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??OBJECTIVE To synthesize hyaluronic acid-octadecene (HOY) copolymers by terminal thiolation modification of hyaluronic acid (HA), prepare doxorubicin-loaded micelles and investigate its pharmaceutical characteristics. METHODS HOY copolymers were synthesized through Michael addition reaction. The doxorubicin-loaded copolymer micelles were prepared with ultrasonic method, then the particle size, Zeta potential, encapsulation efficiency, drug loading efficiency and in vitro release behavior were studied. RESULTS HOY copolymers were synthesized successfully. The particle size and Zeta potential of the drug-loaded micelles were (237.2??2.7) nm and (-22.37??0.38) mV, and the encapsulation efficiency and drug loading rate were (89.8??0.011)% and (5.4??0.007)%, respectively. Moreover, the accumulative release of doxorubicin in vitro was about 70% in 48 h, indicating that the drug was released slowly from the micelles. CONCLUSION This study develops a new micellar system based on terminal modified HA, and provides a reference for the study of HA nanocarrier.
     

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??OBJECTIVE To prepare atorvastatin-loaded tetracycline-PEG-PLGA(TC-PEG-PLGA/ATO) polymeric micelles, and investigate its pharmaceutical characteristics and targeting function in vitro. METHODS The amphiphilic TC-PEG-PLGA conjugate was synthesized via an esterification reaction and identified by the ¹H-NMR. Water insoluble atorvastatin was loaded on TC-PEG-PLGA conjugate micelles via dialysis method. The morphology of TC-PEG-PLGA/ATO micelles was observed under transmission electron microscope. The particle size distribution and Zeta potential of TC-PEG-PLGA/ATO micelles were determined by dynamic light scattering method. The drug loading and encapsulation efficiency were measured by HPLC, and in vitro release behavior was investigated via dialysis method. In vitro cytotoxicity was assessed via MTT assay, and bone-targeting activity was investigated via binding to the hydroxyapatite powder. RESULTS TC-PEG-PLGA/ATO micelle was prepared successfully, and its particle size and Zeta potential were (47.2??4.7) nm and (-14.25??0.31) mV. The encapsulation efficiency and drug loading rate were(98.2??1.51)% and (8.71??0.23)%, respectively. Moreover, the accumulative release of ATO in vitro was about 70% in 48 h, which indicated that the drug was released slowly from the micelles. In vitro cell evaluation showed that TC-PEG-PLGA conjugate micelles were great biocompatibility with MC3T3-E1 cells within the concentration range of 100-500 ??g??mL^-1. In vitro targeting performance indicated that the proportion of the TC-PLGA NPs bound to Hap(87.94%) was greater than the bound proportion of PLGA NPs(18.59%). CONCLUSION The TC-PEG-PLGA/ATO micelles exhibit small partical size and good stability, and significantly increased ATO content in aqueous solution. TC-PEG-PLGA/ATO micelles have good delayed release behavior, safety and binding efficacy to the hydroxyapatite powder.     

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??OBJECTIVE To prepare heparan sulfate-vitamin E succinate (HDV) amphipathic copolymers and explore the pharmaceutical properties of doxorubicin (DOX)-loaded HDV copolymer micelles (DOX/HDV). METHODS HDV copolymers were prepared by amide reaction and its structure was confirmed by ¹H-NMR. DOX/HDV micelles were prepared by ultrasonic method. The particle size, morphology, Zeta potential, drug loading, entrapment efficiency, and in vitro drug release and cytotoxicity were evaluated. RESULTS HDV amphipathic copolymers were synthesized successfully. The particle size, PDI value and Zeta potential of drug-loaded micelles were (105.0??7.3) nm, (0.239??0.484) and (-21.4??2.6) mV, respectively. The encapsulation and drug loading rate were (76.22??0.76)% and (9.53?? 0.58)%, respectively. The results of drug release test in vitro showed that DOX was released slowly from the micelles. Cytotoxicity experiments indicated that blank micelles had no apparent toxicity against both tumor cells and normal cells. However, DOX/HDV micelles could inhibit the tumor cells growth obviously. CONCLUSION HDV copolymers can effectively load DOX with properties of drug sustained release and enhanced cytotoxicity against tumor cells in vitro, which indicates that HDV may be a potential candidate for cancer therapy.     

伊马替尼胶束的制备与体外克服肿瘤耐药性的研究

目的 伊马替尼(imatinib,IMN)包埋于托可索仑(tocofersolan,TPGS)胶束中,以提高其水溶性,并对其理化性质进行表征,及与人源耐药细胞株MCF-7/ADR的作用效果。通过TPGS胶束运输IMN进入细胞,可克服肿瘤细胞的多药耐药性,提高抗肿瘤效果,为进一步体内药效研究提供基础。方法 采用薄膜分散法制备IMN-TPGS胶束,对其粒径、电位、形态、载药量和包封率及体外释放行为进行表征,考察该胶束对MCF-7/ADR细胞的抗肿瘤效果。结果 IMN-TPGS胶束平均粒径为(22.69±2.39)nm,表面呈电中性,外观圆整,载药量为(1.55±0.06)%,包封率为(63.49±2.42)%;具有较高的耐稀释性,血清稳定性和冻干-复溶稳定性;在体外释放72 h后,累积释放度近100%,释放速率缓慢;IMN-TPGS胶束对MCF-7/ADR的IC₅₀为12.27 μmol·L^-1,细胞毒性大,细胞内药物含量高,可诱导近半数细胞凋亡。结论 IMN-TPGS胶束粒径均一,分散性良好,稳定性高,具有较强抗稀释性,有利于体液长循环,对耐药细胞株有明显的抗肿瘤效果,在一定程度上可以克服其多药耐药性。     

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??OBJECTIVE To enhance the anticancer activity of doxorubicin(DOX) by conjugating DOX and vitamin E succinate (VES) and loading the conjugate into hyaluronic acid-octadecylamine (HA-C₁₈) copolymer micelles.METHODS DOX and VES were conjugated by amide reaction.DOX-VES/HA-C₁₈micelles were prepared via a probe-type ultrasonication technique.The morphology of the micelles was determined using a transmission electron microscopy (TEM).Dynamic light scattering (DLS) technique was used to determine the particle size distribution, hydrodynamic diameters, and stability of the micelles.Ultracentrifugation was exploited for measuring the drug loading (DL) and encapsulation efficiency (EE), and the in vitro release was investigated using a dialysis tubing.The cellular uptake and cellular distribution of drug-loaded micelles in MCF-7 cells were observed by fluorescence microscope, and the fluorescence intensity of DOX was evaluated by flow cytometer.The cytotoxicity of free DOX and drug-loaded micelles was tested by MTT assay against MCF-7 cells.RESULTS DOX-VES/HA-C₁₈ showed a nearly spherical morphology and good stability in PBS (pH 7.4) and 10% FBS.The particle size and zeta potential were (184.6??9.42) nm and (-20.7??1.23) mV, respectively.The DL and EE were (15.8??2.85)% and (94.2??1.32)%, respectively.DOX-VES/HA-C₁₈had a good controlled drug release property.Furthermore,DOX-VES/HA-C₁₈with accumulation in nucleipresented higher anti-tumor activity than free DOX and DOX/HA-C₁₈. CONCLUSION DOX-VES conjugate has synergistic anti-tumor effect and good application prospects.     

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??OBJECTIVE To prepare pyridostigmine bromide-phospholipids complex nanoemulsion (PPNE) and carry out in vitro and in vivo evaluation. METHODS The pyridostigmine bromide-phospholipids and PPNE were prepared by solvent evaporation method and pseudo-ternary phase diagram method, respectively. The morphology, particle size, Zeta potential, in vitro release and oral bioavailability of PPNE were evaluated. RESULTS The PPNE was approximately circular. The particle size and Zeta potential were 26.16 nm and -3.88 mV, respectively. The in vitro release behavior of PPNE was similar to pyridostigmine bromide. The relative oral bioavailability of PPNE was 208.1% to pyridostigmine bromide. CONCLUSION PPNE was successfully prepared with a simple and repeatable method, which may be a fundamental formulation for further research of pyridostigmine bromide.     

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??In vitro release is an important index to evaluate the quality of nano preparation, but there is no pharmacopoeia standard of in vitro release evaluation METHODS of nano preparation exists at present, it seriously restricts the safety improvement of nano preparation and the progress of its product development. The main in vitro release evaluation METHODS of nano preparation at present are sample and separate method, flow through cell method, dialysis method, franz diffusion cell method, combination METHODS , and the new METHODS of electrochemical method, nonelectrochemical method and microdialysis method. With the aim to optimize the improvement and development of in vitro release evaluation METHODS of nano preparation, this paper combined with the special properties of nano preparation and provided mainly the research status of in vitro release evaluation METHODS of nano preparation in recent years and their strengths and shortcomings.