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WO2025207803A1 - Composés lipidiques, compositions et méthodes d'utilisation associées - Google Patents

Composés lipidiques, compositions et méthodes d'utilisation associées

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Publication number
WO2025207803A1
WO2025207803A1 PCT/US2025/021600 US2025021600W WO2025207803A1 WO 2025207803 A1 WO2025207803 A1 WO 2025207803A1 US 2025021600 W US2025021600 W US 2025021600W WO 2025207803 A1 WO2025207803 A1 WO 2025207803A1
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WO
WIPO (PCT)
Prior art keywords
alkenyl
antigenic polypeptide
carbons
alkyl
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/021600
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English (en)
Inventor
Jiangsheng XU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
General Therapeutics Inc
Original Assignee
General Therapeutics Inc
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Filing date
Publication date
Application filed by General Therapeutics Inc filed Critical General Therapeutics Inc
Publication of WO2025207803A1 publication Critical patent/WO2025207803A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C07J71/0015—Oxiranes at position 9(11)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle

Definitions

  • compositions address these and other needs.
  • compositions including the lipid compounds described herein and an active agent.
  • Described herein are also methods of using the compositions for delivering an active agent to a subject.
  • FIGs. 12A-12P show NMR spectra for indicated ionizable lipids (12A) for compound G0011; (12B) for compound G0012; (12C) for compound G0016; (12D) for compound G0025; (12E) for compound G0056; (12F) for compound G0156; (12G) for compound G0211; (12H) for compound G0212; (12I) for compound G0017; (12J) for compound G0077; (12K) for compound G0107; (12L) for compound G0066; (12M) for compound G0505; (12N) for compound G0013; (12O) for compound G0054; (12P) for compound G0404.
  • FIG. 12A-12P show NMR spectra for indicated ionizable lipids (12A) for compound G0011; (12B) for compound G0012; (12C) for compound G0016; (12D) for compound G0025; (12E) for compound G0056; (12F) for compound G0156; (12G) for compound G0211; (12
  • FIG. 13 shows G0013-based LNP formulation at different lipid ratios.
  • FIGs. 14A-14C show transfection efficiency of G0013-based mCherry mRNA-LNP in 293T cells at 500 ng mRNA in 24-well plate for 24 hours.
  • FIG. 15 G0017-based LNP formulation.
  • FIG. 16 shows transfection efficiency of G0017-based EGFP mRNA-LNP in PK15 procine cells at 500 ng mRNA in 24-well plate for 24 hours.
  • FIGs.17A-17B show transfection efficiency of G0025-based mCherry mRNA-LNP in 293T cells at 500 ng mRNA in 24-well plate for 24 hours using flow cytometry (17A) and fluorescent imaging (17B) assays.
  • alkylamino specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like.
  • alkyl is used in one instance and a specific term such as “alkylalcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkylalcohol” and the like. This practice is also used for other groups described herein.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” etc., where n is some integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxyl group, an amine group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • R b is H, C1-C12 alkyl, or C1-C12 alkenyl
  • p, q, and r are each independently an integer from 0 to 4
  • A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is In some emb odiments, A is . In some e mbodiments, A is . In some embodiments, A is, . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is In some embodiments, R is a linear C3-C25 alkyl or cycloalkyl. In some embodiments, R is a linear C3-C25 alkynyl or cycloalkynyl.
  • R is a linear C3-C25 alkenyl or cycloalkenyl. In some embodiments, R is a branched C 6 -C 40 alkyl. In some embodiments, R is a branched C 6 -C 40 alkenyl.
  • R can have the following structures: , o . I n some embodiments, R is In some embodiments, R is In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some embodiments, R is . In some
  • A is . In some embodiments, A is In some embodiments, A is . In some embodiments, A is . In some embodiments, A is In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is, . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is In some embodiments, A is In some embodiments, p, q, and r are independently 0, 1, 2, 3 or 4. In some embodiments, p is 0, 1, 2, 3 or 4. In some embodiments, q is 0, 1, 2, 3 or 4. In some embodiments, r is 0, 1, 2, 3 or 4.
  • p is 2, q is 4, and r is 1. In some embodiments, p is 2, q is 4, and r is 2. In some embodiments, p is 2, q is 4, and r is 3. In some embodiments, p is 2, q is 4, and r is 4. In some embodiments, p is 3, q is 2, and r is 0. In some embodiments, p is 3, q is 2, and r is 1. In some embodiments, p is 3, q is 2, and r is 2. In some embodiments, p is 3, q is 2, and r is 3. In some embodiments, p is 3, q is 2, and r is 4. In some embodiments, p is 4, q is 3, and r is 0.
  • p is 0 and q is 2. In some embodiments, p is 0 and q is 3. In some embodiments, p is 0 and q is 4. In some embodiments, p is 1 and q is 0. In some embodiments, p is 1 and q is 1. In some embodiments, p is 1 and q is 2. In some embodiments, p is 1 and q is 3. In some embodiments, p is 1 and q is 4. In some embodiments, p is 2 and q is 0. In some embodiments, p is 2 and q is 1. In some embodiments, p is 2 and q is 2. In some embodiments, p is 2 and q is 3. In some embodiments, p is 2 and q is 4.
  • p is 3 and q is 0. In some embodiments, p is 3 and q is 1. In some embodiments, p is 3 and q is 2. In some embodiments, p is 3 and q is 3. In some embodiments, p is 3 and q is 4. In some embodiments, p is 4 and q is 0. In some embodiments, p is 4 and q is 1. In some embodiments, p is 4 and q is 2. In some embodiments, p is 4 and q is 3. In some embodiments, p is 4 and q is 4. In some embodiments, the lipid compound of Formula I is defined by one of formulae Ia-Ih:
  • the lipid compound of Formula I is a lipid compound of formula Ia. In some embodiments, the lipid compound is a lipid compound of formula Ib. In some embodiments, the lipid compound is a lipid compound of formula Ic. In some embodiments, the lipid compound is a lipid compound of formula Id. In some embodiments, the lipid compound is a lipid compound of formula Ie. In some embodiments, the lipid compound is a lipid compound of formula If. In some embodiments, the lipid compound is a lipid compound of formula Ig. In some embodiments, R 1 is a linear C3-C25 alkyl or cycloalkyl.
  • R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, the lipid compound of Formula I can be selected from: , , , , or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid compound of Formula II is defined by one of formulae IIa-IIe:
  • R a is wherein a is an integer from 0 to 12;
  • G is selected from , R 1 and R 2 are each independently a linear or cyclic alkyl, alkenyl, or alkynyl comprising of 2 to 25 carbons; a branched alkyl or alkenyl comprising of 6 to 40 carbons;
  • the lipid compound of Formula II is a lipid compound defined by Formula IIa. In some embodiments, the lipid compound of Formula II is a lipid compound defined by Formula IIb. In some embodiments, the lipid compound of Formula II is a lipid compound defined by Formula IIc. In some embodiments, the lipid compound of Formula II is a lipid compound defined by Formula IId. In some embodiments, the lipid compound of Formula II is a lipid compound defined by Formula IIe. In some embodiments, R 1 and R 2 are each independently a linear C3-C25 alkyl or cycloalkyl. In some embodiments, R 1 and R 2 are each independently a linear C3-C25 alkynyl or cycloalkynyl.
  • R 1 and R 2 are each independently a linear C 3 -C 25 alkenyl or cycloalkenyl. In some embodiments, R 1 and R 2 are each independently a branched C6-C40 alkyl. In some embodiments, R 1 and R 2 are each independently a branched C 6 -C 40 alkenyl.
  • R 1 and R 2 can each independently have the following structures: I n some embodiments, R1 is . In some embodiments, . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is .
  • R a is , wherein a is an integer from 0 to 12;
  • G is selected from , , , , , , , , , , , , , , , or ;
  • R 1 is a linear or cyclic al
  • the lipid compound of Formula III is a compound of formula IIIa. In some embodiments, the lipid compound of Formula III is a compound of formula IIIb. In some embodiments, the lipid compound of Formula III is a compound of formula IIIc. In some embodiments, the lipid compound of Formula III is a compound of formula IIId.
  • the lipid compound of Formula III is a compound of formula IIIe. In some embodiments, the lipid compound of Formula III is a compound of formula IIIf.
  • R 1 is a linear C3-C25 alkyl or C3-C25 cycloalkyl. In some embodiments, R 1 is a linear C 1 3-C25 alkynyl or C3-C25 cycloalkynyl. In some embodiments, R is a linear C 3 -C 25 alkenyl or C 3 -C 25 cycloalkenyl. In some embodiments, R 1 is a branched C 6 - C 40 alkyl. In some embodiments, R 1 is a branched C 6 -C 40 alkenyl.
  • R 1 has the following structures: , , , or . I n some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is G3. In some embodiments, the lipid compound of Formula III is selected from:
  • the lipid compound of Formula IV is a compound of formula IVa. In some embodiments, the lipid compound of Formula IV is a compound of formula IVb. In some embodiments, the lipid compound of Formula IV is a compound of formula IVc. In some embodiments, the lipid compound of Formula IV is a compound of formula IVd.
  • the lipid compound of Formula IV is a compound of formula IVe. In some embodiments, the lipid compound of Formula IV is a compound of formula IVf.
  • R 1 is a linear C 3 -C 25 alkyl or C 3 -C 25 cycloalkyl. In some embodiments, R 1 is a linear C 3 -C 25 alkynyl or C 3 -C 25 cycloalkynyl. In some embodiments, R1 is a linear C3-C25 alkenyl or C3-C25 cycloalkenyl. In some embodiments, R 1 is a branched C6- C40 alkyl.
  • R 1 is a branched C6-C40 alkenyl.
  • R 1 has the following structures: , , , or . I n some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is G3. In some embodiments, the lipid compound of Formula IV is selected from:
  • R b is H, C1-C12 alkyl or C1-C12 alkenyl; and p, q, and r are each independently an integer from 0 to 4.
  • the compound of Formula V is a compound of formula Va. In some embodiments, the compound of Formula V is a compound of formula Vb. In some embodiments, the compound of Formula V is a compound of formula Vc. In some embodiments, the compound of Formula V is a compound of formula Vd. In some embodiments, the compound of Formula V is a compound of formula Ve. In some embodiments, R 1 is a linear C3-C25 alkyl or cycloalkyl. In some embodiments, R 1 is a linear C 3 -C 25 alkynyl or cycloalkynyl. In some embodiments, R 1 is a linear C 3 -C 25 alkenyl or cycloalkenyl.
  • the lipid compound of Formula V is selected from: , , , or it’s the Zn 2+ form, or it’s the Zn 2+ form,
  • A is N. In some embodiments, A is CH. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is In some embodiments, A is . In some embodiments, A is In some embodiments, A is . In some embodiments, A is In some embodiments, A is . In some embodiments, A is In some embodiments, A is . In some embodiments, A is In some embodiments, A is . In some embodiments, A is . In some embodiments, A is In some embodiments, A is .
  • A is, . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is In some embodiments, R 3 is 3 In some embodiments, R is In some embodiments, the compounds of Formula I can be defined by Formulae Ba- Bi:
  • x, y, and z are each independently an integer from 1 to 12;
  • R a is , wherein a is an integer from 0 to 12;
  • R 1 and R 2 are each independently selected from:
  • the compounds of Formula B can be selected from: , ,
  • the mRNA encoding at least one functional protein, antigenic polypeptide, or an immunogenic fragment thereof capable of inducing an immune response to the antigenic polypeptide is encapsulated by the nanoparticle.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a nanoparticle comprising a compound of Formula A, A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an mRNA encoding at least one antigenic polypeptide or an immunogenic fragment thereof capable of inducing an immune response to the antigenic polypeptide.
  • the helper lipid can be present in a molar ratio of from 0% to 40% (e.g., from greater than 0% to 30%, from greater than 0% to 20%, from greater than 0% to 10%, from greater than 0% to 5%, from greater than 0% to 1%, from greater than 0% to 0.5%, from 1% to 30%, from 1% to 20%, from 1% to 10%, from 1% to 5%, from 5% to 30%, from 5% to 20%, from 5% to 10%, from 10% to 30%, from 10% to 20%, from 20% to 30%, from 20% to 40%, or from 30% to 40%).
  • the nanoparticle includes a polyethylene glycol-lipid (PEG- lipid).
  • the polyethylene glycol-lipid can be present in a molar ratio of at least 0%, (e.g., at least 0.25%, at least 0.5%, at least 0.75%, at least 1%, at least 1.5%, at least 2%, at least 3%, at least 4%, or at least 5%). In some embodiments, the polyethylene glycol-lipid can be present in a molar ratio of 5% or less, (e.g., 4% or less, 3% or less, 2% or less, 1% or less, or 0.5% or less). The polyethylene glycol-lipid can be present in a molar ratio ranging from any of the minimum values described above to any of the maximum values described above.
  • the polyethylene glycol-lipid can be present in a molar ratio of from 0% to 5% (e.g., from greater than 0% to 4%, from greater than 0% to 3%, from greater than 0% to 2%, from greater than 0% to 1%, from greater than 0% to 0.5%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1% to 2%, from 2% to 5%, 2% to 4%, 2% to 3%, from 3% to 5%, from 3% to 4%, or 4% to 5%).
  • the polyethylene glycol-lipid in a molar ratio of 0.75%.
  • the nanoparticle includes a sterol.
  • Sterols are well known to those skilled in the art and generally refers to those compounds having a perhydrocyclopentanophenanthrene ring system and having one or more OH substituents.
  • Examples of sterols include, but are not limited to, cholesterol, campesterol, ergosterol, sitosterol, and the like.
  • the sterol is selected from a cholesterol-based lipid.
  • the one or more cholesterol-based lipids are selected from cholesterol, PEGylated cholesterol, DC-Choi (N,N-dimethyl-N- ethylcarboxamidocholesterol), l,4-bis(3- N-oleylamino-propyl)piperazine, or combinations thereof.
  • the sterol can be used to tune the particle permeability and fluidity base on its function in cell membranes.
  • the sterol is cholesterol.
  • the sterol in a molar ratio of at least 0%, (e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80%).
  • the sterol in a molar ratio of 80% or less, (e.g., 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less).
  • the sterol can be present in a molar ratio ranging from any of the minimum values described above to any of the maximum values described above.
  • the sterol can be present in a molar ratio of from 0% to 80%, (e.g., from greater than 0% to 70%, from greater than 0% to 60%, from greater than 0% to 50% from greater than 0% to 40%, from greater than 0% to 30%, from greater than 0% to 20%, from greater than 0% to 10%, from greater than 0% to 5%, from greater than 0% to 1%, from 5% to 70%, from 5% to 60%, from 5% to 50% from 5% to 40%, from 5% to 30%, from 5% to 20%, from 5% to 10%, from 10% to 70%, from 10% to 60%, from 10% to 50% from 10% to 40%, from 10% to 30%, from 10% to 20%, from 20% to 70%, from 20% to 60%, from 20% to 50%, from 20% to 40%, from 20% to 30%, from 30% to 70%, from 30% to 60%, from 30% to 50%, from 30% to 40%, from 0%
  • the disclosure provides a nanoparticle comprising: a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an active agent encapsulated in the nanoparticle.
  • nanoparticles including: a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE); 1,2-dimyristoyl-sn-glycerol, methoxypolyethylene glycol (DMG-PEG 2000 ); Beta-sitosterol ; and an active agent encapsulated in the nanoparticle.
  • DOPE 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
  • DMG-PEG 2000 1,2-dimyristoyl-sn-glycerol, methoxypolyethylene glycol
  • Beta-sitosterol an active agent encapsulated in the nanoparticle.
  • the disclosure provides a nanoparticle comprising: a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE); 1,2-dimyristoyl-sn-glycerol, methoxypolyethylene glycol (DMG-PEG 2000 ); cholesterol; and an active agent encapsulated in the nanoparticle.
  • POPE 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine
  • DMG-PEG 2000 methoxypolyethylene glycol
  • cholesterol an active agent encapsulated in the nanoparticle.
  • the disclosure provides a nanoparticle comprising: a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); 1,2-dimyristoyl-sn-glycerol, methoxypolyethylene glycol (DMG-PEG 2000 ); and cholesterol.
  • DSPC 1,2-distearoyl-sn-glycero-3-phosphocholine
  • DMG-PEG 2000 1,2-dimyristoyl-sn-glycerol, methoxypolyethylene glycol
  • the disclosure provides a nanoparticle comprising: a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)- 2000] (DSPE-PEG2000); Beta-sitosterol; and an active agent encapsulated in the nanoparticle.
  • the nanoparticle can further include an active agent.
  • the nanoparticle can further include a therapeutic agent.
  • Therapeutic agent includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins and minerals such as essential amino acids, calcium, iron, potassium, zinc, vitamin B12, and the like; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; an antimicrobial agents (including antibiotics, antiviral agents, antiparasitic, and anti-fungal agents), anti-inflammatory agents (including steroids and non-steroidal anti- inflammatory agents), anti-coagulant agents, ophthalmic agents, gastrointestinal drugs, antiplatelet agents, and antiseptic agents, steroidal agent, anti-neoplastic agent, anti-cancer agent, antigen, antibody (e.g., cetuximab, anti-CD24 antibody, panitumumab and bevacizumab), birth control agent, progestational agent, anti-cholinergic, nutritional agent, analgesics and analgesic combinations such as acetaminophen, acetylsalicylic acid, and the like; anesthetics such as lidocaine, xylocaine, and the like, anorexics such as dexadrine,
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • the agent to be delivered may be a mixture of active agents.
  • antibiotics include amikacin, amoxicillin, ampicillin, atovaquone, azithromycin, aztreonam, bacitracin, carbenicillin, cefadroxil, cefazolin, cefdinir, cefditoren, cefepime, cefiderocol, cefoperazone, cefotetan, cefoxitin, cefotaxime, cefpodoxime, cefprozil, ceftaroline, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, chloramphenicol, colistimethate, cefuroxime, cephalexin, cephradine, cilastatin, cinoxacin, cip
  • antiviral agents include, but are not limited to, abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, balavir, baloxavir marboxil, boceprevir, cidofovir, cobicistat, daclatasvir, darunavir, delavirdine, didanosine, docasanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, forscarnet, fosnonet, famciclovir, favipravir, fomivirsen, foscavir, ganciclovir, ibacitabine, idoxuridine, indinavir, in
  • anticoagulant agents include, but are not limited to, heparin, warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparin, and fondaparinux.
  • antiplatelet agents include, but are not limited to, clopidogrel, ticagrelor, prasugrel, dipyridamole, dipyridamole/aspirin, ticlopidine, and eptifibatide.
  • antifungal agents include, but are not limited to, voriconazole, itraconazole, posaconazole, fluconazole, ketoconazole, clotrimazole, isavuconazonium, miconazole, caspofungin, anidulafungin, micafungin, griseofulvin, terbinafine, flucytosine, terbinafine, nystatin, and amphotericin b.
  • Folic acid analogs or antifolates generally function by inhibiting dihydrofolate reductase (DHFR), an enzyme involved in the formation of nucleotides; when this enzyme is blocked, nucleotides are not formed, disrupting DNA replication and cell division.
  • DHFR dihydrofolate reductase
  • the folic acid analog may be selected from the group consisting of denopterin, methotrexate (amethopterin), pemetrexed, pteropterin, raltitrexed, trimetrexate, and salts, analogs, and derivatives thereof.
  • the antimetabolite agent is a purine analog.
  • Purine-based antimetabolite agents function by inhibiting DNA synthesis, for example, by interfering with the production of purine containing nucleotides, adenine and guanine which halts DNA synthesis and thereby cell division.
  • Purine analogs can also be incorporated into the DNA molecule itself during DNA synthesis, which can interfere with cell division.
  • the purine analog may be selected from the group consisting of acyclovir, allopurinol, 2-aminoadenosine, arabinosyl adenine (ara-A), azacitidine, azathiprine, 8-aza-adenosine, 8-fluoro-adenosine, 8-methoxy-adenosine, 8-oxo-adenosine, cladribine, deoxycoformycin, fludarabine, gancylovir, 8-aza-guanosine, 8-fluoro-guanosine, 8- methoxy- guanosine, 8-oxo-guanosine, guanosine diphosphate, guanosine diphosphate-beta- L-2- aminofucose, guanosine diphosphate-D-arabinose, guanosine diphosphate-2- fluorofucose, guanosine diphosphat
  • the antimetabolite agent is a pyrimidine analog. Similar to the purine analogs discussed above, pyrimidine-based antimetabolite agents block the synthesis of pyrimidine-containing nucleotides (cytosine and thymine in DNA; cytosine and uracil in RNA). By acting as “decoys,” the pyrimidine-based compounds can prevent the production of nucleotides, and/or can be incorporated into a growing DNA chain and lead to its termination.
  • 5-chlorouracil 5-chlorouracil
  • cytarabine cytosine arabinoside
  • cytosine dideoxyuridine, 3′-azido-3′-deoxythymidine, 3′- dideoxycytidin-2′-ene, 3′-deoxy-3′-deoxythymidin-2′-ene, dihydrouracil, doxifluridine, enocitabine, floxuridine, 5-fluorocytosine, 2-fluorodeoxycytidine, 3-fluoro-3′- deoxythymidine, fluorouracil (e.g., 5-fluorouracil (also known as 5-FU), gemcitabine, 5- methylcytosine, 5- propynylcytosine, 5-propynylthymine, 5-propynyluracil, thymine, uracil, uridine, and salts, analogs, and derivatives thereof.
  • 5-fluorouracil also known as 5-
  • the pyrimidine analog is other than 5- fluorouracil. In another aspect, the pyrimidine analog is gemcitabine or a salt thereof.
  • the antimetabolite agent is selected from the group consisting of 5- fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In other aspects, the antimetabolite agent is selected from the group consisting of capecitabine, 6- mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof.
  • the antimetabolite agent is other than 5-fluorouracil.
  • the antimetabolite agent is gemcitabine or a salt or thereof (e.g., gemcitabine HCl (Gemzar®)).
  • antimetabolite anti-cancer agents may be selected from, but are not limited to, the group consisting of acanthifolic acid, aminothiadiazole, brequinar sodium, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, Wellcome EHNA, Merck & Co.
  • EX-015 benzrabine, fludarabine phosphate, N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly LY-188011; Lilly LY-264618, methobenzaprim, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC- 612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, tiazofurin, Erbamont TIF, tyrosine kinase inhibitors, Taiho UFT and uricytin, among others.
  • the antimitotic anti-cancer agent is a microtubule inhibitor or a microtubule stabilizer.
  • microtubule stabilizers such as taxanes and epothilones, bind to the interior surface of the beta-microtubule chain and enhance microtubule assembly by promoting the nucleation and elongation phases of the polymerization reaction and by reducing the critical tubulin subunit concentration required for microtubules to assemble.
  • the microtubule stabilizers such as taxanes, decrease the lag time and dramatically shift the dynamic equilibrium between tubulin dimers and microtubule polymers towards polymerization.
  • the microtubule stabilizer is a taxane or an epothilone.
  • the microtubule inhibitor is a vinca alkaloid.
  • the anti-cancer agent may comprise a taxane or derivative or analog thereof.
  • the taxane may be a naturally derived compound or a related form, or may be a chemically synthesized compound or a derivative thereof, with antineoplastic properties.
  • Taxane derivatives include, but are not limited to, galactose and mannose derivatives described in International Patent Application No. WO 99/18113; piperazino and other derivatives described in WO 99/14209; taxane derivatives described in WO 99/09021, WO 98/22451, and U.S. Pat. No. 5,869,680; 6-thio derivatives described in WO 98/28288; sulfenamide derivatives described in U.S. Pat. No.
  • deoxygenated paclitaxel compounds such as those described in U.S. Pat. No. 5,440,056; and taxol derivatives described in U.S. Pat. No. 5,415,869.
  • it further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927; WO 98/13059; and U.S. Pat. No.5,824,701.
  • the taxane may also be a taxane conjugate such as, for example, paclitaxel-PEG, paclitaxel-dextran, paclitaxel-xylose, docetaxel-PEG, docetaxel- dextran, docetaxel-xylose, and the like.
  • the antimitotic anti-cancer agent can be a microtubule inhibitor; in one preferred aspect, the microtubule inhibitor is a vinca alkaloid. In general, the vinca alkaloids are mitotic spindle poisons.
  • the vinca alkaloid agents act during mitosis when chromosomes are split and begin to migrate along the tubules of the mitosis spindle towards one of its poles, prior to cell separation. Under the action of these spindle poisons, the spindle becomes disorganized by the dispersion of chromosomes during mitosis, affecting cellular reproduction.
  • the vinca alkaloid is selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine, and salts, analogs, and derivatives thereof.
  • the antimitotic anti-cancer agent can also be an epothilone.
  • epothilones In general, members of the epothilone class of compounds stabilize microtubule function according to mechanisms similar to those of the taxanes. Epothilones can also cause cell cycle arrest at the G2-M transition phase, leading to cytotoxicity and eventually apoptosis.
  • Suitable epithiolones include epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, and epothilone F, and salts, analogs, and derivatives thereof.
  • One particular epothilone analog is an epothilone B analog, ixabepilone (IxempraTM).
  • the antimitotic anti-cancer agent is selected from the group consisting of taxanes, epothilones, vinca alkaloids, and salts and combinations thereof.
  • the antimitotic agent is a taxane. More preferably in this aspect the antimitotic agent is paclitaxel or docetaxel, still more preferably paclitaxel.
  • the antimitotic agent is an epothilone (e.g., an epothilone B analog).
  • the antimitotic agent is a vinca alkaloid.
  • cancer drugs examples include, but are not limited to: thalidomide; platinum coordination complexes such as cisplatin (cis-DDP), oxaliplatin and carboplatin; anthracenediones such as mitoxantrone; substituted ureas such as hydroxyurea; methylhydrazine derivatives such as procarbazine (N- methylhydrazine, MIH); adrenocortical suppressants such as mitotane (o,p′-DDD) and aminoglutethimide; RXR agonists such as bexarotene; and tyrosine kinase inhibitors such as sunitimib and imatinib.
  • platinum coordination complexes such as cisplatin (cis-DDP), oxaliplatin and carboplatin
  • anthracenediones such as mitoxantrone
  • substituted ureas such as hydroxyurea
  • methylhydrazine derivatives such
  • Examples of additional cancer drugs include alkylating agents, antimetabolites, natural products, hormones and antagonists, and miscellaneous agents. Alternate names are indicated in parentheses.
  • alkylating agents include nitrogen mustards such as mechlorethamine, cyclophosphainide, ifosfamide, melphalan sarcolysin) and chlorambucil; ethylenimines and methylmelamines such as hexamethylmelamine and thiotepa; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine (BCNU), semustine (methyl- CCNU), lomustine (CCNU) and streptozocin (streptozotocin); DNA synthesis antagonists such as estramustine phosphate; and triazines such as dacarbazine (DTIC, dimethyl- triazenoimidazolecarboxamide) and temozolomide.
  • DTIC dimethyl- tri
  • antimetabolites include folic acid analogs such as methotrexate (amethopterin); pyrimidine analogs such as fluorouracin (5- fluorouracil, 5-FU, SFU), floxuridine (fluorodeoxyuridine, FUdR), cytarabine (cytosine arabinoside) and gemcitabine; purine analogs such as mercaptopurine (6-mercaptopurine, 6- MP), thioguanine (6-thioguanine, TG) and pentostatin (2′-deoxycoformycin, deoxycoformycin), cladribine and fludarabine; and topoisomerase inhibitors such as amsacrine.
  • folic acid analogs such as methotrexate (amethopterin)
  • pyrimidine analogs such as fluorouracin (5- fluorouracil, 5-FU, SFU), floxuridine (fluorodeoxyuridine, FUdR), cytarabine (cytos
  • Examples of natural products include vinca alkaloids such as vinblastine (VLB) and vincristine; taxanes such as paclitaxel, protein bound paclitaxel (Abraxane) and docetaxel (Taxotere); epipodophyllotoxins such as etoposide and teniposide; camptothecins such as topotecan and irinotecan; antibiotics such as dactinomycin (actinomycin D), daunorubicin (daunomycin, rubidomycin), doxorubicin, histrelin, bleomycin, mitomycin (mitomycin C), idarubicin, epirubicin; enzymes such as L-asparaginase; and biological response modifiers such as interferon alpha and interlelukin 2.
  • VLB vinblastine
  • vincristine taxanes
  • paclitaxel protein bound paclitaxel
  • Abraxane protein bound paclitaxel
  • hormones and antagonists include luteinising releasing hormone agonists such as buserelin; adrenocorticosteroids such as prednisone and related preparations; progestins such as hydroxyprogesterone caproate, rnedroxyprogesterone acetate and megestrol acetate; estrogens such as diethylstilbestrol and ethinyl estradiol and related preparations; estrogen antagonists such as tamoxifen and anastrozole; androgens such as testosterone propionate and fluoxymesterone and related preparations; androgen antagonists such as flutamide and bicalutamide; and gonadotropin- releasing hormone analogs such as leuprolide.
  • releasing hormone agonists such as buserelin
  • adrenocorticosteroids such as prednisone and related preparations
  • progestins such as hydroxyprogesterone caproate, rnedroxyprogesterone
  • the anti-cancer agent may comprise a chemotherapeutic agent.
  • Suitable chemotherapeutic agents include, but are not limited to, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents and their synthetic derivatives, anti-angiogenic agents, differentiation inducing agents, cell growth arrest inducing agents, apoptosis inducing agents, cytotoxic agents, agents affecting cell bioenergetics i.e., affecting cellular ATP levels and molecules/activities regulating these levels, biologic agents, e.g., monoclonal antibodies, kinase inhibitors and inhibitors of growth factors and their receptors, gene therapy agents, cell therapy, e.g., stem cells, or any combination thereof.
  • alkylating agents include, but are not limited to, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents and their synthetic derivatives, anti-angiogenic agents, differentiation inducing agents, cell growth arrest inducing agents, apoptosis inducing agents, cytotoxic agents, agents affecting cell bioenergetics
  • the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, chlorambucil, melphalan, mechlorethamine, ifosfamide, busulfan, lomustine, streptozocin, temozolomide, dacarbazine, cisplatin, carboplatin, oxaliplatin, procarbazine, uramustine, methotrexate, pemetrexed, fludarabine, cytarabine, fluorouracil, floxuridine, gemcitabine, capecitabine, vinblastine, vincristine, vinorelbine, etoposide, paclitaxel, docetaxel, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin, hydroxyurea, topotecan, irinotecan, amsacrine, tenipos
  • Anti-neoplastic agent can be selected from the group consisting of Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Adrucil (Fluorouracil), Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alemtuzumab, Alimta (Pemetrexed Disodium), Aloxi (Palonosetron Hydrochloride), Ambochlorin (Chlorambucil), Am
  • Growth factors useful as therapeutic agents include, but are not limited to, transforming growth factor- ⁇ (“TGF- ⁇ ”), transforming growth factors (“TGF- ⁇ ”), platelet-derived growth factors (“PDGF”), fibroblast growth factors (“FGF”), including FGF acidic isoforms 1 and 2, FGF basic form 2 and FGF 4, 8, 9 and 10, nerve growth factors (“NGF”) including NGF 2.5s, NGF 7.0s and beta NGF and neurotrophins, brain derived neurotrophic factor, cartilage derived factor, bone growth factors (BGF), basic fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (G- CSF), insulin like growth factor (IGF) I and II, hepatocyte growth factor, glial neurotrophic growth factor (GDNF), stem cell factor (SCF), keratinocyte growth factor (KGF), transforming growth factors (TGF), including TGFs alpha, beta, beta1, beta2, beta3, skeletal growth factor, bone
  • Immunoglobulins useful in the present disclosure include, but are not limited to, IgG, IgA, IgM, IgD, IgE, and mixtures thereof.
  • Some preferred growth factors include VEGF (vascular endothelial growth factor), NGFs (nerve growth factors), PDGF-AA, PDGF-BB, PDGF-AB, FGFb, FGFa, and BGF.
  • Other molecules useful as anti-cancer agents include but are not limited to growth hormones, leptin, leukemia inhibitory factor (LIF), tumor necrosis factor alpha and beta, endostatin, thrombospondin, osteogenic protein-1, bone morphogenetic proteins 2 and 7, osteonectin, somatomedin-like peptide, osteocalcin.
  • LIF leukemia inhibitory factor
  • Tumor antigens can be based on specific mutations (neoepitopes) and those expressed by cancer-germline genes (antigens common to tumors found in multiple patients, referred to herein as “traditional cancer antigens” or “shared cancer antigens”).
  • a traditional antigen is one that is known to be found in cancers or tumors generally or in a specific type of cancer or tumor.
  • a traditional cancer antigen is a non- mutated tumor antigen.
  • a traditional cancer antigen is a mutated tumor antigen.
  • Diagnostic agents include gases; metals; commercially available imaging agents used in positron emissions tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI); and contrast agents.
  • PET positron emissions tomography
  • CAT computer assisted tomography
  • MRI magnetic resonance imaging
  • suitable materials for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium.
  • Examples of materials useful for CAT and x-ray imaging include iodine-based materials.
  • Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, cell extracts, and RNA encoding at least one antigenic polypeptide or an immunogenic fragment thereof (e.g., an immunogenic fragment capable of inducing an immune response to the antigenic polypeptide).
  • Active agents may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, Freund's adjuvant, etc.
  • Prophylactic agents can include infection agents such as antigens of such bacterial organisms as Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallid
  • antigens may be in the form of whole killed organisms, peptides, proteins, glycoproteins, carbohydrates, or combinations thereof.
  • the active agent is a polynucleotide.
  • Polynucleotides or oligonucleotides that can be introduced according to the methods herein include DNA, cDNA, and RNA sequences of all types.
  • the polynucleotide can be double stranded DNA, single-stranded DNA, complexed DNA, encapsulated DNA, naked RNA, encapsulated RNA, messenger RNA (mRNA), tRNA, short interfering RNA (siRNA), double stranded RNA (dsRNA), micro-RNA (miRNA), antisense RNA (asRNA), self-amplify mRNA (saRNA), guide RNA (gRNA), circRNA and combinations thereof.
  • the polynucleotides can also be DNA constructs, such as expression vectors, expression vectors encoding a desired gene product (e.g., a gene product homologous or heterologous to the subject into which it is to be introduced), and the like.
  • the RNA may be used to induce a balanced immune response against an infection agent.
  • the RNA e.g., mRNA
  • the RNA may be used to induce a balanced immune response against an viruses as Metapneumovirus such as human Metapneumovirus (hMPV), parainfluenza viruses such as human parainfluenza viruses (hPIV) types 1, 2, and 3 (hPIV1, hPIV2 and hPIV3, respectively), respiratory syncytial virus (RSV), measles virus (MeV), coronaviruses (e.g., MERS-CoV, SARS-CoV, SARS- CoV2, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH, HCoV-HKU1), poxviruses (e.g., smallpox, monkeypox), African swine virus, influenza
  • hMPV human Metapneumovirus
  • the RNA may be used to induce a balanced immune response against.
  • the RNA e.g., mRNA
  • respiratory viruses refers herein to viruses causing respiratory diseases.
  • negative-sense, single-stranded RNA virus of the family Paramyxoviridae such as human Metapneumovirus (hMPV), human parainfluenza viruses (hPIV) types 1, 2, and 3 (hPIV1, hPIV2 and hPIV3, respectively), RSV, and Measles virus (MeV).
  • hMPV human Metapneumovirus
  • hPIV human parainfluenza viruses
  • RSV and Measles virus
  • Measles virus Measles virus
  • Coronaviruses are enveloped viruses with a positive- sense single-stranded RNA genome and with a nucleocapsid of helical symmetry. Coronaviruses are species of virus belonging to the subfamily Coronavirinae in the family Coronaviridae, in the order Nidovirales.
  • betacoronaviruses include, but are not limited to an embecovirus 1 (e.g., Betacoronavirus 1, Human coronavirus OC43, China Rattus coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus), a hibecovirus (e.g., Bat Hp- betacoronavirus Zhejiang2013), a merbecovirus (e.g., Hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), Pipistrellus bat coronavirus HKU5, Tylonycteris bat coronavirus HKU4), a nobecovirus (e.g., Rousettus bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9), a sarbecovirus (e.g., severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • embecovirus 1
  • gammacoronaviruses include, but are not limited to, a cegacovirus (e.g., Beluga whale coronavirus SQ1) and an Igacovirus (e.g., Avian coronavirus (IBV)).
  • a cegacovirus e.g., Beluga whale coronavirus SQ1
  • an Igacovirus e.g., Avian coronavirus (IBV)
  • deltacoronaviruses include, but are not limited to, an andecovirus (e.g., Wigeon coronavirus HKU20), a buldecovirus (e.g., Bulbul coronavirus HKU11, Porcine coronavirus HKU15 (PorCoV HKU15), Munia coronavirus HKU13, White- eye coronavirus HKU16), a herdecovirus (e.g., Night heron coronavirus HKU19), and a moordecovirus (e.g., Common moorhen coronavirus HKU21).
  • the coronavirus is a human coronavirus.
  • human coronaviruses include, but are not limited to, human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV- HKU1), Human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Middle East respiratory syndrome-related coronavirus (MERS-CoV).
  • HCV-229E human coronavirus OC43
  • HKU1 HKU1
  • HKU1 Human coronavirus NL63
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • antigenic polypeptide encompasses immunogenic fragments of the antigenic polypeptide (an immunogenic fragment that induces (or is capable of inducing) an immune response human Metapneumovirus (hMPV), human parainfluenza viruses (hPIV) types 1, 2, and 3 (hPIV1, hPIV2 and hPIV3, respectively), respiratory syncytial virus (RSV), measles virus (MeV), varicella-zoster, influenza virus, herpes simplex virus 1 (HSV1), herpes simplex virus 2 (HSV2), poxvirus (e.g., smallpox, monkeypox), African swine virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella, coxsackieviruses, equine encephalitis, Japanese encephalitis, yellow fever
  • hMPV human Meta
  • the agent is an RNA (e.g., mRNA) that can induce a balanced immune response against hMPV, PIV, RSV, MeV, and/or coronaviruses (e.g., MERS-CoV, SARS-CoV, SARS-CoV2, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH and/or HCoV-HKU1), or any combination of two or more of the foregoing viruses, comprising both cellular and humoral immunity, without risking the possibility of insertional mutagenesis, for example.
  • RNA e.g., mRNA
  • coronaviruses e.g., MERS-CoV, SARS-CoV, SARS-CoV2, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH and/or HCoV-HKU
  • the agent is an RNA (e.g., mRNA) that can induce a balanced of therapeutics protein; In some embodiments, the agent is an RNA (e.g., siRNA) that can inhibit the expression of protein; In some embodiments, the agent is RNA (e.g., mRNA and gRNA) that can induce CAS protein for gene editing, base editing, RNA editing, prime editing. In some embodiments, the agent is an RNA (e.g., miRNA) that can induce a balanced of protein. In some embodiments, the agent is an DNA that can induce a balanced immune response as the aforementioned purposes against viruses. In some embodiments, the agent is an DNA that can induce a balanced of protein as the aforementioned purposes of therapy.
  • RNA e.g., mRNA
  • siRNA RNA
  • RNA e.g., mRNA and gRNA
  • RNA e.g., miRNA
  • the agent is an DNA that can induce a balanced immune response as the aforementioned purposes against viruses.
  • composition of the present invention can be utilized as a composition for the diagnosis, prevention and treatment of a disease or disorder (e.g., an infection, of cancer, of pain, of depression, of an inflammatory disease, of an intestinal disease, of a brain disease, of an allergic disease, of arrhythmia, of hypertension, of an eye disease, of an endocrine disease, or of a cardiovascular disease), depending on the type of the active agent.
  • a disease or disorder e.g., an infection, of cancer, of pain, of depression, of an inflammatory disease, of an intestinal disease, of a brain disease, of an allergic disease, of arrhythmia, of hypertension, of an eye disease, of an endocrine disease, or of a cardiovascular disease
  • Described herein are methods for the delivery of an active agent (for example, a polynucleotide) into an organ, a tissue, and/or cell including: introducing into the organ, tissue and/or cell a composition or nanoparticle described herein including: a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an active agent.
  • an active agent for example, a polynucleotide
  • Described herein are methods for diagnosing, treating or preventing diseases comprising administering to a subject in need thereof an effective amount of a composition or nanoparticle described herein including a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an active agent.
  • Described herein are methods for treating or preventing an infection comprising administering to a subject in need thereof an effective amount of a composition or nanoparticle described herein including a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an active agent.
  • Described herein are methods for treating or preventing a respiratory infection comprising administering to a subject in need thereof an effective amount of a composition or nanoparticle described herein including a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an active agent.
  • Described herein are also methods inducing an immune response against viruses, the method comprising administering to a subject in need thereof an effective amount of a composition or nanoparticle described herein including a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an active agent.
  • Described herein are also methods inducing an immune response against respiratory viruses, the method comprising administering to a subject in need thereof an effective amount of a composition or a nanoparticle including a compound of Formula A, I, II, III, IV, V, B, Ba, Bb, Bc, Bd, Be, Bf, Bg, Bh, Bi, or any combination thereof; and an active agent.
  • methods for the delivery of polynucleotides for example, mRNA to provide expression of the polynucleotides (and translation to produce a protein) in a cell.
  • delivery of an antisense mRNA or shRNA, or siRNA to tumor cells can regulate the protein expression encoded by the mRNA or shRNA.
  • the methods for delivery of an active agent can introduce polynucleotide to a cell or tissue for cell reprogramming where the polynucleotide can be used to modulate cell behavior by expressing transcription factors or growth factors.
  • the method for delivery of an active agent can include introducing a polynucleotide into a specific cell or tissue ex vivo to express a polypeptide encoded by the polynucleotide on the specific cell or tissue to generate a chimeric cell or tissue; and administering the chimeric cell or tissue to a subject for tumor treatment.
  • the specific cell can include CAR T cells, CAR-NK cells or other cells derived from a subject that can be used to for immunotherapy.
  • compositions and methods described herein are useful for treating or preventing metastasis or recurrence of a cancer. In some embodiments, the compositions and methods described herein are useful for the prevention of recurrence of excised solid tumors. In some embodiments, the compositions and methods described herein are useful for the prevention of metastasis of excised solid tumors.
  • the methods described herein are used to treat cancer, for example, melanoma, lung cancer (including lung adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, bronchogenic carcinoma, non- small-cell carcinoma, small cell carcinoma, mesothelioma); breast cancer (including ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma, serosal cavities breast carcinoma); colorectal cancer (colon cancer, rectal cancer, colorectal adenocarcinoma); anal cancer; pancreatic cancer (including pancreatic adenocarcinoma, islet cell carcinoma, neuroendocrine tumors); prostate cancer; prostate adenocarcinoma; ovarian carcinoma (ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cystadenocarcinoma, sex- cord-stromal tumor
  • the compositions and methods described herein are useful in treating or preventing a cancer.
  • the cancer is a circulating cancer cell (circulating tumor cell).
  • the cancer is a metastatic cancer cell.
  • the method further comprises administering an additional therapeutic agent.
  • the additional therapeutic agent comprises an additional immunotherapeutic agent, or an anti-neoplastic agent.
  • methods of treating a disease or a condition such as an inflammation disorder (including an autoimmune disease) or lymphoid proliferative diseases, comprising administering to a subject in need thereof an effective amount of a compound, a combination of compounds, or a composition provided herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as provided herein.
  • a disease or a condition such as an inflammation disorder (including an autoimmune disease) or lymphoid proliferative diseases
  • administering comprising administering to a subject in need thereof an effective amount of a compound, a combination of compounds, or a composition provided herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as provided herein.
  • a method of treating an inflammation disorder, including autoimmune diseases in a subject comprises administering to said subject a therapeutically effective amount of a compound, a combination of compounds, or a composition provided herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as provided herein.
  • autoimmune diseases include but are not limited to acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, autoimmune skin disease, coeliac disease, Crohn's disease, Diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also known as “giant cell arteritis”), warm autoimmune hemolytic an
  • disorders include bone-resorption disorders and thrombosis.
  • Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative inflammation.
  • Exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus,
  • the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatistis.
  • the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection).
  • the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease).
  • the compounds can also be useful in treating inflammation associated with trauma and non-inflammatory myalgia.
  • Immune disorders such as auto-immune disorders include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers, regional
  • provided herein is a method of treating an infection in a subject, the infection caused by an infection agent.
  • the method comprises administering to said subject a therapeutically effective amount of a compound, a combination of compounds, or a composition provided herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as provided herein.
  • the infection agents can include, but are not limited to, bacterial organisms as Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Le
  • the infection can be a coronavirus infection.
  • the coronavirus infection is an infection of the upper and/or lower respiratory tract.
  • the “upper respiratory tract” includes the mouth, nose, sinus, middle ear, throat, larynx, and trachea.
  • the “lower respiratory tract” includes the bronchial tubes (bronchi) and the lungs (bronchi, bronchioles and alveoli), as well as the interstitial tissue of the lungs.
  • the coronavirus infection is an infection of the gastrointestinal tract.
  • the “gastrointestinal tract” may include any area of the canal from the mouth to the anus, including the mouth, esophagus, stomach, and intestines.
  • the coronavirus infection is a renal infection. It is understood and herein contemplated that the coronavirus infections disclosed herein can cause a pathological state associated with the coronavirus infection referred to herein as a “coronavirus disease.”
  • the coronavirus disease is selected from a common cold, pneumonia, pneumonitis, bronchitis, severe acute respiratory syndrome (SARS), coronavirus disease 2019 (COVID-2019), Middle East respiratory syndrome (MERS), sinusitis, porcine diarrhea, porcine epidemic diarrhea, avian infections bronchitis, otitis and pharyngitis.
  • the coronavirus infection is a common cold.
  • the coronavirus infection is selected from SARS, COVID-19, and MERS.
  • the coronavirus infection is COVID-19.
  • the coronavirus infection is IBV, PorCoV HKU15, or PEDV.
  • Most patients identified with SARS were previously healthy adults aged 25–70 years. A few suspected cases of SARS have been reported among children under 15 years. The case fatality among persons with illness meeting the current World Health Organization case definition for probable and suspected cases of SARS is around 3%.
  • Other indications associated with coronavirus infections are described in Gralinski & Baric, 2015, J. Pathol.
  • coronaviridae a review of coronavirus and toroviruses”, Coronaviruses with Special Emphasis on First Insights Concerning SARS 1, ed. By A. Schmidt, M.H. Wolff and O. Weber, Birkhauser Verlag Baser, Switzerland, each of which is incorporated herein by reference in their entirety.
  • the coronavirus causing the infection may be selected from an alphacoronavirus, a betacoronavirus, a gammacoronavirus, or a deltacoronavirus.
  • Eye disorders that may be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, corneal neovascularization diseases, post- corneal transplant rejection prophylaxis and treatment, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, an inflammatory disease of the vitreous or retina, endophthalmitis prophylaxis and treatment, macular edema, macular degeneration, age related macular degeneration, proliferative and non-proliferative
  • Endocrine disorders that may be treated according to the compositions and methods disclosed herein include thyroid disorders (e.g., hyperthyroidism, hypothyroidism, thyroiditis, goitre, diabetes, hypoglycemia, glucagonoma, calcium homeostasis disorders (e.g., parathyroid gland, osteoporosis, osteomalacia, rickets, sex hormone disorders (e.g, disorders of sex development, hypogonadism, disorders of puberty, menstrual function or fertility disorders).
  • thyroid disorders e.g., hyperthyroidism, hypothyroidism, thyroiditis, goitre, diabetes, hypoglycemia, glucagonoma
  • calcium homeostasis disorders e.g., parathyroid gland, osteoporosis, osteomalacia, rickets
  • sex hormone disorders e.g, disorders of sex development, hypogonadism, disorders of puberty, menstrual function or fertility disorders
  • Example 1 Synthetic scheme for ionizable lipid (compound G0025) Procedure for preparation of compound 3: To a solution of compound 1 (1.39 mmol) and NEt 3 (2.23 mmol) in 7 mL dichloromethane at 0 °C, dropwise 2 (1.67 mmol) in 20 min. Stir the mixture at 25 °C for 16 hrs. Charge 200 mLH2O into the mixture, and extract the reaction with dichloromethane (200 mL * 3) at 25 °C.
  • Example 2 Synthetic scheme for ionizable lipid (compound G0012, G0211 and G0212) Compound G0012, G0211 and Compound G0212 were produced using a similar synthesitic route as Compound G0025 with slightly modification.
  • Example 3 Synthetic scheme for ionizable lipid (compound G0056) Procedure for preparation of compound 3: To a solution of compound 1 (1.39 mmol) and NEt 3 (2.23 mmol) in 7 mL dichloromethane at 0 °C, dropwise 2 (1.67 mmol) in 20 min.
  • Procedure for preparation of compound G0056 To a solution of compound 5 (165 mg) in 8 mL ACN, charge 162 mg K2CO3 and 55 mg KI, charge compound 8 (0.82 mL) and CPME (1 mL) into the solution at 25 °C. Heat the mixture to 90 °C and stirred at 90 °C for 16 hrs. Cool down to 25 °C and charge 100 mL H 2 O into the mixture. Extract the reaction with ethyl acetate (60.0 mL * 3), and wash the reaction with saturated brine (50.0 mL * 3) at 25 °C. Dry the reaction with anhydrous Na2SO4 at 25 °C. Concentrate organic phase below 40 ⁇ 50 °C to give a residue.
  • Example 4 Synthetic scheme for ionizable lipid (compound G0016, G0156 and G0116) Compound G0016, G0156, Compound G0116 and other Compound were produced using a similar synthesitic route as Compound G0056 and Compound G0025 with slightly modification.
  • Example 5 Representative synthetic route 1 (compounds G0013 and G0017) Procedure for preparation of compound 3: To a solution of compound 1 (600 mg, 1.39 mmol) and NEt 3 (2.23 mmol, 0.31mL) in 7 mL dichloromethane at 0 °C, dropwise 2 (1.67 mmol, 0.26 mL) in 20 min. Stir the mixture at 25 °C for 16 hrs. Charge 200 mLH2O into the mixture, and extract the reaction with dichloromethane (200 mL * 3) at 25 °C. Wash the reaction with saturated brine (200 mL * 3) at 25 °C. Dry the reaction with anhydrous Na 2 SO 4 at 25 °C.
  • Lipid nanoparticles for nucleic acid delivery Lipid nanoparticle (LNP) plays a key role in effectively protecting and delivering nucleic acid to cells for the application of prevention and therapeutics. Despite promising data from ongoing clinical trials, the clinical use of gene medicine requires the discovery and development of more efficient delivery systems. Described herein are nanoparticles for gene and drug delivery applications. EGFP mRNA, mCHerry mRNA, PEDV mRNA lipid nanoparticles (LNPs).
  • Lipid nanoparticle (LNP) formulations were prepared herein using either indicated lipids or commercially available SM-102 lipid for comparison.
  • LNP formulations were prepared using lipids dissolved in ethanol at molar ratios of 50:10:38.5:1.5 (ionizable lipid: DSPC: cholesterol: PEG-lipid), or 50:10:38.5:1.5 (two or more ionizable lipids: DSPC: cholesterol: PEG-lipid), or 50:48.5:1.5 (ionizable lipid: cholesterol: PEG-lipid), or 50:48:2.0 (ionizable lipid: cholesterol: PEG-lipid), or 40:10:10:38.5:1.5 (ionizable lipid A: ionizable lipid B: DSPC: cholesterol: PEG-lipid), or indicated otherwise.
  • the lipid mixture was combined with 10 mM sodium citrate buffer (pH 4.0) containing mRNA at a volume ratio of 3:1 (aqueous: ethanol) to form LNP.
  • Formulations were dialyzed against 10 mM Tris (pH 7.4) with 8% sucrose in Slide-A-Lyzer dialysis cassettes for at least 16 h and concentrated using Amicon ultra-centrifugal filters and then passed through a 0.22 ⁇ m filter and stored at 4°C or ⁇ 20°C until use.
  • FIG. 6 shows the in vitro expression of EGFP after transfecting cells with 0.5 ⁇ g mRNA in24-well plate for 24 hr. Transfection efficiency was evaluated using flow cytometer. The results of the study are shown in Figs 15-17
  • LNPs formulated with indicated ionizable lipids and 1 ⁇ g of luciferase-expressing mRNA were injected intramuscularly or 5 ⁇ g of luciferase-expressing mRNA were injected intravascularly.
  • luciferase expression was determined by whole body bioluminescence imaging using an IVIS Spectrum in vivo imaging system at 6, 24, and 48 hours, respectively. Results of the in vivo transfection efficiency study of luciferase-expressing mRNA is shown in Figs. 18-22. 1 ⁇ g of vaccine formulated with indicated lipids and mRNA was injected intramuscularly as scheduled. A formulation including commercially available lipid SM-102 and mRNA encoding the same mRNA was prepared and used as comparison. After 12 hours, the weight distribution assay was conducted to measure the pain at the injection site of mice. Afterward, the tissues were collected and performed H&E staining and the inflammation and tissue damage were shown in Fig. 23. Data was presented as Mean ⁇ SD.

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Abstract

L'invention concerne des composés, des compositions et des méthodes d'administration d'agents thérapeutiques, diagnostiques ou prophylactiques (par exemple, un acide nucléique).
PCT/US2025/021600 2024-03-26 2025-03-26 Composés lipidiques, compositions et méthodes d'utilisation associées Pending WO2025207803A1 (fr)

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US20220162521A1 (en) * 2020-11-25 2022-05-26 Akagera Medicines, Inc. Ionizable cationic lipids
US20230285310A1 (en) * 2020-08-06 2023-09-14 Modernatx, Inc. Compositions for the delivery of payload molecules to airway epithelium
WO2024035710A2 (fr) * 2022-08-08 2024-02-15 Advanced Rna Vaccine (Arv) Technologies, Inc. Lipides ionisables à base de stérol et nanoparticules lipidiques les comprenant

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230285310A1 (en) * 2020-08-06 2023-09-14 Modernatx, Inc. Compositions for the delivery of payload molecules to airway epithelium
US20220162521A1 (en) * 2020-11-25 2022-05-26 Akagera Medicines, Inc. Ionizable cationic lipids
WO2024035710A2 (fr) * 2022-08-08 2024-02-15 Advanced Rna Vaccine (Arv) Technologies, Inc. Lipides ionisables à base de stérol et nanoparticules lipidiques les comprenant

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