled release polymer or matrix. Alternatively, the drug particles can be coated with one or more controlled release coatings prior to incorporation in to the finished dosage form. In another form, the one or more compounds and optional one or more additional active agents are dispersed in a matrix material, which gels or emulsifies upon contact with an aqueous medium, such as physiological fluids. In the case of gels, the matrix swells entrapping the active agents, which are released slowly over time by diffusion and/or degradation of the matrix material. Such matrices can be formulated as tablets or as fill materials for hard and soft capsules. In still another form, the one or more compounds, and optional one or more additional active agents are formulated into a sold oral dosage form, such as a tablet or capsule, and the solid dosage form is coated with one or more controlled release coatings, such as a delayed release coatings or extended-release coatings. The coating or coatings may also contain the compounds and/or additional active agents. Extended-release dosage forms The extended-release formulations are generally prepared as diffusion or osmotic systems, which are known in the art. A diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble polymers, hydrophilic polymers, and fatty compounds. Polymeric matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and Carbopol® 934, polyethylene oxides and mixtures thereof. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof. In certain preferred forms, the polymeric material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In certain preferred forms, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In one preferred form, the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the tradename EUDRAGIT®. In further preferred forms, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the tradenames EUDRAGIT® RL30D and EUDRAGIT ® RS30D, respectively. EUDRAGIT® RL30D and EUDRAGIT ® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT ® RL30D and 1:40 in EUDRAGIT® RS30D. The mean molecular weight is about 150,000. EUDRAGIT ® S-100 and EUDRAGIT ® L-100 are also preferred. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. EUDRAGIT ® RL/RS mixtures are insoluble in water and in digestive fluids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids. The polymers described above such as EUDRAGIT ® RL/RS may be mixed together in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems may be obtained, for instance, from 100% EUDRAGIT® RL, 50% EUDRAGIT® RL and 50% EUDRAGIT t® RS, and 10% EUDRAGIT® RL and 90% EUDRAGIT® RS. One skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, EUDRAGIT® L. Alternatively, extended-release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion. The devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads, or granules. An immediate release portion can be added to the extended-release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads. Extended-release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In the congealing method, the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed. Delayed release dosage forms Delayed release formulations can be created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit® (Rohm Pharma; Westerstadt, Germany), including EUDRAGIT® L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT® L-100 (soluble at pH 6.0 and above), EUDRAGIT® S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and EUDRAGITS® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied. The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies. The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating. The plasticizer will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition. Inhaler Formulations The present inhibitors can be delivered locally to the respiratory system, for example to the nose, sinus cavities, sinus membranes or lungs. The present miR-21 inhibitory nucleic acid- peptide analogs, or pharmaceutical compositions containing one or more miR-21 inhibitory nucleic acid-peptide analogs, can be delivered to the respiratory system in any suitable manner, such as by inhalation via the mouth or intranasally. The present compositions can be dispensed as a powdered or liquid nasal spray, suspension, nose drops, a gel or ointment, through a tube or catheter, by syringe, by packtail, by pledget, or by submucosal infusion. The compounds of the preferred embodiments of the present invention may be conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellent, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent. The compound of compounds of the present invention can be delivered in the form of an aerosol spray presentation from a nebulizer or the like. In some embodiments, the active ingredients are suitably micronized so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the dry powder formulation, thus the active ingredients will have a particle size of less than 100 microns, desirably less than 20 microns, and preferably in the range of 1 to 10 microns. The following examples are provided to illustrate certain embodiments of the invention. They are not intended to limit the invention in any way. Example I Targeted, low toxicity molecular therapy to extend survival constitutes a critical unmet need for TNBC, a US market potential of $7 billion/yr. As noted above, the miR-21 inhibitory nucleic acid-peptide analog includes an IGF1 receptor ligand as TNBC cells show strong IGF1R signaling activation, correlating with poor survival. However, there is no known signaling feedback between miR-21 and IGF1R (Dobre, et al. Cells 10(8):1856, 2021). The miR-21 inhibitory nucleic acid-peptide analog provides a unique approach to inhibit miR-21 mediated gene expression, by targeting and delivering the inhibitory nucleic acid-peptide analog into the TNBC cells via the ligand for the IGF1R. Administration of the miR-21 inhibitory nucleic acid-peptide analog described here elevated tumor suppressor proteins, suppressed immune checkpoint gene expression, slowed migration, slowed proliferation, and increased apoptosis in multiple TNBC lines. 5 mg/kg of the miR-21 inhibitory nucleic acid- peptide analog administered intraperitoneally in sterile saline twice a week, inhibited the growth of murine EMT6 TNBC orthotopic allografts by 74% after 14 days, compared with vehicle or scrambled control. Thus, a new TNBC therapeutic and variants thereof for treatment of this devastating disease, and significantly increasing TNBC patient survival is provided. Our design for miR-21 inhibitory nucleic acid-peptide analogs was informed by previous work in which we generated a miR-17-5p blocker that actively mimicked a full length miR-17- 3p passenger strand, thereby creating previously unknown off-target effects by undesirably down-regulating PDCD4 and PTEN tumor suppressor proteins. See Figure 4A and Jin, Y.-Y., et al. PLoS One 10(12): e0142574 (2015). The newly created miR-21 inhibitory nucleic acid-peptide analog described herein includes a 15 nt sequence designed to specifically block miR-21-5p (identical in mice and humans) without mimicking the opposing strand (FIGS. 2A-2C, FIG 15). In a pre-miR-21 hairpin structure (FIG. 2A), most of the nucleotides in miR-21-5p guide strand base pair with most of nucleotides in miR-21-3p passenger strand. Either the guide strand or the passenger strand can be selected as the active mature miRNA in an RNA-induced silencing complex (RISC). The 15 nt miR-21-5p guide strand inhibitory nucleic acid sequence in the 5’ to 3’ orientation exerts high sequence homology to a continuous sequence region on the miR-21-3p passenger strand in the 5’ to 3’ orientation, excluding the seed region (nt 1 – 9 in 5’ – 3’ orientation) of the miR-21-3p passenger strand (FIG. 2B – 2C). Particularly preferred for exclusion are at least 2, 3, 4, 5, 6, 7, or 8, nucleosides shown in blue in SEQ ID NO: 4. In certain embodiments, 3 nucleosides are omitted or excluded. In other embodiments 4 nucleosides are omitted. In other embodiments, 5 nucleosides are omitted. In other embodiments, 6 nucleosides are omitted. In other embodiments, 7 nucleosides are omitted. In other embodiments, 8 nucleosides are omitted. Since miRNAs function mainly through complementary base-pairing between the seed region and regulatory binding sites on target mRNAs, nucleic acid inhibitor sequences of the miR-21-5p guide strand that exclude or partially exclude the miR-21-3p passenger strand seed region can be expected to inhibit miR-21-5p guide specifically without creating additional side- effects from mimicking the miR-21-3p passenger strand. The miR-21 inhibitory nucleic acid portion of the miR-21 blockers of the invention include 8 to 17 linked nucleosides as shown in FIGS. 2B -2C. As explained below, certain sections of the nucleic acid portion are more tolerant to modification than others. For example, the first 4 to 5 contiguous nucleosides can comprise BNAs with phosphorothioate linkages, and the last 4 to 5 contiguous nucleosides can comprise BNAs with phosphorothioate linkages in the 5’ to 3’ orientation. The linked nucleosides in between the contiguous BNAs at the 5’ and the 3’ end may contain one or more of the following modifications: phosphorothioate, boranophosphonate, (SC5’ Rp)-α,β-dioxaphosphorinane-constrained Nucleic Acid, (E)- vinylphosphonate, 5’ methyl phosphonate, 5’-phosphorothioate, (s)-5’-methyl with phosphate, 5’-methoxy, 2-hydroxyethylphosphate, 3’-dideoxyCytosine, 3’amino, 2’-thio-dT, 2’ O-Methyl, 2’-O-MethOxy, 2’-NH2, 2’-F-RNA, 2’-F-ANA, LNA, 2’-O,4’-C-ethylene-bridged Nucleic Acid, (s)-cEt, Fluoro Hexitol Nucleic Acid, (s)-5’-C-methyl, Unlocked Nucleic Acid, 4’-thio-RNA. As mentioned above, it is preferable to insert such modifications outside the minimal binding region. As indicated above, we incorporated the RNA analog 2’4’-BNA^NC (BNA) backbone modification (FIG. 3) to minimize hybridization-dependent and hybridization-independent toxicity, with superior hybridization affinity. 2’4’-BNA^NC (BNA) is a nuclease-resistant derivative of 2’O,4’-C-methylene-bridged nucleic acid (LNA) (FIG. 15). miR-21 blocker efficacy in cells. We observed IC50 of 22 nM for a 15mer BNA miR-21 gapmer BND5412 (FIG. 4A) blocking miR-21 derepression of luciferase expression from a luciferase-3’-UTR vector upon transfection into human MDA-MB-231 TNBC cells (FIG. 4B). Transfection of the same miR-21 blocker significantly increased the expression of miR-21 target protein PDCD4, with follow-on depression of CD47, PD-L1, PD-L2, and Jak2 immune checkpoints (FIG. 5A-5B), and decreased cell proliferation by up to 8-fold in MDA-MB-231, HCC1806, BT-20, MDA-MB-157, MDA-MB-436, BT-549, and HCC1937 (FIG. 6). As a contrast to BNA drugs, we also tested FANA oligonucleotides at 50 nM transfected into human MDA-MB-231 TNBC cells for 48 hr. FANA sequences 1 – 7 did not show significant inhibition compared to scrambled BNA or vehicle control (FIG. 7). However, miR- 21 and MYCC BNAs slowed proliferation by ≈50% in 48 hr. Thus, BNA oligonucleotides were unexpectedly more effective than FANA oligonucleotides, a different backbone derivative being developed for therapeutic uses by other laboratories. We observed significant correlation between anti-miR-21 IC50 for inhibiting cell proliferation with miR-21 copies/cell in 7 human TNBC cell lines, consistent with our hypothesized mechanism of action. A non-tumorigenic human breast epithelial cell line MCF- 10A was significantly less sensitive to anti-miR-21 treatment (FIG. 8). 50 nM miR-21 blocker BND5412 also induced significant apoptosis in human MDA- MB-231 TNBC cells, measured by LDH assay (FIG. 9). Similar results were observed in human HCC1937, HCC1806, BT-549, and BT-20 TNBC cells. In addition, 50 nM miR-21 blocker BND5412 treatment revealed fewer MDA-MB-231 cells migrating into the wound area compared to a random sequence control. Furthermore, 50 nM miR-21 blocker BND5412 drastically reduced (p<0.01) immune checkpoint mRNAs for PD-L1, PD-L2, CD47, and JAK2 (FIG. 10), as well as the corresponding PD-L1, PD-L2, CD47, and JAK2 immune checkpoint proteins (FIGS. 5A-5B), in human HCC1806 TNBC cells, suggesting that miR-21 blockade could induce T-cell recognition of TNBC cells. RNA expression profile post miR-21 blockade. We performed RNA-seq analysis on RNA samples from human HCC1806 TNBC cells transfected with IC90 concentration of miR-21 blocker BND5412, as well as vehicle treated cells. To evaluate changes in miR-21 regulated transcripts globally, a list of predicted miR-21 target genes was obtained from TargetScan (https://www.targetscan.org/vert_80/). The Kolmogorov-Smirnov test comparing cumulative distributions of transcripts between miR-21 targets and all other genes showed a significant difference (FIG. 11A), indicating that miR-21 blocker BND5412 treatment had global on-target effects on miR-21 regulated transcripts. Off-target effects in the treated HCC1806 cells were assessed with GGGenome, (a program on the world wide web at gggenome.dbcls.jp) on human spliced RNAs containing 0-2 mismatches, insertions, or deletions from the miR-21 blocker BND5412 sequence. Over 300 RNA targets were predicted from the search result. Among those, no transcripts containing 0-1 mismatches were significantly down-regulated by at least 2 fold. 8 genes containing 2 mismatches to miR-21 blocker BND5412 were decreased by at least 2 fold. Among them, SH3PXD2A, DIAPH2, PTPRK, MGAT5, and NLGN4X were identified as oncogenes. The remaining 3 genes, ERC1, ATRN, and FHOD3, were not found to be associated with any disease in their wildtype form when down-regulated. No off-target effect of more than 4-fold change in RNA levels was observed. Gene Set Enrichment Analysis on HallMark genes from MSigDB dataset (GSEA, https://www.gsea-msigdb.org/gsea/index.jsp) on differentially expressed genes identified the top 3 enriched pathways. The enrichment results showed that miR-21 blockade activated interferon α and interferon γ response, (FIG. 11B) both of which have a positive effect on anti-tumor immunity (Jorgovanovic, et al. 2020, Biomark Res 8:49; Vidal, P., 2020, Scand J Immunol 91(5):e12863). In addition, the KRAS inhibitory pathway was also significantly enriched in anti- miR-21 BND5412-treated samples (FIG. 11B). Disease enrichment analysis with iDEP platform (http://bioinformatics.sdstate.edu/idep96/) using the Jensen Disease database showed significant enrichment of breast cancer among down-regulated genes. In addition, top enriched cancers in down-regulated genes also include kidney cancer, liver cancer, melanoma, pancreatic cancer, and malignant glioma. Significant enrichment of other diseases include Alzheimer’s disease, schizophrenia, heart conduction disease, obesity, and acquired metabolic disease such as type 2 diabetes. No disease association was enriched among upregulated genes. These results indicate that miR-21 blockade might be effective for many additional indications. Cell-specific delivery Directed targeting of therapeutics is the biggest challenge for RNA analog therapy. Current delivery approaches using liposomes or nanoparticles can be utilized but are not ideal for long-term clinical use due to low delivery efficiency, toxicity, and primary biodistribution to liver and kidneys. Our designs provide safe, efficient, extra-hepatic delivery of nucleic acid therapeutics. Conjugating RNA analogs to receptor targeting peptides (Fig. 12) provides cell- type selective delivery. IGF1R is elevated in aggressive breast cancers, including TNBC. Most importantly, TNBC cells show strong IGF1R signaling activation, correlating with poor survival. However, there is no known signaling feedback between miR-21 and IGF1R (Dobre, et al. Cells 10(8):1856, 2021). We pioneered polyamide nucleic acid (PNA) oligomers with a protease-resistant retro- inverso cyclized D(CSKC) tetrapeptide IGF1 analog at the C-terminus of PNA to direct endocytosis into IGF1R-overexpressing cells in earlier studies. For example, see Tian, X et al. Journal of Nuclear Medicine vol. 48 (10): 1699-1707, 2007. We found that radiolabeled PNA 12mers with a C-terminal cyclo-D(CSKC) stay in circulation by complexing with IGF1BP (Opitz, et al., Oligonucleotides 20(3):117-25, 2010), extending the lifetime of the agent in the body, which reduces the necessary dose. Urine from mice injected with a [^99mTc]MYCC PNA- cyclo-D(CSKC) showed 83% of the radioactivity in an intact probe peak, illustrating in vivo stability. We observed receptor-mediated PNA-cyclo-D(CSKC) knockdown of cyclin D1 protein in MCF7 breast cancer xenografts. We have also used cyclo-^D(CSKC) for tissue-specific delivery of various radioimaging agents. Thus, we were able to image CCND1, MYCC, HER2, or KRAS2 mRNAs with radionuclide-PNA-cyclo-D(CSKC) PET agents in mice bearing ER+ breast cancer xenografts, Her2+ breast cancer xenografts, illustrating DOX response by reduction of HER2 mRNA PET SUV, pancreas cancer xenografts, and transgenic mice with spontaneous mammary or lung tumors, illustrating response to cisplatin, with single mismatch specificity. Importantly, specific PET imaging was blocked by excess IGF1, consistent with our hypothesized mechanism of cellular uptake by IGF1R-mediated endocytosis. Upon treating Her2+ breast cancer xenografts with doxorubicin (DOX), we observed a HER2 mRNA SUV decrease to 54±17% after 1 wk of DOX therapy, concordant with 7 wk CT volume decreasing to 80±47%, and a HER2 mRNA SUV increase to 145±82% after 1 wk of non-therapy, concordant with 7 wk CT volume increasing to 213±78%. The newly designed miRNA blockers (FIG. 13) minimize and avoid passenger strand mimicry by excluding the seed region of the opposing strand. Thus, the miR inhibitory nucleic acid-peptide composition effectively blocks the target miRNA without exerting the function of the opposing strand, unlike the LNA inhibitor described in our earlier work. As shown in FIG. 13, human HCC1806 TNBC cells took up fluorescent AF647-miR-21 BNA-D(CSKC) BND7673 without transfection and trafficked it to the cytoplasm, illustrating efficient IGF1R-mediated endocytosis and cytoplasmic delivery (FIG. 14). Cell-specific activity of non-fluorescent drug. A non-fluorescent anti-miR-21 RNA-peptide analog BND6482 (FIG. 15) was synthesized and taken into TNBC cells via endocytosis. Like the fluorescent BND7673, internalization and function of the inhibitory blocking molecule effectively increased expression of the desirable tumor suppressor proteins, thereby inhibiting TNBC cell growth. BND6482 liberated miR-21 luciferase reporter vector expression in high IGF1R-expressing human HCC1806 TNBC cells with dose dependence (FIG. 16A), without transfection. In contrast, low IGF1R-expressing human MDA-MB-157 TNBC cells displayed little response to miR-21 blocker BND6482 without lipofection (FIG. 16B). Example II miR-21 RNA-peptide analog uptake in EMT6 allografts. A single administration of fluorescent miR-21 blocker BND7673 intraperitoneally at 5 mg/kg in immunocompetent female Balb/c mice bearing murine EMT6 TNBC allografts resulted in efficient fluorescent drug distribution to tumors, apparent by 24 h, and persisting at least until 96 h (FIG. 17). TNBC allograft 3-day response. Tumor inhibition by 5 mg/kg fluorescent miR-21 blocker BND7673 was observed after 3 days of daily intraperitoneal dosing (FIG. 18). It is apparent that several treated tumors are markedly smaller than vehicle tumors. Fluorescent imaging showed drug concentration in treated tumors extracted from each animal. While tumor images (FIG. 18) show differences between treated and vehicle tumors, broad scatter of the measured masses (FIG. 19) after only 3 days of therapy showed only an average of 28% reduction in tumor mass. Consistent with the hypothesis, BND7673 treatment reduced miR-21 and elevated miR-21 target transcript PDCD4 mRNA in tumors (FIG. 20). TNBC allograft 13-day response. Subsequently, we performed a 2-week long trial with non-fluorescent anti-miR-21 BNA- peptide BND6482 (FIG. 15). After murine EMT6 TNBC allografts reached around 5 mm in diameter, 5 mg/kg of scrambled BNA-peptide BND6372, or anti-miR-21 BNA-peptide BND6482, in sterile saline vehicle was injected intraperitoneally twice a week for 2 weeks at days 0, 3, 7, 10. Tumor volumes were measured at the same time as the injection. At day 13, tumors were harvested and weighed. miR-21 blocker BND6482-treated tumors stayed small without apparent tumor progression over 2 weeks (FIG. 21). At the end of 2 weeks, miR-21 blocker-treated tumors had significantly reduced tumor masses (74% mean reduction) compared to vehicle or scrambled treated tumors (FIG. 22). Toxicity markers in serum samples from treated tumor-bearing mice after twice a week IP injection of 5 mg/kg of miR-21 blocker-peptide BND6482, or scrambled BND6372, over 13 days or 3 IP injections of 6.25 mg/kg were indistinguishable from each other by One-way ANOVA with Dunnett’s multiple comparison test. See FIG. 23. Error bars show mean with SEM. This result means that no liver or kidney toxicity was detected as a result of RNA-peptide analog treatment. As can be seen from the foregoing, a new molecular therapeutic agent and variants thereof that work alone and in conjunction with chemotherapy with greater efficacy, specificity, and safety is now available for targeted effective TNBC therapy. Example III Compositions and Method for Ameliorating Symptoms Associated with miR-21 Modulated Disorders, Particularly TNBC In order to treat an individual having a miR-21 modulated disorder, particularly TNBC and other cancers, to alleviate a sign or symptom of the disease for example, the miR-21 inhibitory nucleic acid-peptide analog inhibitors described in Example I can be administered alone or in combination with other agents useful for the variety of symptoms associated with malignancy in order to provide therapeutic benefit to the patient. Such agents are administered in an effective dose to modulate cancer cell proliferation, cell cycle check points, cell migration, and metastasis. It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established tumors or symptoms. In certain embodiments, a biological sample is obtained from a patient to confirm the presence and number of miR-21 copies/cell and IGF1R copies/cell in the tumor. In other embodiments this information will already be available. The total treatment dose can be administered to a subject as a single dose or can be administered using a fractionated treatment protocol, in which multiple/separate doses are administered over a more prolonged period of time, for example, over the period of a day to allow administration of a daily dosage or over a longer period of time to administer a dose over a desired period of time. One skilled in the art would know that the amount of miR-21 inhibitory nucleic acid-peptide analog inhibitors required to obtain an effective, minimally toxic dose in a subject depends on many factors, including the age, weight and general health of the subject, as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled artisan would adjust the particular dose so as to obtain an effective dose for treating an individual having a cancer that can be treated using the miR-21 inhibitory nucleic acid-peptide analog inhibitors described herein. In an individual suffering from cancer, in particular a more severe, advanced form of cancer, administration of the miR-21 inhibitory nucleic acid-peptide analog inhibitors described herein can be particularly useful when administered in combination with other modified nucleic acid oligonucleotides or nucleotide peptide analogs, including but not limited to compounds targeting the mRNAs encoding c-Myc transcription factor, tropomyosin kinase receptor (TRK), MAPK pathway, androgen receptor (AR) pathway, growth factor receptor pathway, PI3K-AKT pathway, immune checkpoints, DNA-damage repair pathway, CDK4/6, CHK1, CHK2, WEE1, ATR, and/or symptoms of the cancer are reduced, as compared to a control. Thus, in certain embodiments, the methods of the invention include administration of an additional chemotherapeutic agent or chemotherapy. In certain embodiments the additional therapy is surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy, and/or hormone therapy. In certain embodiments, the chemotherapeutic agents is alkylating agent, anti-metabolic antineoplastic agent, anti-tumor antibiotic, anti-tumor botanical, platinum compound antineoplastic agent, hormonal balance antineoplastic agent, and miscellaneous antineoplastic agent, For example, the inhibitors described may act additively or synergistically with a chemotherapeutic agent for treating and inhibiting cancer cell growth. Such agents include without limitation, rituximab, bevacizumab, trastuzumab, imatinib, dinoxetine, cetuximab, nilotinib, sorafenib, bemcentinib, crizotinib, bosutinib, gilteritinib, amuvatinib, and sunitinib, cabozantinib, foretinib, rebastinib, celastrol, dihydroartemisinin, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, PARP inhibitors, cyclophosphamide, ifosfamide, thiotepa, methotrexate, mercaptopurine, fluorouracil and cytarabine, bleomycin, daunorubicin, actinomycin D, mitomycin, doxorubicin, mitoxantrone, vincristine, etoposide, teniposide, paclitaxel and docetaxel, cisplatin, carboplatin and oxaliplatin, euprolide, tamoxifen, flutamide and formestane, and arsenic trioxide. In some embodiments, the tumor shrinks or is eradicated. The inhibitors described may act additively or synergistically with a PARP inhibitor for treating and inhibiting cancer cell growth. Examples of PARP inhibitors include, but are not limited to, orlaparib, talazoparib, veliparib, rucaparib, niraparib, pamiparib, fluzoparib. The inhibitors described may act additively or synergistically with an antibody drug conjugate (ADC) for treating and inhibiting cancer cell growth. Examples of ADC include, but are not limited to, Sacituzumab govitecan, ladiratuzumab vedotin, patritumab deruxtecan, trastuzumab deruxtecan, datopotamab deruxtecan, enfortumab vedotin, SKB264, MGC018, PTK7-ADC. The inhibitors described may act additively or synergistically with a PI3K-AKT pathway inhibitor for treating and inhibiting cancer cell growth. Examples of PI3K-AKT pathway inhibitors include, but are not limited to, alpelisib, taselisib, samotolisib, copanlisib, eganelisib, gedatolisib. The inhibitors described may act additively or synergistically with an androgen receptor inhibitor for treating and inhibiting cancer cell growth. Examples of androgen receptor inhibitors include, but are not limited to, bicalutamide, enzalutamide, abiraterone, enobosarm, darolutamide. The inhibitors described may act additively or synergistically with a TRK inhibitor for treating and inhibiting cancer cell growth. Examples of TRK inhibitors include, but are not limited to, larotrectinib, selitrectinib, repotrectinib. The inhibitors described may act additively or synergistically with a mutant Her2 inhibitor for treating and inhibiting cancer cell growth. Examples of mutant Her2 inhibitors include, but are not limited to, neratinib. The inhibitors described may act additively or synergistically with an immune checkpoint inhibitor for treating and inhibiting cancer cell growth. Examples of immune checkpoint inhibitors include, but are not limited to, pembrolizumab, atezolizumab, avelumab, JS001, nivolumab, duralumab. The inhibitors described may act additively or synergistically with a CDK4/6 inhibitor for treating and inhibiting cancer cell growth. Examples of CDK4/6 inhibitors include, but are not limited to, palbociclib, abemaciclib, ribociclib. The inhibitors described may act additively or synergistically with a CHK1 inhibitor for treating and inhibiting cancer cell growth. Examples of CHK1 inhibitors include, but are not limited to, LY2880070, prexasertib. The inhibitors described may act additively or synergistically with a WEE1 inhibitor for treating and inhibiting cancer cell growth. Examples of WEE1 inhibitors include, but are not limited to, AZD1175, ZN-c3. The inhibitors described may act additively or synergistically with a CHK2 inhibitor for treating and inhibiting cancer cell growth. Examples of CHK2 inhibitors include, but are not limited to, LY2606368. The inhibitors described may act additively or synergistically with a ATR inhibitor for treating and inhibiting cancer cell growth. Examples of ATR inhibitors include, but are not limited to, ceralasertib. The inhibitors described may act additively or synergistically with a RAD51 inhibitor for treating and inhibiting cancer cell growth. Examples of RAD51 inhibitors include, but are not limited to, CYT-0851. The skilled artisan would administer miR-21 inhibiting therapeutic agent(s), alone or in combination with at least one chemotherapeutic and would monitor the effectiveness of such treatment using routine methods such as, radiologic, immunologic assays, or, where indicated, histopathologic methods. Administration of the pharmaceutical preparation is preferably in an "effective amount" this being sufficient to show benefit to the individual. This amount prevents, alleviates, abates, or otherwise reduces the severity of cancer in a patient. In a preferred embodiment of this invention, a method is provided for the treatment of cancer using the therapeutic agents disclosed in the present example in combinatorial approaches. Advantageously, the additive or preferably synergistic method of this invention reduces the progression of cancer, or reduces symptoms of cancer in a mammalian host. Importantly, the information provided herein guides the clinician in new treatment modalities for the management of this disease. The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of one or more of the mimetics described above in pharmaceutically acceptable carriers or diluents. The compositions comprising the miR-21 inhibitors of the present invention may be administered orally or parenterally including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. In general, the compounds listed above do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. For example, first compound may be administered orally to generate and maintain good blood levels thereof, while a second compound may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician. References 1. American_Cancer_Society. (2020 Breast Cancer Facts and Figures. 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PMID:34440625 PMC8391367 While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims.

Claims

What is Claimed: 1. A miR-21 inhibitory nucleic acid-peptide analog having sequence complementarity to miRNA-21-5p, to sequester miR-21-5p and its isomiRs from binding to regulatory sites present in mRNAs. 2. The miR-21 inhibitory nucleic acid-peptide analog of claim 1, said nucleic acid having a modification selected from BNA, LNA, FANA, PNA, 2′-fluoro,

2’-O-alkyl, morpholino, piperazine, phosphorothioate, boranophosphate and boranophosphate mixed with phosphodiester linkages, phosphorodithioate or methylphosphonate linkages.

3. The miR-21 inhibitory nucleic acid-peptide analog of claim 1 or claim 2, comprising at least one inhibitory sequence shown in Figure 2B - 2C. 4. The miR-21 inhibitory-peptide analog of claim 3, wherein said at least one inhibitory nucleic acid sequence of (SEQ ID NO: 5) reduces unwanted side-effects associated with mimicking miR-21-3p passenger strand function by substantially excluding the miR-21-3p passenger strand seed region. 5. The miR-21 inhibitory-peptide analog of claim 3, wherein at least 3,

4,

5, 6, 7, 8, or 9 nucleosides of SEQ ID NO: 4 are excluded.

6. The miR-21 inhibitory-peptide analog of any one of claims 1 to 5, comprising 5’ and 3’ BNA modifications as shown in Figure 15.

7. The miR-21 inhibitory-peptide analog of claim 1, wherein the cyclic peptide is selected from CSKC, CRKC, CVKC, CGKC, CKGC, CFKC, CDKC, CHRC, CRVC, CGRC, CIRC, CQRC, CTRC, CRHC, CRGC, CRSC CRKC, CSRC, CERC, in which all residues are D-amino acids, and a disulfide bond is formed between the N-terminal cysteine and the C-terminal cysteine.

8. The miR-21 inhibitory-peptide analog of claim 1, wherein said peptide is a ligand for the insulin-like growth factor 1 receptor of SEQ ID NO: 26, CSKC, and the inhibitor nucleic acid sequence is selected from SEQ ID NOS: 5 to 25, GATAAGCTA, TGATAAGCT, CTGATAAGC, ATAAGCTA, GATAAGCT, and TGATAAGC.

9. The miR-21 inhibitory-peptide analog of claim 1, wherein the nucleic acid includes between 8 and 17 nucleotides.

10. The miR-21 inhibitory-peptide analog of claim 1, wherein the nucleic acid is a gapmer.

11. The miR-21 inhibitory-peptide analog of claim 10, wherein the gapmer includes three portions.

12. The miR-21 inhibitory-peptide analog of claim 11, wherein the three portions include a first BNA portion, a DNA portion, and a second BNA portion.

13. A method of inhibiting binding of miR-21-5p to one or more binding sites in an mRNA encoding a protein that modulates cellular proliferation, migration, metastasis, stress, or inflammation, comprising contacting the miR-21-5p with the inhibitor of any of the preceding claims, wherein said inhibitor binds and sequesters said miR-21-5p and thereby inhibiting or preventing miR-21-5p binding to regulatory sites present in an mRNA encoding a protein that modulates malignant cell growth, and, or, metastasis.

14. The method for the treatment of triple negative breast cancer (TNBC) in a patient in need thereof, comprising; administering an effective amount of a miR-21 inhibitory-peptide analog as claimed in any one of claims 1 to 12, said analog causing TNBC stasis or cell death.

15. The method of claim any one of claims 13 or 14, wherein said analog is shown in Figure 15.

16. The method of any one of claims 13 or 14, or 15 further comprising administration of a chemotherapeutic agent selected from rituximab, bevacizumab, trastuzumab, imatinib, dinoxetine, cetuximab, nilotinib, sorafenib, bemcentinib, crizotinib, bosutinib, gilteritinib, amuvatinib, and Sunitinib, cabozantinib, foretinib, rebastinib, celastrol, dihydroartemisinin, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, cyclophosphamide, ifosfamide, thiotepa, methotrexate, mercaptopurine, fluorouracil and cytarabine, bleomycin, daunorubicin, actinomycin D, mitomycin, doxorubicin, mitoxantrone, vincristine, etoposide, teniposide, paclitaxel and docetaxel, cisplatin, carboplatin and oxaliplatin, euprolide, tamoxifen, flutamide and formestane, and arsenic trioxide.

17. The methods claims 13, 14, or 15, wherein disease-driving protein levels are decreased by said inhibitor treatment.

18. The method of any one of claims 13, 14, or 15, wherein disease-limiting protein levels are increased by said inhibitor treatment.

19. The method of any one of claims 13, 14, or 15, wherein said disease-limiting mRNA encodes a tumor suppressor protein.

20. The method of claim any one of claims 13, 14, or 15, wherein said disease-driving or disease-limiting mRNAs encode a protein shown in Figure 1.

21. The method of claim 19, wherein said tumor suppressor protein is selected from PTEN and PDCD4.