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CN113350526B - Polysaccharide supramolecular polymer drug carrier based on host-guest effect and preparation method thereof - Google Patents

Polysaccharide supramolecular polymer drug carrier based on host-guest effect and preparation method thereof Download PDF

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CN113350526B
CN113350526B CN202110716004.XA CN202110716004A CN113350526B CN 113350526 B CN113350526 B CN 113350526B CN 202110716004 A CN202110716004 A CN 202110716004A CN 113350526 B CN113350526 B CN 113350526B
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许志刚
胡峻峰
梁梦云
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Abstract

本发明公开了一种基于主客作用的多糖超分子聚合物药物载体及其制备方法，制备方法包括以下步骤：（1）葡聚糖（DEX）与对羧基苯甲醛（4‑CBA）合成多糖聚合物主链DA的制备；（2）多糖聚合物主链DA与单(6‑氨基‑6‑去氧)‑β‑环糊精（CD‑NH2）共聚物DA‑CD的制备；（3）阿霉素前药DA‑DOX的制备（4）通过大分子之间主客作用力将DA‑CD与阿霉素前药DA‑DOX结合，命名为DCD SNs。所得的两亲性聚合物前药可在水中形成超分子药物胶束，具有高胶束稳定性、胶束形状可控、高药物上载量、低毒副作用、良好的药物控释等优势，该纳米颗粒有助于构建长循环深渗透的智能给药系统，用于高效抗肿瘤治疗。

Figure 202110716004

The invention discloses a host-guest-based polysaccharide supramolecular polymer drug carrier and a preparation method thereof. The preparation method includes the following steps: (1) Dextran (DEX) and p-carboxybenzaldehyde (4-CBA) synthesize polysaccharide polymerization Preparation of polymer backbone DA; (2) Preparation of polysaccharide polymer backbone DA and mono(6-amino-6-deoxy)-β-cyclodextrin (CD-NH 2 ) copolymer DA-CD; (3) ) Preparation of doxorubicin prodrug DA-DOX (4) DA-CD is combined with doxorubicin prodrug DA-DOX through host-guest interaction between macromolecules, named DCD SNs. The obtained amphiphilic polymer prodrugs can form supramolecular drug micelles in water, and have the advantages of high micellar stability, controllable micellar shape, high drug loading, low toxicity and side effects, and good drug controlled release. Nanoparticles facilitate the construction of a long-circulating and deep-penetrating smart drug delivery system for efficient anti-tumor therapy.

Figure 202110716004

Description

Polysaccharide supramolecular polymer drug carrier based on host-guest effect and preparation method thereof
Technical Field
The invention relates to the field of high-molecular chemical drugs, in particular to a polysaccharide supramolecular polymer drug carrier based on a host-guest effect and a preparation method thereof.
Background
Cyclodextrin (CD) is a general name of a series of cyclic oligosaccharides produced by amylose under the action of Cyclodextrin glucosyltransferase produced by bacillus, and generally contains 6-12D-glucopyranose units. Since the outer Rim (Rim) of cyclodextrin is hydrophilic and the inner Cavity (Cavity) is hydrophobic, it can provide a hydrophobic binding site like an enzyme to envelop various suitable Guest (Guest) such as organic molecules, inorganic ions, and gas molecules as a Host (Host). The characteristics of hydrophobic inner cavity and hydrophilic outer part enable the complex to form inclusion compounds and molecular assembly systems with a plurality of organic and inorganic molecules according to Van der Waals force, hydrophobic interaction force, matching action among host and object molecules and the like, and become research objects which are interested by chemical and chemical researchers. This selective encapsulation is known as molecular recognition, which results in the formation of Host-Guest complexes (Host-Guest complexes). Cyclodextrins are ideal host molecules found to date to resemble enzymes and have the properties of an enzyme model in their own right. Therefore, cyclodextrin is very important and widely used in the fields of catalysis, separation, food, medicine, and the like. Due to the solubility and inclusion ability of cyclodextrin in water, changing the physicochemical properties of cyclodextrin has become one of the important purposes for chemically modifying cyclodextrin.
The glucan is a homotype polysaccharide which is composed of glucose as monosaccharide, and glucose units are connected by glycosidic bonds. Which can be further classified into alpha-glucan and beta-glucan according to the type of glycosidic bond. The alpha-glucan is mostly studied and used as dextran, also known as dextran. Dextran is most physiologically active as beta-dextran. In the fortiets of the twentieth century, the bellemer doctor discovered and reported for the first time that yeast cell walls have a substance with an effect of enhancing immunity. A
Doxorubicin (DOX) is an antitumor antibiotic, can inhibit the synthesis of RNA and DNA, has the strongest inhibition effect on RNA, has a wider antitumor spectrum, has effects on various tumors, belongs to a periodic nonspecific medicament, and has killing effects on tumor cells in various growth periods. Is mainly suitable for acute leukemia, is effective for acute lymphocytic leukemia and granulocytic leukemia, and can be used as a second-line drug, namely, the drug can be considered to be applied when drug resistance is first selected. Malignant lymphoma can be used as the first choice drug for alternate use. Doxorubicin as broad-spectrum antineoplastic can produce wide biochemical effect to organism, has strong cytotoxicity. The mechanism of action is mainly that the product intercalates into DNA to inhibit nucleic acid synthesis. The traditional Chinese medicine composition is clinically used for treating acute lymphocytic leukemia, acute myelocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, breast cancer, lung cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, nephroblastoma, neuroblastoma, bladder tumor, thyroid tumor, chorioepithelial cancer, prostatic cancer, testicular cancer, gastric cancer, liver cancer and the like.
The nanometer platform based on the supermolecule polymer integrates the advantages of reversibility and stability, and provides a flexible and changeable way for drug delivery. Compared with the traditional supermolecule system, the combination of a plurality of repeating units and a long-chain polymer is used as a supermolecule carrier, so that the stability is enhanced, and the blood circulation is prolonged. Multivalent inclusion bodies of hosts and guests have enhanced binding affinity and can produce strong self-assembly. Cyclodextrins (CDs) are classical carriers for supramolecular nanosystem engineering due to their inherently hydrophobic cavity and superior biocompatibility. More recently, supramolecular polymers based on various structures of CDs have been prepared with desirable stability and extended cycle times. However, such nanosystems will face the difficult problem of separation from the tumor stroma. It can only accumulate in the area around the tumor and is difficult to infiltrate into the filled tumor cells, resulting in insufficient drug content in solid tumors. Therefore, deep tumor penetration remains an indispensable problem to achieve high performance therapeutic effects of supramolecular polymer systems.
Disclosure of Invention
Aiming at the problem that the nano particles are separated from tumor stroma, the nano particles can only gather in the tumor surrounding area and are difficult to infiltrate into filled tumor cells, so that the medicine amount in solid tumors is insufficient. Therefore, deep tumor penetration remains an indispensable problem to achieve high performance therapeutic effects of supramolecular polymer systems. The invention aims to provide a polysaccharide supramolecular polymer drug carrier based on a guest-host effect, a preparation method thereof and application thereof in the field of drug therapy of cancers.
The technical scheme of the invention is as follows:
polysaccharide supramolecular polymer drug carrier based on host-guest action and preparation method thereof, the preparation method comprises the following steps:
(1) the preparation of polysaccharide polymer backbone DA, the synthetic route of which is shown below, comprises the following steps: firstly, water molecules in DEX are completely removed by azeotropy with toluene; DA is synthesized by DEX and 4-CBA through esterification; dissolving DEX and 4-CBA in anhydrous dimethyl sulfoxide (DMSO), and reacting under the argon condition; then adding dicyclohexylcarbodiimide DCC and 4-dimethylaminopyridine DMAP which are dissolved in anhydrous DMSO respectively, and stirring for 48 hours at room temperature; the obtained product is filtered and purified, then is precipitated by ether and is washed three times by dichloromethane;
(2) preparation of polysaccharide Polymer backbone DA and Mono 6-amino-6-deoxy-beta-Cyclodextrin CD-NH2The copolymer DA-CD has the following synthetic route and comprises the following steps: DA-CD is obtained by an ammonia-aldehyde reaction; respectively adding DA and CD-NH2Dissolving in anhydrous DMSO; then triethylamine TEA is added, stirring is carried out for 24 h at the temperature of 50 ℃, and the product is precipitated by diethyl ether and washed by dichloromethane; subsequently, dialyzing in deionized water for 48h, wherein the molecular weight cut-off of the dialysis bag is 3500 kDa, and freeze-drying to obtain a final product, namely white solid DA-CD;
(3) the synthesis route for preparing the adriamycin prodrug DA-DOX is shown as follows, and comprises the following steps: dissolving DA and DOX by using anhydrous DMSO, and adding TEA; the mixture was stirred at 50 ℃ for 24 hours; to remove unreacted DOX, the resulting product was dialyzed against methanol for 48 hours, wherein the cut-off of the dialysis bag was 3500 kDa, and the resulting solution was precipitated with diethyl ether; vacuum drying to obtain DA-DOX product;
(4) the preparation method of the DA-CD/DA-DOX supermolecule nano-assembly particle DCD SNs is characterized in that the synthetic route is as follows, and comprises the following steps: adding DA-DOX drop by drop to deionized water containing DA-CD under vigorous stirring, and further stirring for 24 h; subsequently, the mixed liquid is transferred into a dialysis bag for dialysis for 48h, wherein the molecular weight cut-off of the dialysis bag is 3500 kDa, and DA-CD/DA-DOX supramolecular nano-assembly particles DCD SNs are obtained.
Further, in the step (1), the molar ratio of DEX to 4-CBA is (2-2.3): (1-1.2) mmol, and the molar concentrations of DEX and 4-CBA dissolved in anhydrous DMSO are respectively 0.08-0.1 mol.L-1And 0.5 to 0.55 mol.L-1The molar concentration ranges of DCC and DMAP dissolved in anhydrous DMSO are 0.4-0.45 mol.L respectively-1And 0.035 to 0.04 mol.L-1。
Further, DEX-CBA and CD-NH in step (2)2The mass ratio of (3.5: 1), the molar amount of TEA was 1.65mmol, and the volume of anhydrous DMSO was 2 mL.
Further, in step (3), DEX-CBA and DOX have a mass of 1:1.3, anhydrous DMSO has a volume of 2mL, and TEA has a volume of 150. mu.L.
Further, the molar ratio of DA-DOX to DA-CD in the step (4) is 1:1.
The main advantages of the invention are:
1. aiming at the problems of the existing supramolecular polymer platform system, the project creatively provides a polysaccharide supramolecular polymer drug carrier based on host-guest action and a preparation method thereof. Aiming at the problem that the nano particles are separated from tumor stroma, the nano particles can only gather in the area around the tumor and are difficult to infiltrate into the filled tumor cells, the method can effectively solve the problem of tumor infiltration and increase the long circulation of the medicine in vivo.
2. The supermolecule nano-particles prepared by the method have good stability and are not easy to decompose, and the medicine is released in response in the tumor acidic environment.
Drawings
In order to make the purpose, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings:
fig. 1 is a schematic diagram of the synthesis of the polysaccharide supramolecular polymer-based drug carrier DCD SNs of example 1.
FIG. 2 is an infrared schematic diagram of DCD SNs as a polysaccharide supramolecular polymer-based drug carrier in example 1.
FIG. 3 is a diagram of DCD SNs DLS based polysaccharide supramolecular polymer drug carrier in example 1.
Figure 4 is a schematic diagram of the in vitro drug release of the polysaccharide supramolecular polymer-based drug carrier DCD SNs in example 1.
Fig. 5 is a graph of the toxicity of the polysaccharide supramolecular polymer-based drug carrier DCD SNs on cells in example 1.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1 polysaccharide supramolecular polymer drug carriers based on guest-host effect and method for preparing same
The general synthesis schematic diagram of the polysaccharide supramolecular polymer drug carrier based on the host-guest effect and the preparation method thereof is shown in figure 1, and the polysaccharide supramolecular polymer drug carrier mainly comprises the following steps:
(1) the preparation of polysaccharide polymer backbone DA, the synthetic route of which is shown below, comprises the following steps: first, DEX-CBA was synthesized by esterification of DEX and 4-CBA by azeotropic distillation with toluene to completely remove water molecules in DEX. DEX (1 g, Mn =10000, 5.6 mmol) and 4-CBA (420.36 mg, 2.8 mmol) were dissolved in 5mL of anhydrous DMSO and the reaction was carried out under argon. DCC (693.27 mg, 3.36 mmol) and DMAP (30.54 mg, 0.25 mmol) dissolved in 2mL of anhydrous DMSO were then added, respectively, and stirred at room temperature for 48 h. Filtering and purifying the obtained product, then precipitating with diethyl ether, and washing with dichloromethane for three times;
(2) preparation of polysaccharide Polymer backbone DA and Mono 6-amino-6-deoxy-beta-Cyclodextrin CD-NH2The copolymer DA-CD has the following synthetic route and comprises the following steps: DA-CD was obtained by the aldol reaction, DEX-CBA (72mg) and CD-NH2(255.81 mg, 0.224 mmol) were dissolved in anhydrous DMSO, respectively. Then TEA (250 μ L, 1.65 mmol) was added, stirred at 50 ℃ for 24 h, and the crude product was precipitated with ether and washed with dichloromethane. Subsequently, dialyzing in deionized water for 48h, whereinThe molecular weight cut-off of the bag is 3500 kDa, and a final product is obtained after freeze-drying;
(3) the synthesis route for preparing the adriamycin prodrug DA-DOX is shown as follows, and comprises the following steps: DEX-CBA (72mg) and DOX (129.92 mg, 0.224 mmol) were dissolved in 2mL of LDMSO, and 150. mu.L of TEA was added. The mixture was stirred at 50 ℃ for 24 hours. To remove unreacted DOX, the resulting product was dialyzed against methanol for 48 hours, wherein the cut-off of the dialysis bag was 3500 kDa, and the resulting solution was precipitated with diethyl ether. Vacuum drying to obtain DA-DOX product;
(4) the preparation method of the DA-CD/DA-DOX supermolecule nano-assembly particle DCD SNs is characterized in that the synthetic route is as follows, and comprises the following steps: DA-DOX was added dropwise to the DA-CD containing deionized water with vigorous stirring and further stirred for 24 h. The molar ratio of DA-DOX and DA-CD is 1:1, and then the mixed liquid is transferred into a dialysis bag for dialysis for 48 hours, wherein the molecular weight cut-off of the dialysis bag is 3500 kDa, and DA-CD/DA-DOX supermolecule DCD SNs are obtained.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (5)

1. The preparation method of the polysaccharide supramolecular polymer drug carrier based on the host-guest effect is characterized by comprising the following steps:
(1) the preparation of polysaccharide polymer backbone DA, the synthetic route of which is shown below, comprises the following steps: firstly, water molecules in DEX are completely removed by azeotropy with toluene; DA is synthesized by DEX and 4-CBA through esterification; dissolving DEX and 4-CBA in anhydrous dimethyl sulfoxide (DMSO), and reacting under the argon condition; then adding dicyclohexylcarbodiimide DCC and 4-dimethylaminopyridine DMAP which are dissolved in anhydrous DMSO respectively, and stirring for 48 hours at room temperature; the obtained product is filtered and purified, then is precipitated by ether and is washed three times by dichloromethane;
Figure 252468DEST_PATH_IMAGE001
(2) preparation of polysaccharide Polymer backbone DA and Mono 6-amino-6-deoxy-beta-Cyclodextrin CD-NH2The copolymer DA-CD has the following synthetic route and comprises the following steps: DA-CD is obtained by an ammonia-aldehyde reaction; respectively adding DA and CD-NH2Dissolving in anhydrous DMSO; then triethylamine TEA is added, the mixture is stirred for 24 hours at 50 ℃, and the product is precipitated by ether and washed by dichloromethane; subsequently, dialyzing in deionized water for 48h, wherein the molecular weight cut-off of the dialysis bag is 3500 kDa, and freeze-drying to obtain a final product, namely white solid DA-CD;
Figure 310554DEST_PATH_IMAGE002
(3) the synthesis route for preparing the adriamycin prodrug DA-DOX is shown as follows, and comprises the following steps: dissolving DA and DOX by using anhydrous DMSO, and adding TEA; the mixture was stirred at 50 ℃ for 24 hours in the dark; to remove unreacted DOX, the resulting product was dialyzed against methanol for 48 hours, wherein the cut-off of the dialysis bag was 3500 kDa, and the resulting solution was precipitated with diethyl ether; vacuum drying to obtain DA-DOX product;
Figure 621450DEST_PATH_IMAGE003
(4) the preparation method of the DA-CD/DA-DOX supermolecule nano-assembly particle DCD SNs is characterized in that the synthetic route is as follows, and comprises the following steps: adding DA-DOX drop by drop to deionized water containing DA-CD under vigorous stirring, and further stirring for 24 h; subsequently, the mixed liquid is transferred into a dialysis bag for dialysis for 48h, wherein the molecular weight cut-off of the dialysis bag is 3500 kDa, and DA-CD/DA-DOX supramolecular nano-assembly particles DCD SNs are obtained.
2. Root of herbaceous plantThe method for preparing polysaccharide supramolecular polymer drug carriers based on guest-host effect as claimed in claim 1, characterized in that: in the step (1), the molar ratio of DEX to 4-CBA is (2-2.3): (1-1.2), and the molar concentration ranges of DEX and 4-CBA dissolved in anhydrous DMSO are 0.08-0.1 mol.L-1And 0.5 to 0.55 mol.L-1The molar concentration ranges of DCC and DMAP dissolved in anhydrous DMSO are 0.4-0.45 mol.L respectively-1And 0.035 to 0.04 mol.L-1。
3. The method for preparing polysaccharide supramolecular polymer drug carriers based on guest-host effect as claimed in claim 1, characterized in that: DA and CD-NH in the step (2)2The mass ratio of (3.5: 1), the molar amount of TEA was 1.65mmol, and the volume of anhydrous DMSO was 2 mL.
4. The method for preparing polysaccharide supramolecular polymer drug carriers based on guest-host effect as claimed in claim 1, characterized in that: in the step (3), the mass of DA and DOX is 1:1.3, the volume of anhydrous DMSO is 2mL, and the volume of TEA is 150 muL.
5. The method for preparing polysaccharide supramolecular polymer drug carriers based on guest-host effect as claimed in claim 1, characterized in that: the molar ratio of DA-DOX to DA-CD in the step (4) is 1:1.
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CN115124723B (en) * 2022-07-10 2023-05-09 西南大学 Nanocages Formed Based on Doxorubicin-Cyclodextrin Multiple Forces and Its Preparation

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005847A1 (en) * 2008-07-08 2010-01-14 The Regents Of The University Of California Acid-degradable and bioerodible modified polyhydroxylated materials
KR20110114914A (en) * 2010-04-14 2011-10-20 가톨릭대학교 산학협력단 PH-sensitive nanoparticles for drug delivery and preparation method thereof
CN103656670A (en) * 2013-12-25 2014-03-26 中国科学院长春应用化学研究所 Glucan-adriamycin conjugate drug and preparation method thereof
CN104922674A (en) * 2015-04-10 2015-09-23 南京理工大学 PH-stimulation response type intelligent nanometer container and preparation method thereof
CN106963733A (en) * 2017-05-15 2017-07-21 西南大学 The preparation method of one class amphiphilic star-like adriamycin polymeric prodrugs
WO2017201407A1 (en) * 2016-05-20 2017-11-23 Massachusetts Institute Of Technology Hydrogel particle of cystamine cross-linked dextran aldehyde containing imine conjugated doxorubicin and rgd peptide for chemotherapy
CN107596383A (en) * 2017-09-17 2018-01-19 西南大学 The preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses
CN108014344A (en) * 2017-12-06 2018-05-11 华中科技大学 PH and the chitosan nano pharmaceutical carrier and preparation method of temperature-responsive and application
CN108774301A (en) * 2018-07-11 2018-11-09 西南大学 The preparation method and applications of sour responsive polymer drug of the one kind based on glucan
CN108794709A (en) * 2017-04-27 2018-11-13 西南大学 A kind of amphiphilic star-like block polymer preparation method of superelevation pH stimuli responsives
CN109364262A (en) * 2018-11-07 2019-02-22 西南大学 A kind of preparation method of redox double-responsive polymer camptothecin prodrug
CN110302176A (en) * 2019-06-25 2019-10-08 中国人民解放军陆军军医大学 A kind of anti-inflammatory polypeptide nano drug and preparation method

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9644039B2 (en) * 2006-03-24 2017-05-09 The Regents Of The University Of California Acid-degradable and bioerodible modified polyhydroxylated materials
US8697098B2 (en) * 2011-02-25 2014-04-15 South Dakota State University Polymer conjugated protein micelles
US8772355B2 (en) * 2010-11-23 2014-07-08 Howard University Stealth polymeric particles for delivery of bioactive or diagnostic agents

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005847A1 (en) * 2008-07-08 2010-01-14 The Regents Of The University Of California Acid-degradable and bioerodible modified polyhydroxylated materials
KR20110114914A (en) * 2010-04-14 2011-10-20 가톨릭대학교 산학협력단 PH-sensitive nanoparticles for drug delivery and preparation method thereof
CN103656670A (en) * 2013-12-25 2014-03-26 中国科学院长春应用化学研究所 Glucan-adriamycin conjugate drug and preparation method thereof
CN104922674A (en) * 2015-04-10 2015-09-23 南京理工大学 PH-stimulation response type intelligent nanometer container and preparation method thereof
WO2017201407A1 (en) * 2016-05-20 2017-11-23 Massachusetts Institute Of Technology Hydrogel particle of cystamine cross-linked dextran aldehyde containing imine conjugated doxorubicin and rgd peptide for chemotherapy
CN108794709A (en) * 2017-04-27 2018-11-13 西南大学 A kind of amphiphilic star-like block polymer preparation method of superelevation pH stimuli responsives
CN106963733A (en) * 2017-05-15 2017-07-21 西南大学 The preparation method of one class amphiphilic star-like adriamycin polymeric prodrugs
CN107596383A (en) * 2017-09-17 2018-01-19 西南大学 The preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses
CN108014344A (en) * 2017-12-06 2018-05-11 华中科技大学 PH and the chitosan nano pharmaceutical carrier and preparation method of temperature-responsive and application
CN108774301A (en) * 2018-07-11 2018-11-09 西南大学 The preparation method and applications of sour responsive polymer drug of the one kind based on glucan
CN109364262A (en) * 2018-11-07 2019-02-22 西南大学 A kind of preparation method of redox double-responsive polymer camptothecin prodrug
CN110302176A (en) * 2019-06-25 2019-10-08 中国人民解放军陆军军医大学 A kind of anti-inflammatory polypeptide nano drug and preparation method

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Intracellular pH-sensitive supramolecular amphiphiles based on host–guest recognition between benzimidazole and b-cyclodextrin as potential drug delivery vehicles;Zhe Zhang et al;《Polymer Chemistry》;20130313;第11卷;全文 *
pH sensitive polymer nanoassemblies based on cyclodextrin polymer;Catherine Amiel et al;《J Incl Phenom Macrocycl Chem》;20101001;全文 *
Schiff base-containing dextran nanogel as pH-sensitive drug delivery system of doxorubicin: Synthesis and characterization;Hongying Su et al;《Journal of Biomaterials Applications》;20180625;第33卷(第2期);全文 *
The design and synthesis of dextran-doxorubicin prodrug-based pH-sensitive drug delivery system for improving chemotherapy eficacy;Xiaoli Zhang et al;《Asian Journal of Pharmaceutical Sciences》;20191106;第15卷;全文 *
β-Cyclodextrin-dextran polymers for the solubilization of poorly soluble drugs;Massimiliano di Cagno et al;《International Journal of Pharmaceutics》;20140416;第468卷;全文 *
基于超分子聚合物前药的可注射载药水凝胶;熊露;《中国优秀硕士学位论文全文数据库 (工程科技Ⅰ辑)》;20161015;全文 *

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