CN114231042B - Graft copolymer, medicine-carrying assembly thereof and preparation method - Google Patents

Graft copolymer, medicine-carrying assembly thereof and preparation method Download PDF

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CN114231042B
CN114231042B CN202111554431.9A CN202111554431A CN114231042B CN 114231042 B CN114231042 B CN 114231042B CN 202111554431 A CN202111554431 A CN 202111554431A CN 114231042 B CN114231042 B CN 114231042B
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polytetrahydrofuran
propylene glycol
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glycol alginate
graft copolymer
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CN114231042A (en
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吴一弦
高玉壮
陈俊材
崔哲
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Beijing University of Chemical Technology
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Abstract

The invention belongs to the field of biomedical materials, and relates to a graft copolymer, a medicine-carrying assembly and a preparation method thereof. The copolymer takes hydrophilic propylene glycol alginate as a main chain and hydrophobic polytetrahydrofuran as a branched chain. The graft copolymer has a hydrophilic acylated propylene glycol alginate main chain and a hydrophobic polytetrahydrofuran branched chain, has good self-assembly capability, can form a nano-scale drug-loaded assembly, has biocompatibility, pH sensitivity and targeted drug release behavior, and can remarkably improve the drug effect.

Description

Graft copolymer, medicine-carrying assembly thereof and preparation method
Technical Field
The invention belongs to the field of biomedical materials, and relates to a graft copolymer, a medicine-carrying assembly thereof and a preparation method thereof, in particular to an acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer, an acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer medicine-carrying assembly and a preparation method thereof.
Background
The drug carrier plays an important role in the safe and low-toxicity transportation of the drugs in vivo. Some insoluble drugs, biodegradable drugs, drugs with very low bioavailability and drugs with high toxicity to biological systems (such as anticancer drugs) are delivered through drug carriers, the drugs are coated and safely delivered into target cells, the drugs are protected from being cleared by phagocytes or prematurely degraded, the drug release is regulated, the drug stability is improved, the toxic effect of the drugs on tissues or organs in vivo is reduced, but the treatment effect of the anticancer drugs can also be reduced. See: journal of Drug Delivery Science and Technology,2008,18: 59-68; journal of Controlled Release,2017,253: 97-109. The size of the drug carrier is a key factor for cellular uptake, and only the nanoscale drug carrier is suitable for cellular uptake. For nano-scale polymer-based drug carriers, the killing capacity for cancer cells is increased due to their enhanced permeability and retention effects. See: ACS Nano,2015,9: 8655-8671; expert opinion on biological therapy,2005,5: 1557-; journal of intellectual organics, 2005,8: 77-84. The physiological pH values of normal parts and pathological parts in vivo are different, so that the pH-responsive drug delivery and targeted drug release behaviors have important significance. See: international Journal of pharmaceuticals, 2018,535: 253-260; drug Discovery Today,2002,7: 569-.
The natural polysaccharide has biocompatibility, biological tolerance, biodegradability and unique biological activity, such as chitosan, sodium alginate, pectin, glucan, starch and the like are one of the preferable materials for preparing the drug carrier, the natural polysaccharide containing rich functional groups (such as hydroxyl, amino and carboxyl) can provide a simple particle form and a carrier structure which is easy to adjust when the drug carrier is prepared, and the low immunogenicity and the low toxicity of the natural polysaccharide also provide advantages for the development of the drug carrier. In recent years, polysaccharide-based preparation of drug carriers such as microspheres, gels, micelles, vesicles, liposomes, fibers and emulsions has the behaviors of pH response, photoresponse, microwave response, enzyme response, magnetic field response, ultrasonic response, electric field response or redox response and the like, and drug controlled release and drug sustained release are realized. See: polymers,2021,13: 3342; materials Science and Engineering C,2016,68: 964-981; current medical Chemistry,2012,19: 3212-3229; progress in Polymer Science,2019,99: 101164; w Journal of Functional Biomaterials,2019,10: 34. However, since the solubility of polysaccharide is limited by the existence of a large number of hydrogen bonds between molecules, encapsulation of hydrophobic drugs is difficult to achieve by conventional means, and hydrophobic modification such as introduction of C is required 8 、C 12 、C 16 The alkane groups are used for preparing amphiphilic polysaccharide derivatives for drug carriers. See: polymer,2000,41: 899-906; international Journal of Biological Macromolecules,2013,57: 92-98.
Sodium alginate is polyanionic polysaccharide derived from sea, has good biocompatibility, biodegradability and easy gelling property, and has wide application in the fields of biomedical science and engineering. The propylene glycol alginate is a hydrophilic polysaccharide derivative prepared by esterification reaction of sodium alginate and propylene oxide under an acidic condition, and the esterification degree is about 50-85%.
The performance of the sodium alginate can be improved by grafting modification of the sodium alginate. Sodium alginate graft copolymers are largely classified into water-soluble graft copolymers and amphiphilic graft copolymers according to the difference in solubility of the branched chains. The water-soluble sodium alginate graft copolymer mainly comprises a sodium alginate-g-polyacrylamide graft copolymer, a sodium alginate-g-poly (N-isopropylacrylamide) graft copolymer and a sodium alginate-g-polyethylene glycol graft copolymer, the water-soluble sodium alginate graft copolymer can only coat the drug by means of blending, adsorption, adhesion and the like with the drug, and the effects of controllable drug delivery with pH response and targeted drug controlled release are difficult to achieve. See: journal of Biomaterials Science 2010,21: 1799-1814; current World Environment Journal,2014,9: 109-; ACS Applied Materials & Interfaces,2017,9: 35673-; carbohydrate Polymers,2017,175: 337-346. The problems of hydrophobicity, mechanical strength, burst release of drugs and the like of the sodium alginate can be solved by introducing a hydrophobic part (such as an alkyl chain and a hydrophobic polymer chain) into an alginate main chain to synthesize an amphiphilic sodium alginate derivative and forming particles, emulsion, gel and the like through self-assembly. See: progress in Polymer Science,2012,37: 106-; bioprocess and Biosystems Engineering,2010,33: 457-; progress in Polymer Science,2018,76: 151-. The amphiphilic sodium alginate graft copolymer mainly comprises: sodium alginate-g-polymethyl methacrylate synthesized by the method of 'grating from', acylated sodium alginate-g-polytetrahydrofuran and acylated sodium alginate-g-polyisobutene synthesized by the method of 'grating onto'. The amphiphilic graft copolymer of acylated sodium alginate-g-polytetrahydrofuran, namely Polytetrahydrofuran (PTHF), or polytetramethylene ether glycol (PTMG) or polytetramethylene oxide (PTMO), has excellent biological inertia, biocompatibility, wet strength, flexibility, antibacterial property and hydrolytic stability, has an obvious microphase separation structure, self-assembly capability, limited crystallization behavior and enhanced protein absorption resistance, can encapsulate drug-loaded microspheres formed by Ibuprofen (IBU) and has pH-responsive drug-release behavior, but can only form micron-sized drug-loaded microspheres. See: CN 104419008A; biomacromolecules,2015,16: 2040-; applied Surface Science,2019,483: 1027-1036; carbohydrate Polymers, 2019, 219: 201-209.
To date, there has been no published report on a graft copolymer involving propylene glycol alginate as a backbone and its use.
Disclosure of Invention
The invention aims to provide an acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer and a medicine-carrying composite body thereof.
In order to achieve the above object, a first aspect of the present invention provides an acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer having propylene glycol alginate as a main chain and polytetrahydrofuran as a branch chain. Polytetrahydrofuran is also known as polytetramethylene ether glycol or polytetramethylene oxide. The acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer is an amphiphilic copolymer, wherein the propylene glycol alginate as a main chain is hydrophilic, and the polytetrahydrofuran as a branched chain is hydrophobic.
The molecular weight and the grafting density of the branched polytetrahydrofuran graft can be regulated, the molecular weight of the branched chain is preferably 300-6000 g/mol, more preferably 500-4000 g/mol, and the grafting density is the average number of branched polytetrahydrofuran branches grafted on every 1000 alginic acid monosaccharides, preferably 2-35/1000 alginic acid monosaccharides, and more preferably 3-27/1000 alginic acid monosaccharides.
According to the invention, the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer is prepared by nucleophilic substitution reaction of a polytetrahydrofuran active chain obtained by ring-opening polymerization of tetrahydrofuran and a hydroxyl group on propylene glycol alginate.
According to a specific embodiment of the present invention, the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer is prepared by a method comprising the following steps:
(1) synthesis of acylated propylene glycol alginate
Putting propylene glycol alginate in a first organic solvent, adding a second organic solvent at a low temperature (preferably-10 to-5 ℃), slowly adding decanoyl chloride, reacting under stirring, precipitating a reaction system in methanol and/or ethanol, repeatedly washing with methanol and/or ethanol for many times to remove excessive decanoyl chloride and the first organic solvent, then adding the second organic solvent into a solid product, removing the solvent from a supernatant, and carrying out vacuum drying on the obtained Acylated Propylene Glycol Alginate (APGA) solid product;
(2) synthesis of polytetrahydrofuran active chain
Adding certain amount of initiator and co-initiator into pre-cooled tetrahydrofuran or its mixed solution with third organic solvent under nitrogen atmosphere, and bulk polymerizing or solution polymerizing the above system under stirring to obtain polytetrahydrofuran active chain PTHF with certain molecular weight + Mixed solution of/tetrahydrofuran or PTHF + A mixed solution of tetrahydrofuran/a third organic solvent;
(3) synthesis of acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer
Will contain PTHF + PTHF of living chains + Tetrahydrofuran mixed solution or PTHF + Mixing the mixed solution of tetrahydrofuran and the third organic solvent with the mixed solution of APGA and the fourth organic solvent, reacting, and reactingPurifying and separating the reaction system to obtain the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer (APGA-g-PTHF).
More specifically, in step (1), the first organic solvent is preferably triethylamine and/or pyridine, and the second organic solvent is preferably at least one of dichloromethane, chloroform and dichloroethane.
More specifically, in the step (2), the initiator is preferably at least one of allyl bromide, allyl chloride, benzyl bromide and benzyl chloride, the co-initiator is preferably silver perchlorate, the third organic solvent is preferably at least one of dichloromethane, trichloromethane and dichloroethane, and the reaction temperature is-4 ℃ to 4 ℃.
More specifically, in the step (3), the fourth organic solvent is preferably at least one of dichloromethane, trichloromethane, dichloroethane and tetrahydrofuran.
According to a more specific embodiment of the present invention, the synthesis method is as follows:
(1) synthesis of acylated propylene glycol alginate
Placing 5.0g of propylene glycol alginate in a certain amount of triethylamine or pyridine for 2h, adding 50mL of dichloromethane at the temperature of-10 to-5 ℃, slowly dripping 17.8mL of decanoyl chloride in the 2h, reacting for 5h under magnetic stirring, precipitating a reaction system by using a large amount of methanol or ethanol, repeatedly washing for many times, removing excessive decanoyl chloride and triethylamine or pyridine, then adding 80mL of dichloromethane into solid residue, and storing supernatant. After the solvent is removed, the obtained solid is put at 60 ℃ for vacuum drying for 24h to obtain an Acylated Propylene Glycol Alginate (APGA) product;
(2) synthesis of polytetrahydrofuran active chain
Under the atmosphere of nitrogen, adding a certain amount of initiator allyl bromide and coinitiator silver perchlorate into a pre-cooled mixed solvent of tetrahydrofuran and dichloromethane, and stirring the system at 0 ℃ for reacting for 4 hours to obtain polytetrahydrofuran active chain PTHF with a certain molecular weight + The molecular weight of the synthesized polytetrahydrofuran active chain can be adjusted by regulating the concentration of an initiator and/or the polymerization conversion rate of the tetrahydrofuran or can be adjusted by regulating the concentration of the initiator and/or the polymerization conversion rate of the tetrahydrofuranThe theoretical molecular weight was predicted by referring to the inventor's previous research results (Chinese Journal of Polymer Science, 2015, 33:23-35) and the derivation formula;
(3) synthesis of acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer
Subjecting a volume of PTHF + And further mixing the mixed solution of the active chain/tetrahydrofuran/dichloromethane and the mixed solution of APGA/dichloromethane, reacting for 3.5h, and then purifying the reaction system to obtain the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer (APGA-g-PTHF).
In the present invention, the graft density of the copolymer can be adjusted by the ratio of the polytetrahydrofuran active chain to the propylene glycol alginate, and the higher the ratio, the higher the graft density.
The molecular weight of the polytetrahydrofuran branch chain can be regulated and controlled according to the concentration or the using amount of the initiator and the polymerization conversion rate of the monomer. If low molecular weight polytetrahydrofuran needs to be synthesized, high initiator concentration is needed; if it is desired to synthesize high molecular weight polytetrahydrofuran, a low initiator concentration is required. Preferably, the concentration of the initiator is 0.6-25.0 mmol/L, and the polymerization conversion rate of the monomer tetrahydrofuran is 4-40%.
The graft copolymer has a hydrophilic acylated propylene glycol alginate main chain and a hydrophobic polytetrahydrofuran branched chain, has good self-assembly capability, and can form nanospheres with uniform sizes in a water/organic solvent system. The organic solvent is preferably at least one of dichloromethane, trichloromethane and dichloroethane, and more preferably dichloromethane or trichloromethane.
The invention provides an acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer medicine-carrying assembly, which comprises the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer and a medicine as carriers.
In the present invention, the term "drug-carrying composition" refers to a substance comprising a polymeric carrier and a drug.
The classes of drugs include, but are not limited to: ibuprofen (IBU), Curcumin (CUR), Paclitaxel (PTX), Doxorubicin (DOX), Camptothecin (CPT) and the like, and the drug loading rate is between 1% and 52%, preferably between 4% and 49%. The size of the drug loading rate can be adjusted by the amount of the added drug, and when the amount of the added drug is small, the drug loading rate is low; when the medicine is added in a large amount, the medicine carrying rate is high, but reaches a limit value after a certain dosage is exceeded.
The third aspect of the invention provides a preparation method of the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer drug-loaded assembly, wherein the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer drug-loaded assembly is prepared by forming O/W emulsion, and drug-loaded nanospheres with uniform size distribution are formed. The size of the nanospheres is preferably below 250 nm.
The method comprises the following specific steps:
(1) the graft copolymer is co-dissolved with the drug
20mg of acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer and 40mg of drug were dissolved in 10mL of dichloromethane at 25 ℃.
(2) Preparation of drug-loaded compositions by oil-in-water (O/W) emulsions
Slowly dripping the solution into 50mL of deionized water under stirring to form a uniform and stable emulsification system, removing the solvent, cleaning the drug residue with ethanol to remove the unloaded drug to obtain a drug-loaded composite body, completely drying, weighing and calculating the drug loading rate.
(3) Characterization of drug-loaded combinations
And (3) dispersing a part of the drug-loaded composite body in deionized water, dripping the deionized water on a silicon wafer, drying, spraying gold, and observing the shape of the drug-loaded composite body under a scanning electron microscope.
The outstanding effects obtained by the invention are as follows:
(1) the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer has excellent biocompatibility and very low cytotoxicity.
(2) The acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer has excellent self-assembly capability in organic solvent/water, can entrap nano-scale medicament-carrying composite bodies (less than or equal to 250nm) formed by medicaments, and can be used for entrapping a plurality of medicaments such as Ibuprofen (IBU), Curcumin (CUR), Paclitaxel (PTX), Doxorubicin (DOX), Camptothecin (CPT) and the like. The size of the drug loading rate can be adjusted by the amount of the added drug, and when the amount of the added drug is small, the drug loading rate is low; when the medicine is added in a large amount, the medicine carrying rate is high, but reaches a limit value after a certain dosage is exceeded. For APGA-g-PTHF/CUR and APGA-g-PTHF/IBU, nanospheres with sizes of 115-153 nm (134 +/-19 nm) and 173-233 nm (203 +/-30 nm) can be formed, and the drug loading rate is 1-50%, preferably 4-47%.
(3) The drug-loaded composite nanosphere formed by the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer has pH-sensitive drug release behavior, the drug release rate is fastest when IBU is released at pH 7.4, 100% of drug release can be achieved within 24h, and 94% of accumulated drug release rate can be achieved within 32h when the drug release pH of CUR is 5.5.
(4) The acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer drug-loaded composite nanosphere has a high-efficiency anticancer effect, and can remarkably improve the anticancer effect of the CUR. Pure CUR showed anticancer capacity at relatively high concentration (200 μ g/mL), but due to its very low bioavailability, killing efficiency on HeLa cells was low, with only a small amount of pure CUR entering HeLa cells (weak green fluorescence). Significantly, for the APGA-g-PTHF/CUR nanosphere, when the concentration of the CUR is only 20 mug/mL, the anticancer effect can reach the anticancer effect close to that of pure CUR with the concentration of 200 mug/mL, and the result of a dye experiment on HeLa cells by Hoechst 33342/PI shows that a large amount of CUR in the APGA-g-PTHF/CUR nanosphere enters the HeLa cells (strong green fluorescence), so that the anticancer effect is remarkably enhanced.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent by describing in more detail exemplary embodiments thereof with reference to the attached drawings.
FIG. 1 shows APGA-g obtained in example 1 3 -PTHF 600 TEM photograph of the graft copolymer.
FIG. 2 is an SEM photograph of the APGA-g-PTHF/IBU drug Nanocarrier assembly prepared in example 4.
Figure 3 shows the drug release behaviour of the APGA-g-PTHF/IBU drug-loaded combination at different pH's in test example 2.
FIG. 4 shows fluorescence imaging of HeLa cells co-cultured with APGA-g-PTHF/CUR drug-loaded complex in test example 3.
FIG. 5 shows the comparison of the anticancer effects of APGA-g-PTHF/CUR nano drug-loaded complex and ASA-g-PTHF/CUR micro drug-loaded complex on HeLa cells in test example 3.
FIG. 6 is an SEM photograph of the APGA-g-PTHF/CUR drug Nanoapparatus prepared in comparative example 2.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
Characterization of the graft copolymer:
the chemical structure of the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer is measured by a Nicolet 6700 Fourier infrared transform spectroscopy (FTIR) instrument, and the measuring range is 4000-400 cm -1 (ii) a Characterizing the chemical structure of the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer by a Bruker NMR AVANCE III nuclear magnetic instrument (400 MHz); microscopic morphology of the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer dyed by ruthenium tetroxide was observed on a Hitachi HT-7700 Transmission Electron Microscope (TEM) at an acceleration voltage of 100 kV.
Cytotoxicity test:
HeLa cells at 37 ℃ with 5% CO 2 And 95% relative humidity, adding 10% fetal bovine serum, 1% penicillin and streptomycin Dulbecco's Modified Eagle's Medium (DMEM) in culture. The HeLa cells of 3 groups were inoculated in sterile 96-well plates, and 100. mu.L of complete DMEM medium was added to each well at a density of 5X 10 3 Culturing for 24 hr, and replacing culture medium with culture mediumFresh medium with different concentrations of graft copolymer samples and cells were cultured for an additional 24h, the medium was replaced with 90. mu.L of complete DMEM and 10. mu.L of CCK-8 solution, and after 1h of culture, the cell viability was calculated by measuring the absorbance at 450nm of each well using a microplate reader (Thermo scientific, MULTISCAN MNK 3).
Measurement of the size of the drug-loaded composite:
the size of the drug-loaded composite was observed with a JEOL JSM-7500F scanning electron microscope at an accelerating voltage of 5 kV.
Characterization of drug release of drug-loaded combinations:
the Hitachi U-3010 ultraviolet-visible spectrophotometer is adopted to measure the concentration of the released medicine and calculate the cumulative medicine release rate.
The curative effect of the medicine-carrying combination body is characterized in that:
treating cells by adopting a CCK-8 kit, measuring the absorbance of a CCK-8 reagent by using a Multiscan MK3 enzyme labeling instrument of Thermo Fisher Scientific, and calculating the survival rate of the cells; the effect of cell uptake of CUR was observed using AMG-EVOSf1 fluorescence microscopy.
Example 1
3 600 Acylated propylene glycol alginate-g-polytetrahydrofuranPreparation of graft copolymers
At 25 ℃, 5.0g of PGA is placed in 17.4mL of triethylamine, 30mL of dichloromethane is added, the temperature of the system is adjusted to-10 to-5 ℃, then 17.8mL of decanoyl chloride is slowly added, after stirring and reacting for 5 hours, 500mL of ethanol is added, washing is carried out for multiple times, and redundant triethylamine and decanoyl chloride are removed; subsequently, 100mL of dichloromethane was added to the remaining solid to dissolve the soluble fraction, filtered to obtain a soluble supernatant, and the solvent was removed to obtain Acylated Propylene Glycol Alginate (APGA).
Adding 67 mu L of allyl bromide and 200mg of silver perchlorate into a mixed solution of tetrahydrofuran (30mL) and dichloromethane (32mL) at the temperature of 0 ℃ under a nitrogen atmosphere, wherein the concentration of an initiator is 12.3mmol/L, and reacting for 4 hours under stirring to obtain tetrahydrofuran/dichloro-silver containing a polytetrahydrofuran active chainA methane mixed solution; dissolving 0.5g of acylated propylene glycol alginate in 20mL of dichloromethane; mixing the tetrahydrofuran/dichloromethane mixed solution containing the polytetrahydrofuran active chain with the acylated propylene glycol alginate/dichloromethane solution, stirring for reaction for 3.5h, and dialyzing and purifying the obtained reaction system to obtain the APGA-g-PTHF graft copolymer, wherein: the branched polytetrahydrofuran has a number average molecular weight of 600g/mol and a grafting density of 3 polytetrahydrofuran branches per 1000 alginic acid monosaccharides. The graft copolymer is noted: APGA-g 3 -PTHF 600 . A TEM photograph of the graft copolymer is shown in FIG. 1.
Example 2
23 3400 Acylated propylene glycol alginate-g-polytetrahydrofuranPreparation of graft copolymers
The preparation of Acylated Propylene Glycol Alginate (APGA) is the same as in example 1.
Under the atmosphere of nitrogen and at the temperature of 0 ℃, 6.7 mu L of allyl bromide and 20mg of silver perchlorate are added into a mixed solution of 30mL of THF and 32mL of dichloromethane, the concentration of an initiator is 1.2mmol/L, and a polymerization reaction is carried out for 4 hours to obtain a tetrahydrofuran/dichloromethane mixed solution containing a polytetrahydrofuran active chain; dissolving 0.5g of acylated propylene glycol alginate in 20mL of dichloromethane; and mixing the polytetrahydrofuran active chain solution with the dichloromethane solution of the acylated propylene glycol alginate, and stirring for reaction for 4 hours. Purification work-up the APGA-g-PTHF graft copolymer obtained in the same manner as in example 1 was obtained, in which: the number average molecular weight of the branched polytetrahydrofuran is 3400g/mol, and the grafting density is that 23 polytetrahydrofuran branched chains are grafted on every 1000 alginic acid monosaccharides. The graft copolymer is noted: APGA-g 23 -PTHF 3400 。
Example 3
15 1800 Preparation of acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer
The preparation of Acylated Propylene Glycol Alginate (APGA) is the same as in example 1.
At 0 deg.C under nitrogen atmosphereAdding 20 mu L of allyl bromide and 60mg of silver perchlorate into a mixed solution of tetrahydrofuran (30mL) and dichloromethane (32mL), wherein the concentration of an initiator is 3.7mmol/L, and carrying out polymerization reaction for 4 h; 0.5g of acylated propylene glycol alginate was dissolved in 20mL of dichloromethane; and mixing the polytetrahydrofuran-containing active chain mixed solution with the acylated propylene glycol alginate/dichloromethane solution, and stirring for reaction for 3.5 hours. Purification separation work-up procedure as in example 1 gave APGA-g-PTHF graft copolymer in which: the branched polytetrahydrofuran has a number average molecular weight of 1800g/mol and a grafting density of 15 polytetrahydrofuran branches per 1000 alginic acid monosaccharides. The graft copolymer is noted: APGA-g 15 -PTHF 1800 。
Example 4
Preparation of acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer drug-carrying composite nanospheres
Acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer drug-loaded composite nanospheres were prepared by forming an O/W emulsion. The specific method comprises the following steps: 20mg of the graft copolymer APGA-g were added at 25 deg.C 15 -PTHF 1.8k And 40mg of Ibuprofen (IBU) or Curcumin (CUR) as a drug were dissolved in 10mL of methylene chloride, the solution was slowly added to 50mL of deionized water with stirring to form a uniform and stable emulsion system, after removal of the solvent, the drug residue was washed with ethanol to remove the drug-free drug, a portion of the drug-loaded composite was placed on a silicon wafer and then observed with a scanning electron microscope, as shown in FIG. 2. The scanning electron microscope results show that: APGA-g 15 -PTHF 1.8k IBU drug Carrier and APGA-g 15 -PTHF 1.8k the/CUR drug carrier has nanospheres with uniform size distribution, and the diameters of the nanospheres are respectively 173-233 nm (203 +/-30 nm) and 115-153 nm (134 +/-19 nm). The drug loading rate of the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer to IBU is 45.4-47.8%, and the drug loading rate to CUR is 39.5-48.9%.
Test example 1
For the Ibuprofen (IBU) release experiment, 20mg of APGA-g was added 15 -PTHF 1.8k the/IBU drug-loaded assembly nanospheres are dispersed in 4mL of PBS (phosphate buffer solution) to form dispersion liquid, then the dispersion liquid is transferred into a dialysis bag, the dialysis bag is placed in PBS buffer solutions with different pH values (1.5, 5.5, 6.2, 7.0, 7.4 and 8.0) of 200mL, 2mL of PBS buffer solutions are taken out at intervals of 0.5-2 h at 37 ℃ under stirring to measure the absorbance at 264nm, the cumulative drug release rate is calculated, and the taken out 2mL of PBS buffer solutions are immediately put back after the test is finished. Release experiment of CUR: releasing is carried out at the pH value of 5.5, a small amount of 2mL PBS buffer solution is taken out from a beaker at the temperature of 37 ℃ and in a dark environment and stirred every 0.5-2 h, and the absorbance of the CUR detected at the position of 430nm is measured to calculate the cumulative drug release rate.
The results show that: the nano drug-loaded combination constructed by the acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymer has obvious pH response drug release behavior (as shown in figure 3), when the pH value is 7.4, the release rate of the nano drug-loaded combination to IBU is fastest, 100% of drug release can be achieved within 24h, the cumulative drug release rate of the nano drug-loaded combination of APGA-g-PTHF/IBU at other pH values is higher than that of the ASA-g-PTHF/IBU micron drug-loaded combination (comparative examples 1 and 2), when the pH value is 5.5, the cumulative drug release rate of APGA-g-PTHF/IBU is 59%, and the cumulative drug release rate of ASA-g-PTHF/IBU is 42%.
At a pH of 5.5, compared with micron ASA-g-PTHF/CUR drug-loaded composite (comparative examples 1 and 2), the cumulative drug release rate of the APGA-g-PTHF/CUR nano drug-loaded composite sphere is faster at each time period for encapsulating the CUR drug, the cumulative drug release rate of the APGA-g-PTHF/CUR nano drug-loaded composite sphere reaches 94%, and the cumulative drug release rate of the ASA-g-PTHF/CUR micron drug-loaded composite sphere under the same condition is only 47%.
Test example 2
The toxicity of pure Curcumin (CUR) and APGA-g-PTHF/CUR drug-loaded composite nanospheres to HeLa cells is determined by adopting a CCK-8 method, and the experiment is specifically operated as follows: respectively adding CUR and APGA-g 15 -PTHF 1.8k the/CUR drug-loaded assembly nanospheres are dispersed in the cell culture solution, the concentration of the CUR in the cell culture solution under two conditions is kept to be the same, and the concentration is respectively 20 mu g/mL, 50 mu g/mL, 100 mu g/mL and 200 mu g/mL, and the selection is not carried outThe CUR-added experiment served as a reference. The cell culture solution containing a certain CUR concentration is co-cultured with HeLa cells for 24h, the absorbance of each well at 450nm is measured by a microplate reader (Thermo scientific, MULTISCAN MNK3), at least 3 groups of data are measured for each sample, and the survival rate of the HeLa cells is calculated.
The results show that: the anticancer effect of the APGA-g-PTHF/CUR drug-loaded composite nanosphere containing the CUR with the concentration of 20 mug/mL is close to that of pure CUR with the concentration of 200 mug/mL, which shows that the drug-loaded composite based on acylated propylene glycol alginate-g-polytetrahydrofuran can greatly improve the anticancer effect of the CUR.
Test example 3
HeLa cells co-cultured with CUR (200. mu.g/mL) and APGA-g-PTHF/CUR drug-loaded complex nanospheres (containing a concentration of CUR of 200. mu.g/mL) for 24h were stained with Hoechst 33342/PI staining reagent, and the uptake behavior of the CUR by the HeLa cells was observed (as shown in FIG. 4).
The results show that: in HeLa cells treated by the APGA-g-PTHF/CUR drug-loading assembly nanospheres, obvious green fluorescence (representing the drug CUR) appears, and the HeLa cells can absorb a large amount of CUR (green fluorescence), which shows that the APGA-g-PTHF/CUR drug-loading assembly nanospheres can remarkably improve the bioavailability of the CUR, promote the ingestion of the CUR by the HeLa cells, and cause the death (strong red fluorescence) and the apoptosis (strong blue fluorescence) of the cells, so that the APGA-g 15 -PTHF 1.8k The anticancer effect of CUR in the/CUR drug-loaded composite nanosphere is obvious (as shown in figure 5), and when the concentration of CUR is APGA-g of 20 μ g/mL 15 -PTHF 1.8k The anticancer effect of the/CUR drug-loaded composite nanosphere is close to that of pure CUR with the concentration of 200 mug/mL.
For comparison, via ASA-g 15 -PTHF 2.1k the/CUR drug-loaded complex microspheres (comparative examples 1 and 2) treated HeLa cells showed weak green and red fluorescence, indicating ASA-g 15 -PTHF 2.1k the/CUR drug-loaded combination microsphere is difficult to be absorbed by cells, only a small amount of CUR is absorbed by HeLa cells, the micron ASA-g-PTHF/CUR drug-loaded combination has poor anticancer effect, and the bioavailability of the drug CUR is low.
Comparative example 1
Preparation of acylated sodium alginate-g-polytetrahydrofuran graft copolymer
At the temperature of 25 ℃, 5.0g of sodium alginate is placed in 6.9mL of triethylamine, 50mL of dichloromethane is added, the temperature of the system is adjusted to-10 to-5 ℃, then 16.0mL of decanoyl chloride is slowly dripped, the mixture is stirred and reacted for 5 hours, and 500mL of ethanol is added. The working-up and purification process was the same as in example 1. Acylated Sodium Alginate (ASA) was obtained.
Adding 20 mu L of allyl bromide and 60mg of silver perchlorate into a mixed solution of THF (30mL) and dichloromethane (32mL) at 0 ℃ under a nitrogen atmosphere, and carrying out polymerization reaction for 4 h; 0.5g ASA was dissolved in 20mL dichloromethane; and mixing the tetrahydrofuran/dichloromethane mixed solution containing the PTHF active chain with the acylated sodium alginate/dichloromethane solution, and stirring for reaction for 3.5 h. Working up in the same manner as in example 1 gave an ASA-g-PTHF graft copolymer in which: the branched polytetrahydrofuran has a number average molecular weight of 2100g/mol and a grafting density of 15 polytetrahydrofuran branches per 1000 alginic acid monosaccharides. The graft copolymer is noted: ASA-g 15 -PTHF 2100 A graft copolymer.
Comparative example 2
Preparation of acylated sodium alginate-g-polytetrahydrofuran graft copolymer drug-loaded assembly microspheres
The preparation method of the drug-loaded composite microspheres by forming O/W emulsion from the acylated sodium alginate-g-polytetrahydrofuran graft copolymer comprises the following steps: 20mg of the graft copolymer ASA-g were placed at 25 DEG C 15 -PTHF 2100 And 40mg of the drug (IBU or CUR) were dissolved in 10mL of methylene chloride, and the above solution was dropped into 50mL of deionized water with stirring, to prepare the same solution as in example 4. Scanning electron microscopy (as shown in fig. 6) results show that: ASA-g 15 -PTHF 2100 IBU drug-loaded combination and ASA-g 15 -PTHF 2100 the/CUR drug-loaded composite has microspheres with uniform size distribution, and the diameters of the microspheres are 1.11-1.54 mu m (1326 +/-212 nm) and 0.85-1.16 mu m (1006 +/-157 nm), respectively. Acylated sodium alginate-g-polytetrahydrofuran graft copolymer pair IThe drug loading rate of BU is 31.8-45.8%, and the drug loading rate of the BU to CUR is 32.8-46.2%.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.

Claims (11)

1. Acylation alginic acid propylene glycol ester-g-a polytetrahydrofuran graft copolymer, characterized in that it has propylene glycol alginate as the main chain and polytetrahydrofuran as the side chain;
said acylated propylene glycol alginate-gPolytetrahydrofuran graft copolymers are obtained by a process comprising the following steps:
(1) synthesis of acylated propylene glycol alginate APGA
Putting propylene glycol alginate in a first organic solvent, adding a second organic solvent at low temperature, adding decanoyl chloride, reacting under stirring, precipitating a reaction system in methanol and/or ethanol, repeatedly washing with the methanol and/or the ethanol for many times to remove excessive decanoyl chloride and the first organic solvent, then adding the second organic solvent into a solid product, removing the solvent from a supernatant, and carrying out vacuum drying on the obtained APGA solid product;
(2) synthesis of polytetrahydrofuran active chain PTHF +
Adding initiator and co-initiator into tetrahydrofuran or its mixed solution with third organic solvent under nitrogen atmosphere, and bulk polymerizing or solution polymerizing under stirring to obtain polytetrahydrofuran-containing active chain PTHF + Mixed solution of/tetrahydrofuran or PTHF + A mixed solution of tetrahydrofuran/a third organic solvent;
(3) synthesis of acylated propylene glycol alginate-gPolytetrahydrofuran graft copolymer APGA-g-PTHF
Will contain PTHF + PTHF of living chains + Mixed solution of/tetrahydrofuran or PTHF + Mixing the mixed solution of tetrahydrofuran and the third organic solvent with the mixed solution of APGA and the fourth organic solvent for reaction, and purifying and separating the reaction system to obtain acylated propylene glycol alginate-g-polytetrahydrofuran graft copolymers;
in the step (1), the low temperature is-10 ℃ to-5 ℃, the first organic solvent is triethylamine and/or pyridine, and the second organic solvent is at least one of dichloromethane, trichloromethane and dichloroethane;
in the step (2), the initiator is at least one of allyl bromide, allyl chloride, benzyl bromide and benzyl chloride, the third organic solvent is at least one of dichloromethane, trichloromethane and dichloroethane, and the reaction temperature is-4 ℃ to 4 ℃;
in the step (3), the fourth organic solvent is at least one of dichloromethane, chloroform, dichloroethane and tetrahydrofuran.
2. Acylated propylene glycol alginate according to claim 1gPolytetrahydrofuran graft copolymers, in which the molecular weight of the side chains is between 300 and 6000g/mol and the graft density is 2 to 35 polytetrahydrofuran side chains per 1000 alginic acid monosaccharides.
3. The acylated propylene glycol alginate according to claim 2gPolytetrahydrofuran graft copolymers, in which the molecular weight of the side chains is between 500 and 4000g/mol and the graft density is 3 to 27 polytetrahydrofuran side chains per 1000 monosaccharides alginate.
4. The acylated propylene glycol alginate according to claim 1gPolytetrahydrofuran graft copolymers, where the coinitiator is silver perchlorate.
5. The acylated propylene glycol alginate according to claim 1gPolytetrahydrofuran graft copolymers, in which the grafting of the copolymer is regulated by the ratio of active polytetrahydrofuran chains to propylene glycol alginateThe density of branches.
6. The acylated propylene glycol alginate according to claim 1g-polytetrahydrofuran graft copolymer, wherein the initiator concentration is 0.6 to 25.0 mmol/L.
7. Acylation alginic acid propylene glycol ester-gA polytetrahydrofuran graft copolymer drug-carrying composite comprising the acylated propylene glycol alginate as described in any one of claims 1 to 6g-a polytetrahydrofuran graft copolymer drug carrier and a drug.
8. The acylated propylene glycol alginate according to claim 7gThe polytetrahydrofuran graft copolymer drug-carrying assembly is characterized in that the drug is ibuprofen, curcumin, paclitaxel, adriamycin or camptothecin, and the drug-carrying rate is 1% -52%.
9. The acylated propylene glycol alginate according to claim 8gA polytetrahydrofuran graft copolymer drug-loading assembly, wherein the drug loading rate is between 4% and 49%.
10. Acylated propylene glycol alginate as defined in any of claims 7 to 9gPreparation method of-polytetrahydrofuran graft copolymer drug-carrying composite, wherein acylated propylene glycol alginate-gPolytetrahydrofuran graft copolymers the copolymer drug-loaded assemblies are prepared by forming O/W emulsions and form drug-loaded nanospheres of uniform size distribution.
11. The method of claim 10, wherein the nanospheres are below 250nm in size.
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