CN116999566A - Application of nanodelivery systems in the preparation of anti-colitis-related colorectal cancer drugs - Google Patents
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Abstract
本申请属于生物医药技术领域，具体涉及一种用于炎症相关肿瘤的纳米递送系统，该纳米递送系统包括：布地奈德、吉西他滨和硫缩酮类化合物，硫缩酮类化合物作为分子桥同时连接布地奈德和吉西他滨，硫缩酮类化合物的结构如式(Ⅰ)所示，X和Y为用于连接布地奈德和吉西他滨的连接官能团，连接官能团选自羧基、羟基、氨基、酰卤基和异氰酸酯基中的至少一种，R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自氢、C1‑10烷基、羟基、氨基、羧基、卤素中的至少一种，R9和R10为碳原子个数大于1的烷基。此外，上述纳米递送系统能够应用在制备抗结肠炎相关结直肠癌药物。
This application belongs to the field of biomedical technology, and specifically relates to a nano-delivery system for inflammation-related tumors. The nano-delivery system includes: budesonide, gemcitabine and thioketal compounds. The thioketal compounds are connected simultaneously as molecular bridges. The structures of budesonide and gemcitabine and thioketal compounds are shown in formula (I). X and Y are connecting functional groups used to connect budesonide and gemcitabine. The connecting functional groups are selected from carboxyl, hydroxyl, amino, and acid halide groups. and at least one of isocyanate groups, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 1‑10 alkyl, hydroxyl, amino, At least one of carboxyl and halogen, R 9 and R 10 are alkyl groups with more than 1 carbon atoms. In addition, the above-mentioned nanodelivery system can be applied in the preparation of anti-colitis-related colorectal cancer drugs.
Description
Technical Field
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a nano delivery system for inflammation-related tumors and application of the nano delivery system in preparation of anti-colonitis-related colorectal cancer drugs.
Background
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, with CRC usually being caused by both genetic and environmental factors. Due to chronic inflammation exposure, many inflammatory bowel disease patients (IBD) develop colorectal cancer (CAC) associated with colitis, a very aggressive subtype of CRC. Unlike sporadic CRC, which progresses from adenomatous dysplasia to cancer, CAC accumulates from somatic mutations to inflamed mucosal dysplasia, and then to tumorigenesis. The progression of CAC is closely related to inflammatory lesions, inflammatory signals mediating tumor development by dynamic cross-talk between cancer cells and Tumor Immune Microenvironment (TIME) cells, including macrophages, neutrophils, lymphocytes and endothelial cells, and in particular tumor-associated macrophages (TAMs) exhibit a number of pro-neoplastic effects, such as increasing proliferation and survival of malignant cells, promoting angiogenesis and metastasis, attenuating adaptive immune responses, and attenuating responses to treatment. Thus, normalization of "TIME" represents a new therapeutic regimen. A large number of experimental researches prove that the inflammation can be relieved, the occurrence of tumors can be delayed, and meanwhile, some anti-inflammatory medicaments, such as steroids, can be used for reversing the inhibited effect of the anti-tumor medicaments.
Clinically, immunomodulating drugs are used in combination with antitumor drugs for the treatment of inflammation-associated cancers. However, the different solubilities and bioavailability of different drugs in co-therapy limit their use. Carrier-based delivery systems, it is theoretically possible to achieve co-administration of two or more drugs. However, excessive excipient carrier delivery systems can result in high manufacturing costs, difficult quality control, increased potential side effects, and difficulty in conversion to clinical use. Pure drug nano-aggregates (PD NA) with natural advantages in achieving synergistic therapy have recently received attention, for example, with the aid of dasatinib, cytotoxic cabazitaxel can form nano-aggregates (CD NA), which show a surprising therapeutic synergy, which can produce a durable decline in tumor growth. In addition, the non-steroidal anti-inflammatory drug indometacin induced paclitaxel nanocrystal aggregate also shows excellent synergistic anti-tumor activity as a carrier-free nano drug.
Gemcitabine (GEM) is a pyrimidine antimetabolite having a broad spectrum of activity against a variety of cancers including colon, lung, pancreas and ovary. Although Gem has excellent anticancer effect, its extremely short half-life hinders therapeutic activity of Gem: rapid metabolic inactivation (by deoxycytidine deaminase) was performed for 8-17 minutes. Thus, large doses are required to achieve adequate therapeutic effects, which further cause adverse effects. Furthermore, CAC can lead to an inhibitory immune microenvironment, which may lead to failure of Gem-induced anti-tumor immune responses.
Disclosure of Invention
The application aims to provide a nano-delivery system for inflammation-related tumors, in particular to a nano-delivery system with an anti-colonitis-related colorectal cancer effect.
In order to achieve the above purpose, the specific technical scheme provided by the application is as follows:
a nano-delivery system for inflammation-associated tumors, the nano-delivery system comprising: budesonide, gemcitabine and thioketals as molecular bridges simultaneously linking the budesonide and the gemcitabine,
the structure of the thioketal compound is shown as a formula (I):
wherein X and Y are linking functional groups for linking the budesonide and the gemcitabine, the linking functional groups being selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Each independently selected from hydrogen, C 1-10 At least one of alkyl, hydroxy, amino, carboxyl, halogen,
R 9 and R is 10 Is an alkyl group having more than 1 carbon atom.
In some embodiments, the thioketal compound is selected from any one of the following:
in some embodiments, the nanodelivery system self-assembles in a hydrophilic medium to form nano-aggregates.
In some embodiments, the hydrophilic medium is at least one of water, physiological saline, PBS buffer.
In some embodiments, the critical aggregation concentration of the nano-delivery system is 0.2-0.5 μg/mL.
In some embodiments, the nano-delivery system has an average particle size of 100-120 nanometers.
In some embodiments, the inflammation-associated tumor is at least one of colorectal cancer associated with colitis, gastric cancer associated with chronic gastritis, liver cancer associated with chronic hepatitis.
In some embodiments, the nano-delivery system is an oral formulation or an injectable formulation.
The nano delivery system provided by the application consists of budesonide, gemcitabine and thioketal compounds, wherein the thioketal compounds are used as molecular bridges and simultaneously connected with budesonide He Jixi tabine, on one hand, the structure of the thioketal compounds is shown as a formula (I), and the nano delivery system has excellent Reactive Oxygen Species (ROS) response activity, so that the thioketal compounds can be hydrolyzed at focus positions to realize drug release; on the other hand, due to interaction of pi-pi accumulation, hydrogen bond, van der Waals and other acting forces in molecules, the nano delivery system can self-assemble in a hydrophilic medium to form nano aggregates with definite spherical shapes and uniform sizes, and compared with a traditional drug delivery system based on a carrier, the nano delivery system has ultrahigh drug loading capacity and ROS concentration-dependent drug release; in yet another aspect, budesonide can modulate the tumor immune microenvironment, restore and enhance the cytotoxicity of gemcitabine, and the nano-delivery system of the present application can achieve a maximized synergistic therapeutic effect by co-delivering budesonide He Jixi-capecitabine; in yet another aspect, the nano-delivery system of the present application can accumulate precisely in AOM/DSS induced CAC mouse diseased colon tissue by oral administration while releasing budesonide He Jixi tabine, and furthermore, the nano-delivery system of the present application can be internalized by colon cancer C26 cells and then triggered by intracellular excess ROS, releasing nearly 100% of the drug, based on which the nano-delivery system of the present application shows a stronger pro-apoptotic effect than free budesonide in combination with free gemcitabine.
Therefore, the application also provides application of the nano delivery system in preparing anti-colonitis related colorectal cancer drugs.
Drawings
FIG. 1 is a synthetic route for a nano-delivery system BAG;
FIG. 2-1 is a mass spectrum of a nano-delivery system BAG obtained by matrix assisted laser Desorption ionization time of flight mass spectrometry (MALDI-TOF-MS);
FIG. 2-2 shows hydrogen nuclear magnetic resonance spectrum of BAG of nano delivery system 1 H-NMR)；
FIGS. 2-3 are BAG chemical structures labeled with codes for hydrogen signals;
FIG. 3 shows the results of a test of the critical aggregation concentration (C.A.C) of BAG, wherein the ordinate is the scattered luminosity and the abscissa is the logarithm of the BAG concentration;
fig. 4 shows microscopic morphology and particle size distribution of BAG NA before and after incubation in hydrogen peroxide, wherein a and B are TEM images of BAG NA before and after incubation in hydrogen peroxide, C is the particle size distribution result of BAG NA before and after incubation in hydrogen peroxide, C is the abundance on the ordinate and the particle size on the abscissa;
FIG. 5 shows hydrolysis of BAG NA and BG/PLGA NP in different reactive oxygen species solutions, wherein the ordinate indicates hydrolysis rate and the abscissa indicates different ROS environments, wherein in each set of ROS environments, the left side corresponds to BAG NA and the right side corresponds to BG/PLGA NP;
FIG. 6 shows the drug loading test results of Bud and Gem in BAG NA and BG/PLGA NP, wherein the ordinate shows the drug loading rate, and each group of drugs corresponds to BAG NA on the left side and BG/PLGA NP on the right side;
FIG. 7 is ESI-MS data of BAG NA before and after incubation in hydrogen peroxide;
FIG. 8 is a Molecular Dynamics (MD) simulation of a BAG self-assembled system, in which pi-pi interactions are pi-pi interactions, N-H … O hydrogen bond formation between N-H and O, where N-H … O hydrogen bond is an amide, C-H … pi and N-H … pi interactions represent C-H interactions and N-H interactions with pi;
FIG. 9 shows the results of quantitative analysis of intracellular uptake behavior of BAG NA in C26 murine colon cancer cells, with fluorescence intensity on the ordinate and DiI/BAG NA concentration on the abscissa;
FIG. 10 shows intracellular drug release rates of C26 cells after 8 hours incubation with BAG NA and BG/PLGA NP, respectively, with the ordinate showing intracellular drug release rates;
fig. 11 shows the apoptosis statistics of C26 cells incubated with BAG NA, (Bud +gem) and (Gem), respectively, under the same conditions, with the ordinate representing the apoptosis rate, all data being expressed as mean ± SD (n=6), p <0.05, p <0.01, p <0.001;
fig. 12 shows accumulation of cy7.5/BAG NA, cy7.5/PLGA NP and cy7.5 in CAC mouse colon after oral administration, a is a representative ex vivo imaging graph, B is a quantitative analysis result, the ordinate of B is fluorescence signal of mouse isolated colon, all data are expressed as mean ± SD (n=6), and p <0.001.
Detailed Description
In the description of the present application, the compounds and derivatives thereof are named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, in golomb, ohio) naming system, and the specific reference to the compound groups are described and illustrated as follows:
"alkyl" refers to a class of saturated chain hydrocarbon radicals containing only two atoms, carbon and hydrogen, having straight and/or branched carbon chains, including but not limited to-CH 3 、-CH 2 -、-CH 2 CH 3 、-CH(CH 3 )-、-CH 2 CH 2 -、-CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 -、-CH(CH 3 ) 2 、-C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH(CH 3 ) 2 、-CH 2 C(CH 3 ) 2 -、-CH(CH 3 )CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 -、-CH 2 CH 2 CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 Etc. C (C) 1-10 Alkyl refers to an alkyl group having 1 to 10 carbon atoms, in particular embodiments, C 1-10 The number of carbon atoms of the alkyl group may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
"halogen" refers to elements of group VIIA of the periodic Table of elements, including elements such as chlorine (Cl), bromine (Br), iodine (I), and the like.
"hydroxy" refers to a group containing only two atoms, oxygen and hydrogen, of the formula-OH.
"amino" refers to a group containing only two atoms, nitrogen and hydrogen, of the formula-NH 2 。
"carboxyl" refers to a group containing only three atoms of carbon, oxygen, and hydrogen, and has the chemical formula-COOH.
"acyl halide" refers to a group containing three atoms of carbon, oxygen and chlorine, and has the chemical formula-COCl.
"isocyanate" refers to a group containing three atoms of carbon, nitrogen, and oxygen, and has the chemical formula-n=c=o.
The present application will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present application more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application.
The present application provides a nano-delivery system for inflammation-associated tumors, the nano-delivery system comprising: budesonide, gemcitabine and thioketals as molecular bridges simultaneously linking the budesonide and the gemcitabine,
the structure of the thioketal compound is shown as a formula (I):
wherein X and Y are linking functional groups for linking the budesonide and the gemcitabine, the linking functional groups being selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Each independently selected from hydrogen, C 1-10 At least one of alkyl, hydroxy, amino, carboxyl, halogen,
R 9 and R is 10 Is an alkyl group having more than 1 carbon atom.
Specifically, budesonide is an immunomodulatory drug that can reduce TAM recruitment by inhibiting MCP-1 and inflammation, reprogramming the tumor microenvironment, modulate the tumor immune microenvironment to restore the cytotoxicity of gemcitabine, thereby enhancing the pharmacodynamic effects with respect to CAC.
As CAC can lead to an inhibitory immune microenvironment, resulting in failure of the gemcitabine-induced anti-tumor immune response. The combined use of gemcitabine and budesonide can solve the problems encountered by the independent use of gemcitabine in the prior art and plays a role in synergistically improving the CAC treatment effect.
The gemcitabine and budesonide used in the examples of the present application are commercially available, and the sources thereof are not particularly limited in the examples of the present application.
In the embodiment of the application, the structure of the thioketal compound is shown as a formula (I):
wherein X and Y are linking functional groups for linking the budesonide and the gemcitabine, the linking functional groups being selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Each independently selected from hydrogen, C 1-10 At least one of alkyl, hydroxy, amino, carboxyl, halogen,
R 9 and R is 10 Is an alkyl group having more than 1 carbon atom.
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 The substituent groups on the fluorene ring can be flexibly adjusted according to the types of drug molecules in the nano delivery system to be constructed and the synthesis difficulty, preferably R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 Each independently selected from hydrogen,C 1-5 An alkyl group.
R 9 And R is 10 For the hydrophobic alkyl chain connected to the S atom, alkyl with the number of carbon atoms being more than 1 is selected, and the types of the hydrophobic alkyl chains can be flexibly adjusted according to the requirements of the nano delivery system to be constructed on hydrophilicity and hydrophobicity and the synthesis difficulty. In some embodiments, R 9 And R is 10 Is C 1-20 Alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. In other embodiments, R 9 And R is 10 Is C 1-10 Alkyl groups may have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
X and Y are used for connecting budesonide He Jixi tabine, and are respectively and independently selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate, and chemical connection with drug molecules is realized through the connecting functional groups.
The thioketal compound has fluorene ring, thioketal structure and active functional groups such as carboxyl, hydroxyl, amino and the like, and experiments prove that the thioketal compound has excellent Reactive Oxygen Species (ROS) response activity, can be used as ROS response unit, and can be hydrolyzed at focus positions to realize drug release. In addition, the thioketal compound cooperates with budesonide He Jixi tabine, and can induce and promote the self-assembly of the nano delivery system in a hydrophilic medium to form nano aggregates with definite spherical shapes and uniform sizes respectively through interaction of pi-pi accumulation, hydrogen bonds, van der Waals forces and the like in molecules, and the nano aggregates have ultrahigh drug loading capacity and ROS concentration-dependent drug release.
In some embodiments, the thioketal is selected from any one of the following:
the thioketal compounds are molecular bridges and are simultaneously connected with budesonide He Jixi tabine, and the nano delivery system can be induced and promoted to self-assemble in a hydrophilic medium to form nano aggregates with definite spherical shapes and uniform sizes respectively through interaction of pi-pi stacking, hydrogen bonds, van der Waals and other acting forces in molecules. In some embodiments, the hydrophilic medium is at least one of water, physiological saline, PBS buffer. In a specific embodiment, the hydrophilic medium is water, and the nano-delivery system of the embodiment of the application is dispersed in the water to form nano-aggregates.
In some embodiments, the critical aggregation concentration of the nano-delivery system is 0.2-0.5 μg/mL, which readily forms nanostructures in low concentration aqueous solutions and remains stable.
In some embodiments, the nano-delivery system has an average particle size of 100-120 nanometers.
In embodiments of the application, an inflammation-associated tumor refers to a disease that develops into a neoplastic condition due to a long-term chronic inflammatory disease. In some embodiments, the inflammation-associated tumor is at least one of colorectal cancer associated with colitis, gastric cancer associated with chronic gastritis, and liver cancer associated with chronic hepatitis. In one embodiment, the inflammation-associated tumor is colorectal cancer associated with colitis.
In embodiments of the present application, there are a variety of alternatives to the dosage forms that the provided nano-delivery system may form, including but not limited to oral formulations, injectable formulations, locally or systemically, that may be administered to a subject in need thereof via oral administration, intravenous injection, intravenous infusion, intraperitoneal injection, intramuscular injection, and/or subcutaneous injection. The drug delivery system can be expressed as a solid preparation or a liquid preparation, and is prepared into a corresponding solution preparation by adopting normal saline before use, and then is injected into a human body through oral administration or injection, so that the drug delivery system has good biocompatibility, is convenient to operate and is convenient for clinical use.
It will be appreciated that when the nano-delivery system of embodiments of the present application is formed into a particular dosage form, pharmaceutically acceptable excipients may be added, wherein the pharmaceutically acceptable excipients include, but are not limited to, pharmaceutically acceptable carriers, solvents, excipients, buffers, stabilizers, and the like. In some embodiments, the carrier is at least one of sugar, starch, cellulose and its derivatives, tragacanth powder, maltose, gelatin and talc. In some embodiments, the excipient is at least one of cocoa butter, suppository wax, oil, glycols, esters, and agar. In some embodiments, the buffer is selected from at least one of magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, and phosphate buffered saline.
In summary, the nano delivery system provided by the embodiment of the application consists of budesonide, gemcitabine and thioketal compounds, wherein the thioketal compounds are used as molecular bridges and simultaneously connected with budesonide He Jixi tarabine, on one hand, the structure of the thioketal compounds is shown as a formula (I), and the nano delivery system has excellent Reactive Oxygen Species (ROS) response activity, so that the thioketal compounds can be hydrolyzed at focus positions to realize drug release; on the other hand, due to interaction of pi-pi accumulation, hydrogen bond, van der Waals and other acting forces in molecules, the nano delivery system of the embodiment of the application can self-assemble in a hydrophilic medium to form nano aggregates with definite spherical shapes and uniform sizes, and compared with a traditional drug delivery system based on a carrier, the nano delivery system of the application has ultrahigh drug loading capacity and ROS concentration-dependent drug release; in yet another aspect, budesonide can modulate the tumor immune microenvironment, restore and enhance the cytotoxicity of gemcitabine, and the nano-delivery system of the present application can achieve a maximized synergistic therapeutic effect by co-delivering budesonide He Jixi-capecitabine; in yet another aspect, the nano-delivery system of the present application can be accurately accumulated in AOM/DSS induced CAC mouse lesion colon tissue by oral administration while releasing budesonide He Jixi tabine, and furthermore, the nano-delivery system of the present embodiment can be internalized by colon cancer C26 cells and then triggered by intracellular excess ROS, releasing nearly 100% of the drug, based on which the nano-delivery system of the present application shows a stronger pro-apoptotic effect than free budesonide in combination with free gemcitabine.
Therefore, the application also provides application of the nano delivery system in preparing the anti-colonitis related colorectal cancer medicament, which is beneficial to promoting development of the anti-colonitis related colorectal cancer medicament.
In order to make the implementation details and operation of the present application clearly understood by those skilled in the art, and the advanced performance of the nano-delivery system for inflammation-related tumor and the application thereof provided by the embodiments of the present application are remarkably shown, the technical scheme of the present application is specifically described below by taking the thioketal compound selected as an ATK as an example.
The thioketal compounds were selected from the following compounds, named Aromatized thioketal in english, denoted ATK:budesonide (Budesonide) is denoted Bud, gemcitabine (Gemcitabine) is denoted Gem, whereby the nano-delivery system is denoted Bud-ATK-Gem, abbreviated as BAG;
in addition, in the reagent consumable used in the examples, dicyclohexylcarbodiimide was represented as DCC, 4-dimethylaminopyridine was represented as DMAP, and dichloromethane was represented as DCM.
Example 1
The nano-delivery system BAG is prepared in the embodiment, the synthetic route of the BAG is shown in fig. 1, and the preparation method comprises the following steps:
s11, dissolving 1mmol Bud,0.2mmol DMAP,1mmol ATK in anhydrous DCM under the nitrogen atmosphere to obtain a first mixed solution; then, a solution of DCM (5 mL) containing 2mmol DCC was slowly dropped into the first mixed solution under ice-bath condition, after 48 hours of reaction, the filtrate was obtained by filtration, after which the filtrate was poured into cold anhydrous diethyl ether, and the precipitate was dried in vacuo to obtain B-ATK in 72.3% yield;
s12, dissolving 0.5mmol Gem, 0.1mmol DMAP and 0.5mmol B-ATK in anhydrous DCM under nitrogen atmosphere to obtain a second mixed solution; then, a solution of DCM (5 mL) containing 1mmol DCC was slowly dropped into the second mixed solution under ice-bath condition, and after 48 hours of reaction, the filtrate was filtered, and then the filtrate was poured into cold anhydrous diethyl ether, and the precipitate was dried in vacuo to obtain the final product BAG in 65.2% yield.
In use, the BAG is dispersed in water to form an aqueous BAG nanoparticle (BAG NP) suspension.
Comparative example 1
In this comparative example, bud and Gem were coated with polylactic acid-glycolic acid copolymer (PLGA) and PEG to prepare a BG/PLGA nanoparticle (BG/PLGA NP).
Test example 1
1. BAG prepared in example 1 was tested for molecular weight and, respectively 1 H-NMR, FIG. 2-1 shows BAG ([ M+H)] + m/z, found: 1061.382, found to have a value of 1061.157) of formula C 55 H 63 F 2 N 3 O 12 S 2 . FIG. 2-2 shows the same 1 H-NMR spectra, 1, 2, 3, 4, 5, 6, 7, a, b, c, d, e, a ', b', c ', d', e ', f' correspond to different hydrogen signals, facilitating hydrogen signal identification, and FIGS. 2-3 are BAG chemical structures labeled with the codes of hydrogen signals. The results of FIGS. 2-1 through 2-3 demonstrate that example 1 does produce BAG.
2. The BAG prepared in example 1 was tested for critical aggregation concentration (c.a.c) by Dynamic Light Scattering (DLS), c.a.c being key data characterizing nanoparticle formation, and fig. 3 being the test results.
As shown, at lower concentrations, no significant change in scattered light intensity was observed in the aqueous suspension of BAG. Notably, the intensity of the detected scattered light increases abruptly when c.a. c is reached or exceeded. BAG NA obtained from the intersection of the best fit lines plotted for the data points was approximately 0.34 μg/mL in aqueous solution. The lower c.a.c means that BAG is prone to nanostructure formation. In other words, BAG NA remains stable even when diluted with large amounts of aqueous solution.
3. BAG NA is respectively dispersed in hydrogen peroxide (1 mmol/L, H) 2 O 2 ) The microscopic morphology of the BAG NA before and after incubation in hydrogen peroxide was observed by a Transmission Electron Microscope (TEM) for 12 hours, and the particle size distribution of the BAG NA before and after incubation in hydrogen peroxide was tested, and the test results are shown in FIG. 4.
As shown in the figure, the BAG NA has a definite spherical shape before incubation in hydrogen peroxide, the particle size distribution of the BAG NA is 100-120nm, the BAG NA disintegrates into particles of about 20nm after incubation in hydrogen peroxide, and the morphology becomes irregular, which indicates that the BAG NA provided by the application has an obvious active oxygen responsive hydrolysis capability.
4. Detection of BAG NA and BG/PLGA NP in superoxide anion (O) 2 - ) Hydroxyl radical (OH), hypochlorite (OCl) - ) Nitrite peroxide (ONOO) - ) And hydrogen peroxide (H) 2 O 2 ) The hydrolysis in different ROS environments is compared with PBS buffer (pH 7.4), and FIG. 5 shows the detection result, wherein the BG/PLGA NP has low hydrolysis degree, but BAG NA is obviously hydrolyzed in different active oxygen solutions, wherein, H 2 O 2 Group and OH group can hydrolyze BAG NA almost 100%, indicating that BAG NA has obvious active oxygen responsive hydrolysis ability.
5. The Drug Loading (DLC) of Bud and Gem in BAG NA and BG/PLGA NP was examined, and FIG. 6 shows the examination result, as shown in the result, when DLC of two drugs in BG/PLGA NP was not more than 5%, BAG NA had significantly higher DLC (Bud: 40.13%, gem: 24.22%), indicating that BAG NA had high drug loading.
6. FIG. 7 is ESI-MS data of BAG NA before and after incubation in Hydrogen peroxide, showing the presence of gamma-butyrolactone ([ M+H)] + m/z, found: 103.521, calculated: 103.014 9-fluorenone ([ M+H)] + m/z, found: 181.165, calculated: 181.058; [ M+Na ]] + m/z, found: 203.263, calculated: 203.058 Precious stone ([ M+H)] + m/z, calculated: 264.455, calculated: 264.198; [ M+Na ]] + m/z, found value: 286.324, calculated: 286.455 And Bud ([ M+H)] + m/z, found value: 431.335, calculated: 431.236). From this, it can be deduced that the ROS response of BAG hydrolyzes: upon exposure to ROS, thioketals are destroyed, forming 9-fluorenones, thiolated buds, and thiolated Gem; subsequently, thiolation Gem or thiolation Bud involves an intramolecular thioester reaction in which one of the molecules gamma-thiolactone is removed and the proto-drug Gem is released, indicating that BAG NP is capable of triggering H 2 O 2 The drug is released without loss, with typical ROS-responsive hydrolysis and drug release characteristics.
Test example 2
The self-assembly behavior of the BAG NA was simulated using the GROMACS program with all-atomic Molecular Dynamics (MD), and the results are shown in fig. 8.
Referring to a in fig. 8, 40 BAG molecules are randomly filled in a lengthIs a cube box; a snapshot of the aggregate was selected from the simulation kinetics to describe the stacking of BAG in the aggregated state.
Referring to B in fig. 8, in the initial state, all molecules are randomly dissociated, and the simulation results in aggregation of the prodrug into a compact structure. During the simulation, non-covalent interactions, including pi-pi stacking, hydrogen bonding, and van der Waals interactions, are driving forces for assembly, which dominate the self-assembly of the BAG and may stabilize the entire nanosystem.
Test example 3
1. DiI was used to label BAG NA to form DiI/BAG NA, C26 cells were incubated with DiI/BAG NA for 2h, and FIG. 9 shows the results of quantitative analysis of intracellular uptake behavior of BAG NA in C26 murine colon cancer cells, as shown by the results, uptake behavior of BAG NA by C26 cells was generally concentration dependent.
2. C26 cells were incubated with BAG NA and BG/PLGA NP for 8 hours, respectively, and drug release was observed in C26 murine colon cancer cells, as shown in fig. 10, BAG NA released Bud and Gem completely in C26 cells, while BG/PLGA NP released less drug (Bud 32.7.7%, gem 13.6%).
3. The apoptotic cells were determined by staining with annexin V and 7AAD by incubating C26 cells with 100 μg/mL BAG NA, equivalent (Bud +gem) and equivalent (Gem), respectively, for 24 hours, and counting the apoptosis results of C26 murine colon cancer cells, as shown in fig. 11, gem group showed a certain ability to promote apoptosis (apoptosis rate 29.2%); free Gem combined with free Bud further promoted apoptosis of C26 cells, suggesting Bud may promote apoptosis in concert with Gem; the apoptosis rate by BAG NA increased by 12% compared to Bud +gem group, presumably because the typical nanoparticle nature of BAG NA ensures high uptake and long retention of BAG NA in C26 cells, unlike free drug entry into cells by free diffusion, and furthermore, sufficient drug release also ensures drug availability.
Taken together with the results of FIGS. 9-11 above, BAG NA is shown to have excellent cell uptake behavior, intracellular drug release profile and greater ability to promote apoptosis of tumor cells.
Test example 4
AOM/DSS induced CAC mice were selected, cy7.5 labeled BAG NA (cy 7.5/BAG NA) was used as the experimental sample, cy7.5 labeled PLGA NA (cy 7.5/PLGA NP) and free cy7.5 were used as the control samples, the experimental sample and the control samples were orally administered to the mice, respectively, and after 4 hours, ex vivo imaging was performed to observe the accumulation of the samples in the colon of the CAC mice.
As shown in fig. 12, the isolated colon of mice dosed with experimental sample cy7.5/BAG NA had a significantly higher fluorescence signal (fig. 12-a) than mice dosed with control sample orally, and the fluorescence signal of cy7.5/BAG NA group was very different from cy7.5/PLGA NP and cy7.5, p <0.001 (fig. 12-B), indicating that the nano-delivery system of the present application can accurately accumulate in AOM/DSS induced CAC mice diseased colon tissue by oral dosing.
The foregoing description of the preferred embodiments of the application is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the application.
Claims (8)
1. Use of a nano-delivery system for inflammation-associated tumors in the preparation of a medicament for treating colorectal cancer associated with colitis, the nano-delivery system comprising: budesonide, gemcitabine and thioketals as molecular bridges simultaneously linking the budesonide and the gemcitabine,
the structure of the thioketal compound is shown as a formula (I):
wherein X and Y are linking functional groups for linking the budesonide and the gemcitabine, the linking functional groups being selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Each independently selected from hydrogen, C 1-10 At least one of alkyl, hydroxy, amino, carboxyl, halogen,
R 9 and R is 10 Is an alkyl group having more than 1 carbon atom.
2. The use according to claim 1, wherein the thioketal is selected from any one of the following:
3. the use of claim 1, wherein the nano-delivery system self-assembles in a hydrophilic medium to form nano-aggregates.
4. The use according to claim 3, wherein the hydrophilic medium is at least one of water, physiological saline, PBS buffer.
5. The use according to claim 3, wherein the critical aggregation concentration of the nano-delivery system is 0.2-0.5 μg/mL.
6. The use according to any one of claims 1 to 5, wherein the nano-delivery system has an average particle size of 100-120 nm.
7. The use according to any one of claims 1 to 5, wherein the inflammation-associated tumor is at least one of colorectal cancer associated with colitis, gastric cancer associated with chronic gastritis, liver cancer associated with chronic hepatitis.
8. The use according to any one of claims 1 to 5, wherein the nano-delivery system is an oral formulation or an injectable formulation.
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