Synthesis and Hydrophilic Performance of Poly(Lactic Acid)-Poly(Ethylene Glycol) Block Copolymers

Lactide was synthesized using lactic acid and stannous octoate as raw material and catalyst, respectively. Poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) was prepared by lactide and poly (ethylene glycol) (PEG) via ring-opening polymerization. The most appropriate technological conditions of synthesis of lactide were researched in the paper. The copolymers were measured by Infrared spectroscopy (IR) and 1H nuclear magnetic resonance (1H NMR). The results proved that the lactide and PLA-PEG were synthesized successfully. Hydrophilic performance of the copolymer was measured by a water contact angle tester after prepared into a flat membrane. The water contact angle changed from 81.5? to 71.6?, which proved that the hydrophily of PLA-PEG was better than PLA.

High-gravity technology intensified Knoevenagel condensation-Michael addition polymerization of poly (ethylene glycol)-poly (n-butyl cyanoacrylate) for blood-brain barrier delivery

Poly(ethylene glycol)-poly(n-butyl cyanoacrylate)(PEG-PBCA)is a remarkable drug delivery carrier for permeating blood-brain barrier.In this work,a novel high-gravity procedure was reported to intensify Knoevenagel condensation-Michael addition polymerization of PEG-PBCA.A series of PEG-PBCA containing different block ratios were synthesized with narrow molecular weight distribution of polydispersity indexes less than 1.1.Furthermore,the reaction time reduced 60%compared to conventional stirred tank reactor process.Chemical structures of as-prepared polymers were characterized.In vitro drug delivery performance was evaluated.The cytotoxicity of PEG-PBCA to brain microvessel endothelial cells(BMVEC)decreases with the extension of the PEG chain and the shortening of the PBCA chain.The polymer cellular uptake to BMVECs was better after improving hydrophilicity by PEG block.Results of bloodbrain barrier permeability demonstrated that medium length of PBCA chain and short PEG chain are favorable for hydrophobic Nile red permeation,while long PEG chain and short PBCA chain are beneficial to delivery water-soluble doxorubicin hydrochloride(Dox).The average apparent permeability coeffi-cient increased 1.7 and 0.25 times than that of raw Nile red and Dox,respectively.High-gravity intensi-fied condensation polymerization should have great potential in brain drug delivery system.

Preparation and characterization of biodegradable nanoparticles from methoxy poly(ethylene glycol)-poly(D,L-lactide)block copolymers as novel drug carriers

Methoxy poly(ethylene glycol)-poly(D,L-lactide) block copolymers (PEG-PLA) were prepared through ring-opening polymerization.The oil in water suspension method was used to prepare block copolymer micelles. The critical micelle concentration (CMC) by fluorescence spectroscopy was 0.0056 mg·ml -1 . The physical state of the inner core region of micelles was characterized with 1HNMR. The size of indomethacin (IMC) loaded micelles measured by dynamic light scattering (DLS) showed narrow monodisperse size distribution and the average diameters were less than 50 nm. In addition, the nanoparticles with relatively high drug loading content (DLC) were obtained.

Aggregation of Sodium Dodecyl Sulfonate in Poly-ethylene Glycol Aqueous Solutions Studied by Two-dimensional Nuclear Overhauser Enhancement Spectroscopy

Two-dimensional nuclear overhauser enhancement (2D NOESY)measurements show that sodium dodecyl sulfonate SDSN molecules co-aggregate with poly-ethylene glycol PEG in their aqueous solution at a concentration range of SDSN between the so-called co-aggregation concentration (cac) and the. Normal critical micellar concentration (cmc). SDSN micelles are formed when the cmc of SDSN is reached with PEG uniformly distributed in the interior.

The biological fate of the polymer nanocarrier material monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid)in rat

Monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid)(PEG-PLA)is a typical amphiphilic di-block copolymer widely used as a nanoparticle carrier(nanocarrier)in drug delivery.Understanding the in vivo fate of PEG-PLA is required to evaluate its overall safety and promote the development of PEG-PLA-based nanocarrier drug delivery systems.However,acquiring such understanding is limited by the lack of a suitable analytical method for the bioassay of PEG-PLA.In this study,the pharmacokinetics,biodistribution,metabolism and excretion of PEG-PLA were investigated in rat after intravenous administration.The results show that unchanged PEG-PLA is mainly distributed to spleen,liver,and kidney before being eliminated in urine over 48 h mainly(>80%)in the form of its PEG metabolite.Our study provides a clear and comprehensive picture of the in vivo fate of PEG-PLA which we anticipate will facilitate the scientifc design and safety evaluation of PEG-PLA-based nanocarrier drug delivery systems and thereby enhance their clinical development.

Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors

Co-delivery of anti-cancer drugs is promising to improve the efficacy of cancer treatment.This study was aiming to investigate the potential of concurrent delivery of resveratrol(RES)and docetaxel(DTX)via polymeric nanocarriers to treat breast cancer.To this end,methoxyl poly(ethylene glycol)-poly(D,L-lactide)copolymer(mPEG-PDLA)was prepared and characterized using FTIR and 1H NMR,and their molecular weights were determined by GPC.Isobologram analysis and combination index calculation were performed to find the optimal ratio between RES and DTX to against human breast adenocarcinoma cell line(MCF-7 cells).Subsequently,RES and DTX were loaded in the mPEG-PDLA micelles simultaneously,and the morphology,particle size distribution,in vitro release,pharmacokinetic profiles,as well as cytotoxicity to the MCF-7 cells were characterized.IC50 of RES and DTX in MCF-7 cells were determined to be 23.0μg/ml and 10.4μg/ml,respectively,while a lower IC50 of 4.8μg/ml of the combination of RES and DTX was obtained.The combination of RES and DTX at a ratio of 1:1(w/w)generated stronger synergistic effect than other ratios in the MCF-7 cells.RES and DTX loaded mPEG-PDLA micelles exhibited prolonged release profiles,and enhanced cytotoxicity in vitro against MCF-7 cells.The AUC(0→t)of DTX and RES in mPEG-PDLA micelles after i.v.administration to rats were 3.0-fold and 1.6-fold higher than that of i.v.injections of the individual drugs.These findings indicated that the co-delivery of RES and DTX using mPEG-PDLA micelles could have better treatment of tumors.

青蒿琥酯纳米胶束制备及其体内药动学、抗肿瘤活性研究

目的制备青蒿琥酯纳米胶束,并考察体内药动学和抗肿瘤活性。方法以聚乙二醇单甲醚-聚乳酸-聚组氨酸(mPEG-PLA-PHis)为载体制备纳米胶束,单因素试验结合Box-Behnken响应面法优化处方,测定包封率、载药量、沉降率、粒径、Zeta电位、体外释药。12只H_(22)荷瘤小鼠随机分为2组,分别尾静脉注射给予青蒿琥酯注射液和青蒿琥酯纳米胶束(1 mg/kg),于不同时间点采血,HPLC法测定青蒿琥酯血药浓度,计算主要药动学参数。36只H_(22)肝癌荷瘤小鼠随机分为6组,即模型组(生理盐水)、阳性组(20 mg/kg环磷酰胺)、青蒿琥酯注射液组(30 mg/kg)及青蒿琥酯纳米胶束低、中、高剂量组(10、20、30 mg/kg),末次给药3 d后记录体质量和瘤重,计算抑瘤率。结果最佳处方为mPEG-PLA-PHis与青蒿琥酯比例10.18∶1,青蒿琥酯质量浓度0.48 mg/mL,水化时间0.96 h,包封率、载药量、沉降率、粒径、Zeta电位分别为(94.27±1.26)%、(8.26±0.18)%、(4.19±0.20)%、(65.14±4.96)nm、-(17.64±1.06)mV。纳米胶束在弱酸性介质中的累积释放度高于在弱碱性介质中,具有pH敏感性。与注射液比较,纳米胶束t_(1/2)、MRT延长(P<0.01),CL降低(P<0.01),AUC_(0~t)升高(P<0.01);与模型组比较,青蒿琥酯纳米胶束不同剂量组小鼠体质量无明显变化(P>0.05),瘤重下降(P<0.05,P<0.01),以中剂量组更明显,抑瘤率达55.40%。结论青蒿琥酯纳米胶束包封率较高,体内抗肿瘤活性较强。

聚乙二醇单甲醚一聚(D,L-乳酸)嵌段共聚物的研究

采用熔融缩聚反应合成一系列聚(D,L-乳酸)(PDLLA)/聚乙二醇单甲醚(mPEG)两亲性二嵌段共聚物(PEDLLA),采用IR、1H-NMR、DSC、WAXD和TEM等手段分析和研究PEDLLA的结构与性能。实验结果表明,PEDLLA的结构和组成与设计相一致,结晶度和熔点均低于均聚物,且随着PEDLLA中PDLLA含量的增加,mPEG嵌段熔点降低,随着PDLLA嵌段相对分子质量的增大,PEDLLA降解速率增大。载药纳米粒呈核壳结构,载药量达30%。

聚乙二醇-b-聚(D，L-丙交酯-CO-碳酸丙二酯)的胶束化及其药物控释研究

通过开环共聚合成了由D，L-丙交酯、碳酸丙二酯和聚乙二醇构成的两亲性嵌段共聚物（PETLA），研究了PETLA胶束化及药物控释行为，嵌段共聚物和胶束通过核磁共振（^1H-NMR）、荧光分光光度计、凝胶渗透色谱（GPC）、动态光散射（DLS）、透射电镜（TEM）和紫外光谱（UV）表征。实验结果发现临界胶束浓度随共聚物疏水链段长度增加而减小，胶束直径随疏水链段长度增加而增大。透射电镜照片表明载药胶束MTI直径为30～40nm，呈规则球形。体外释药表明9-NC以可控方式释放，突释后药物释放速率接近零级恒速。

四臂星形嵌段共聚物s-PDLLA-b-PEG的合成

季戊四醇与D,L-丙交酯开环聚合制得末端为羟基的四臂星形聚乳酸(s-PDLLA);s-PDLLA与羧基封端的聚乙二醇单甲醚(CT-mPEG)完成酯化反应,合成了以季戊四醇为核,以聚乳酸为内部嵌段、聚乙二醇为外部嵌段的四臂星形聚(D,L-乳酸)-聚乙二醇嵌段共聚物(s-PDLLA-b-PEG),其结构经1H NMR,IR和GPC表征。

一种生物可降解材料PDLLA-(MAh-PEG)_n-PDLLA的合成与表征

丙交酯(LA)开环聚合时同时引入功能性单体合成含活性基团的可降解聚合物,是目前对聚乳酸(PLA)类材料进行改性的一个重要研究方向。文中首先以聚乙二醇(PEG)和马来酸酐(MAh)为原料,采用溶液缩聚法制得聚乙二醇与马来酸酐的交替预聚物(MAh-PEG)n;然后以辛酸亚锡为催化剂,(MAh-PEG)n为引发剂,引发D,L-丙交酯(D,L-LA)开环聚合,制得聚(D,L-乳酸)(PDLLA)与(MAh-PEG)n的共聚物PDLLA-(MAh-PEG)n-PDLLA。采用凝胶渗透色谱(GPC)、傅里叶红外(FT-IR)、核磁共振(NMR)等方法对共聚物的结构和性质进行研究。结果发现,随着(MAh-PEG)n用量的增加,共聚物的分子量有所下降。这种聚合物的主链含有不饱和双键和亲水性的链段,预计将成为一种新的生物可降解材料。

紫杉醇两亲嵌段共聚物纳米囊的研究

目的 探讨负载紫杉醇的聚乙二醇 b 聚 (D ,L 乳酸 )两亲性嵌段共聚物核 壳型纳米囊 (PMT)。方法 采用固相分散法制备PMT ,动态光散射 (DLS)测定PMT的粒径 ,透射电子显微镜 (TEM)和 1HNMR表征PMT的形态 ,研究共聚物相对分子质量和紫杉醇投药量对PMT的影响 ,考察PMT对昆明鼠肝癌H2 2的疗效。结果 PMT呈核 壳结构球形 ,粒径为纳米级 ,随着PEDLLA中疏水嵌段相对分子质量或载药量的增大而增大 ,PMT具有与Taxol类似的抑制肿瘤作用。

PLGA-(PEG-ASP)_n共聚物的合成与性能研究

以辛酸亚锡[Sn(Oct)2]为催化剂,聚乙二醇/L天冬氨酸预聚物[(PEGASP)n]为共引发剂,引发D,LLA和GA开环共聚合成具有功能侧氨基的PLGA(PEGASP)n共聚物。通过FTIR、1HNMR、DSC、表面接触角测定和细胞培养等方法研究共聚物的结构与性能。结果表明,共聚物为典型的非晶态聚合物;共聚物的亲水性以及对骨髓基质细胞的粘附能力和粘附效率均明显优于PLGA。

聚乳酸-聚乙二醇共聚物为载体的缓释疫苗微球的制备及特性研究

目的制备缓释疫苗微球。方法以聚乳酸-聚乙二醇共聚物(PELA)为载体,醋酸乙酯为有机溶剂,采用W/O/W溶剂扩散法制备PELA疫苗微球。扫描电子显微镜观察微球的形态,激光散射技术测定其粒径分布;聚丙烯酰胺凝胶电泳(SDS- PAGE)研究微球包裹前后疫苗蛋白的稳定性;BCA法测定疫苗微球的载药量和包封率,同时考察疫苗微球的体外释药性能。结果所得微球呈类球形,平均粒径为5.38μm,疫苗微球载药量为5.12%,包封率达75.25%;包裹前后疫苗蛋白的结构稳定; 体外释药结果显示,疫苗微球前3 d以Higuchi方程(r=0.997 7)释放,3 d后则以零级恒速释放(r=0.992 2),28 d累积释药量为69.10%。结论以PELA为载体的疫苗微球具有较高的包封率、载药量和明显的缓释效果。

甘草次酸修饰PEG-PLGA纳米粒的制备及与肝癌细胞的亲和性

将肝靶向分子甘草次酸偶联至聚乙二醇-聚(乳酸-羟基乙酸)(PEG-PLGA)嵌段共聚物上.以聚乙二醇维生素E(TPGS)为稳定剂,采用溶剂挥发法制备肝靶向纳米粒子,通过核磁共振、红外光谱、激光光散射及透射电镜等方法对共聚物及纳米粒子的理化性质进行表征;运用噻唑蓝(MTT)比色法评价纳米粒子作为药物载体的安全性,并通过荧光显微镜初步考察了纳米粒子与肝癌细胞的亲和能力.结果表明,纳米粒子粒径为128.2 nm,电势为-16.2 mV,在电解质溶液中具有较高的稳定性.细胞实验结果显示,该纳米粒子无明显细胞毒性,且甘草次酸的引入能显著增加肝癌细胞对纳米粒子的摄取几率,显示出其作为肝靶向药物载体的潜在价值.

叶酸接枝聚乙二醇化壳聚糖衍生物的合成

本文通过邻苯二甲酸酐保护壳聚糖的2-NH2,在壳聚糖的6-OH上引入聚乙二醇单甲醚。再经脱保护基团、2-NH2挂接叶酸,合成了叶酸接枝的聚乙二醇化壳聚糖。目标物用FT-IR,1HNMR,UV-Vis进行了表征。

聚乙二醇单甲醚接枝壳聚糖自组装纳米球的制备

目的：合成聚乙二醇单甲醚接枝壳聚糖（monomethoxy poly（ethylene glycol）-grafted—chitosan，mPEG—g—CS），并制备自组装纳米球。方法：利用甲醛连接法将聚乙二醇单甲醚（monomethoxy poly（ethylene glycol），mPEG）接枝于壳聚糖（chitosan，CS）分子，得到聚乙二醇（poly（ethylene glycol），PEG）改性的壳聚糖衍生物，并通过傅立叶红外光谱仪（Fourier transform infrared spectroscopy，FT-1R），核磁共振仪（proton nuclear magnetic resonance，^1H—NMR）对产物进行结构表征；采用超声透析法制备自组装纳米球，并通过透射电镜（transmission electron microscopy，TEM），动态激光粒度分析仪（dynamic laser light scattering，DLLS）表征了纳米球的形态和粒径；以芘为荧光探针，通过荧光检测分析测定了mPEG—g—CS的临界胶束浓度（critical micellar concentration，CMC）。结果：通过FT—IR，^1H—NMR确证了接枝产物的存在；mPEG—g—CS在水溶液中能够自组装形成球状纳米胶束，平均粒径为250nm。结论：通过甲醛连接法制备mPEG—g—CS，具有制备方法简捷、反应周期短、易操作的优点。利用该产物制备的纳米球有望成为长循环纳米药物载体。

mPEG表面修饰的PLGA嵌段共聚物的血液相容性评价

本实验室设计合成了三种不同LA／GA比例的mPEG修饰PLGA(PELGA,含15％mPEG),为了评价它们的血液相容性,我们以硅化玻璃试管为阴性对照,未硅化的试管为阳性对照,参照国际标准(ISO10993)和《中华人民共和国国家标准GB／T 16886医疗器械生物学评价》方法进行了体外评价实验。试验包括溶血率实验,血小板黏附实验,动态凝血时间实验,凝血时间实验,血浆复钙时间实验和凝血酶原时间实验等综合评价指标。结果表明,合成材料具有优良的血液相容性,材料制成的纳米粒有望应用于静脉注射。

聚乳酸/聚乙二醇-聚乳酸新型亲水支架的制备与研究

利用热致相分离／粒子沥滤结合法，制备了聚乳酸（PDLLA）以及聚乳酸与聚乙二醇-聚乳酸共聚物（PELA）复合的PDLLA／PELA组织工程支架。讨论了聚乙二醇（PEG）分子量、PELA含量及组成比对于支架内部结构、力学性能、降解行为和细胞毒性的影响。结果表明，热致相分离／粒子沥滤结合法制备的支架，具有100～250μm大孔与5～40μm小孔兼备的特殊内部结构，PEG含量愈高、PEG分子量愈小，支架的孔隙率愈大。PDLLA／PELA比率的减小，PEG／PLA比率的增大会引起支架力学性能的下降和降解的加速。材料无细胞毒性。当支架中PDLLA／PELA为3：1，PEG5000／PLA为25：75时，其内部孔形态最为理想。

新型聚乙二醇接枝聚乳酸及其降解特性研究

通过直接酰胺化反应,以马来酸酐本体改性聚乳酸（MPLA）和氨基封端聚乙二醇（H2N-PEG-NH2）为原料,合成了聚乙二醇本体改性聚乳酸（PPLA）.通过红外、核磁共振技术对改性聚合物的结构进行了表征;采用FITC标记牛血清白蛋白（FITC-BSA）为模型蛋白质,测试了聚合物对蛋白质的非特异性吸附;利用吸水率表征了聚合物的亲水性;利用聚合物在12周降解过程中pH值、失重率的变化评价了它们的降解特性.结果表明：H2N-PEG-NH2已成功接枝到MPLA上;与聚乳酸（PLA）、MPLA相比,PPLA明显降低了对FITC-BSA的吸附;其亲水性和降解性增加.预计该材料将是一种更适合组织工程和药物缓释应用的聚乳酸类可降解材料.