聚己内酯在药物载体方面的研究进展

聚己内酯(poly-ε-caprolactone,PCL)是一种人工合成的聚酯类高分子材料,对人体无毒,具有良好的生物相容性、生物可降解性和无免疫原性。PCL还对其它聚合物具有良好的相容性,可以制备出多种性能优良的共聚物或共混物,因此PCL及其共聚物、共混物作为药物载体的研究受到国内外研究者的高度重视。此外,PCL因其在人体中的降解过程十分缓慢可作为药物控释材料,目前已经获得美国FDA的批准。本文将从聚己内酯的合成与改性及其各剂型在药物载体方面的研究进展进行综述。     

可聚合脂质体的研究 Ⅳ含丙烯酰基的类脂分子及其与亲水性丙烯酰单体的共聚物

可聚合脂质体的研究Ⅳ含丙烯酰基的类脂分子及其与亲水性丙烯酰单体的共聚物金威曲青蓝李子臣李福绵（北京大学化学与分子工程学院北京１００８７１）关键词可聚合类脂分子，共聚合，自组织，脂质体脂质体因其优异的生物相容性做为药物释放材料而备受瞩目．一般说来，...     

环糊精超分子聚合物在药物/基因递送载体领域的研究进展

超分子聚合物通常以非共价键作为构筑驱动力,其结构具有动态可逆的特点,在新型响应性聚合物材料中具有突出优势。环糊精可通过主客体识别作用与客体分子如二茂铁、偶氮苯、金刚烷、苯环等形成包合,以此构筑的超分子组装体展现出丰富的自组装-解组装特性、刺激响应性、较低的细胞毒性和较好的生物相容性,有望在药物/基因载体领域得到应用。本文从环糊精超分子聚合物的生物医用出发,着重对近年来环糊精超分子聚合物载体在药物控制释放、基因转染以及药物/基因共递送三方面的研究进展进行了总结和评述,并在此基础上展望了环糊精超分子聚合物的研究方向和发展趋势。     

聚乳酸接枝改性纳米生物玻璃/PLGA复合材料的制备、表面性质及生物活性

以丙交酯开环聚合原位接枝改性的纳米生物玻璃(PLLA-g-BG)与聚丙交酯-乙交酯(PLGA)复合材料为研究对象, 采用TGA, ESEM和EDX分析其接枝率, 粒子分散性和表面元素分布, 通过将兔成骨细胞种植于材料膜表面进行体外培养, 采用荧光染色法、NIH Image J图像分析软件、MTT法和流式细胞术等手段检测细胞在材料表面的平均黏附数量、扩展面积比、增殖能力和细胞周期的变化, 综合评价新型改性纳米复合材料的生物相容性和生物活性. 结果表明, 聚乳酸表面接枝改性可明显改善纳米生物玻璃粒子的团聚; PLGA中掺入一定比例的改性PLLA-g-BG可明显促进兔成骨细胞的黏附、扩展与增殖; 改性纳米生物玻璃的应用可提高生物可降解聚酯材料的生物相容性和生物活性.     

两亲性聚(L-谷氨酸γ-苄基酯)-聚乙二醇接枝共聚物的自组装行为和载药性能研究

由氨基酸及其衍生物聚合形成的聚肽,因其独特的结构和性能,近年来在蛋白质结构模拟、分子链构象研究、生物医学等领域备受关注．其中两亲性聚肽共聚物的自组装行为,为开发具有生物相容性、可控释、可降解性的新型药物载体创造了条件．目前对聚肽共聚物自组装及载药性能研究主要集中于聚肽嵌段共聚物胶束,     

纳米抗癌药物载体的研究进展

与传统抗癌药物相比,纳米抗癌药物载体具有可在体内实现长循环,于癌症组织处富集,在体内缓慢可控释放,药物利用率高,药效高,并且生物相容性与可降解性良好的优点。目前已经实现包括纳米微粒、纳米胶束、树枝状大分子等多种结构的纳米抗癌药物载体的设计,选用的药物载体材料也涵盖多种聚酯以及蛋白质多肽等生物相容性良好的材料。     

生物可降解5-氟尿嘧啶载药微球的制备及性能研究

5-氟尿嘧啶(5-Fu)为水溶性嘧啶类抗代谢药,是治疗实体肿瘤的首选药物．但5-Fu毒性很大,血浆中停留半衰期t1／2仅为10～20min．为了减少氟尿嘧啶的毒副作用并提高药物利用率,可以将其制成聚合物载药微球．聚酯类高分子是较为常用的生物降解型药物载体材料,其中聚乳酸(PLA)及其共聚物具有良好的生物相容性及生物可降解性,常被广泛应用于药物缓释材料,     

侧链含羟基聚(D,L-丙交酯-co-碳酸酯)的合成与表征

聚乳酸(PLA)具有良好的生物相容性及可生物降解性,是适用于组织工程及药物释放系统的聚酯材料,一直是生物医用材料领域中研究的热点之一[1,2].但由于这类聚酯材料是疏水性的,因而存在多肽、蛋白质药物包覆量太低,控释系统制备过程及存放过程中易于失活及药物释放过程难于控制等     

吗啉二酮衍生物与L-丙交酯共聚物的体外降解性能

研究了37℃下吗啉二酮衍生物与L-丙交酯的共聚物在磷酸盐缓冲液(PBS)中的降解,并且与聚(L-丙交酯与乙交酯)(PLGA)的降解进行了比较。通过静滴接触角测量、扫描电镜(SEM)、X衍射(XRD)、凝胶色谱仪(GPC)、核磁共振(1H-NMR)和红外光谱(FT-IR)等方法研究了材料的亲水性、表面形貌、结晶结构、失重率、分子量和结构的变化等。结果表明:与PLGA相比,吗啉二酮衍生物与L-丙交酯的共聚物具有更好的亲水性,接触角达到了74°,降解3个月后数均分子量下降80%以上,该共聚物能够实现两组份的同步降解。     

n-Ag/AD/PLGA功能性材料的制备及生物学性能

利用静电纺丝技术制备了纳米银(n-Ag)/山莨菪碱(AD)/聚乳酸-乙醇酸(PLGA)功能性材料.通过场发射扫描电子显微镜(ESEM)和傅里叶变换红外光谱(FTIR)研究了材料的微观结构及组成,评价了材料的体外药物释放、抑菌性、细胞相容性及细胞毒性.FTIR结果表明,山莨菪碱已担载到n-Ag/AD/PLGA材料中,且随着山莨菪碱含量的增加,n-Ag/AD/PLGA材料内纤维的平均直径逐渐增大.药物释放试验结果证明,山莨菪碱可以逐渐释放.当山莨菪碱的质量分数为1%~5%时,n-Ag/AD/PLGA材料无毒性,且有助于小鼠L929成纤维细胞的生长和增殖.研究结果表明,n-Ag/AD/PLGA材料具有良好的抗菌性能和细胞相容性,担载的山莨菪碱可有效释放,为糖尿病足部感染的临床治疗提供新的人工敷料.     

Enhanced gentamicin loading and release of PLGA and PLHMGA microspheres by varying the formulation parameters

The purpose of this study was to develop a suitable formulation for gentamicin sulfate (GS) that gives a sustained release of the drug. Therefore this drug was loaded into poly(D,L-lactide-co-glycolide) (PLGA) and poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres. The effects of various formulation parameters (ethanol, surfactant, osmotic value of the external phase, polymer type and concentration) on particle characteristics (size, loading and release) were investigated. The GS loaded microspheres were prepared using a double emulsion evaporation technique. The results demonstrate that neither ethanol nor surfactants had beneficial effects on the drug loading efficiency (around 4-10%). However, an increase in buffer concentration (and thus osmotic pressure) of the external phase resulted in a substantial increase of GS-loading (from 10 to 28%). Further, an increase of concentration of PLGA in DCM from 10% to 15/20% caused a 4-time increase of the drug loading. The best formulation identified in this study had a loading efficiency of around 70% resulting in PLGA microspheres with a 6% (w/w) loading. The particles showed a burst release of the drug depending on their porosity, followed by a phase of 35 days where hardly any release occurred. The drug was then slowly released for around 25 days likely due to degradation of the microspheres. The drug loading efficiency of GS in PLHMGA was not significantly different from PLGA microspheres (64%). The release of GS from PLHMGA microspheres was faster than that of PLGA because the degradation rate of PLHMGA is more rapid than PLGA. This study shows that prolonged release of gentamicin can be obtained by loading this drug into microspheres made of biodegradable aliphatic polyesters.     

The effect of formulation variables on the characteristics of insulin-loaded poly(lactic-co-glycolic acid) microspheres prepared by a single phase oil in oil solvent evaporation method

Biodegradable polymeric microspheres are ideal vehicles for controlled delivery applications of drugs, peptides and proteins. Amongst them, poly(lactic-co-glycolic acid) (PLGA) has generated enormous interest due to their favorable properties and also has been approved by FDA for drug delivery. Insulin-loaded PLGA microparticles were prepared by our developed single phase oil in oil (o/o) emulsion solvent evaporation technique. Insulin, a model protein, was successfully loaded into microparticles by changing experimental variables such as polymer molecular weight, polymer concentration, surfactant concentration and stirring speed in order to optimize process variables on drug encapsulation efficiency, release rates, size and size distribution. A 2⁴ full factorial design was employed to evaluate systematically the combined effect of variables on responses. Scanning electron microscope (SEM) confirmed spherical shapes, smooth surface morphology and microsphere structure without aggregation. FTIR and DSC results showed drug–polymer interaction. The encapsulation efficiency of insulin was mainly influenced by surfactant concentration. Moreover, polymer concentration and polymer molecular weight affected burst release of drug and size characteristics of microspheres, respectively. It was concluded that using PLGA with higher molecular weight, high surfactant and polymer concentrations led to a more appropriate encapsulation efficiency of insulin with low burst effect and desirable release pattern.     

Biocompatible microspheres based on acetylated polysaccharide prepared from water-in-oil-in-water (W1/O/W2) double-emulsion method for delivery of type II diabetic drug (exenatide)

Polysaccharide microspheres (PAMs) from acetylated pullulan were designed for the long-term delivery of peptide/protein drugs, as an alternative to a PLGA depot system. Three kinds of samples were obtained according to their different degrees of acetylation (0.8(PA1), 1.5(PA2), 2.3(PA3) acetyl groups in one glucose unit in pullulan), and then utilized to prepare a microsphere via a water-in-oil-in-water (W₁/O/W₂) emulsion method. The mean particle size of PAMs was shown to be in a range between 35 and 110 μm, as determined by a particle size analyzer. In order to evaluate their potential as a depot for protein/peptide delivery, exenatide, a drug used for the treatment of type II diabetes, was employed. The encapsulation efficiency of exenatide in PAMs was 69.1%, 80.4%, and 90.3% in PAM 1, PAM 2, and PAM 3, respectively. Although the release of exenatide from the PLGA microspheres evidenced a fast and high-burst behavior, PAMs evidenced a sustained release profile for 21 days. After 16 days, the released peptide was found to have a molecular weight almost identical to that of native exenatide, indicating that the stability of the peptide in the PAMs was maintained. The tissue reaction evidenced by the PAM was characterized by minimal foreign body reaction and minimal configurations of immune cells such as neutrophils and macrophages, but that of the PLGA microspheres was characterized by relatively elevated inflammation. On the basis of these results, we have concluded that the PAM may provide new insights into the development of new protein/peptide depots in long-term delivery.     

A Polysaccharide-based Hydrogel and PLGA Microspheres for Sustained P24 Peptide Delivery: An In vitro and In vivo Study Based on Osteogenic Capability

A bone morphogenetic protein-2(BMP-2) derived synthetic oligopeptide, S [PO4]KIPKASSVPTELSAISTLYLDDD(P24), has shown great potential for facilitating bone regeneration. However, P24 cannot be directly used onto bone defects, while a continuous sustained delivery of P24 may lead to a better formation of bone tissue. Based on this issue, we have developed a sustained delivery system incorporating P24-loaded poly(lactide-co-glycolide)(PLGA) microspheres and nano-hydroxyapatite(n-HA) into the composite hydrogel. The P24-contained compound material was characterized with NMR, FTIR and SEM to demonstrate the fomiation of compound structure containing P24, PLGA and n-HA. A continuous drug release of P24 was observed for over 60 d that evidently enhanced the efficiency in promoting the proliferation of MC3T3-E1 cells and the secrete of alkaline phosphatase(ALP) in vitro. Moreover, the osteoinduction eflect of the hydrogel system with P24 peptide niicrospheres was demonstrated in vivo and manifested by the result of immunohistochemistry. This novel injectable composite hydrogel is expected to be applied to improving the bone defect treatment in bone tissue engineering.     

Stem cell membrane vesicle–coated nanoparticles for efficient tumor‐targeted therapy of orthotopic breast cancer

Nanoparticles‐based drug delivery strategies have been widely researched for cancer therapy. However, most of them are expected to accumulate in tumor sites via the enhanced permeability and retention (EPR) effect, which is insufficient to deliver the loaded drug into tumors. Cell membrane–camouflaged nanoparticles have obtained much attention for their excellent stability and long blood circulation and reduced the macrophage cells uptake in drug delivery. Herein, bone marrow–derived mesenchymal stem cell membrane vesicle (SCV)–coated paclitaxel (PTX)–loaded poly (lactide‐co‐glycolide) (PLGA) nanoparticles (SCV/PLGA/PTX) were fabricated as the efficient orthotopic breast cancer–targeted drug delivery system. The SCV/PLGA/PTX showed excellent stability, more controlled PTX release, and more effective antitumor effect in vitro. After administration in vivo, SCV/PLGA/PTX exhibited the long‐term retention and enhanced accumulation at tumor sites due to the immune escape and mesenchymal stem cell–mimicking cancer‐targeting capacity. As expected, the SCV/PLGA/PTX could significantly suppress the primary tumor growth by increased apoptosis and necrosis areas within tumor tissues and attenuated the toxic side effects of PTX in 4T1 orthotopic breast cancer model. The study indicated the mesenchymal stem cell membrane coating strategy was highly efficient for targeted drug delivery, which provided a new insight for precise and effective breast cancer treatment.     

Development of Multinuclear Polymeric Nanoparticles as Robust Protein Nanocarriers

One limitation of current biodegradable polymeric nanoparticles is their inability to effectively encapsulate and sustainably release proteins while maintaining protein bioactivity. Here we report the engineering of PLGA–polycation nanoparticles with a core–shell structure that act as a robust vector for the encapsulation and delivery of proteins and peptides. The optimized nanoparticles can load high amounts of proteins (>20 % of nanoparticles by weight) in aqueous solution without organic solvents through electrostatic interactions by simple mixing, thereby forming nanospheres in seconds with diameters <200 nm. The relationship between nanosphere size, surface charge, PLGA–polycation composition, and protein loading is also investigated. The stable nanosphere complexes contain multiple PLGA–polycation nanoparticles, surrounded by large amounts of protein. This study highlights a novel strategy for the delivery of proteins and other relevant molecules.     

同载基因和药物的超微载体粒子的制备及体外评价

以聚乳酸_乙醇酸共聚物 (PLGA)和自行制备的O_羧甲基壳聚糖 (O_CMC)为原料 ,以 5_氟尿嘧啶 (5 Fu)为抗癌药物模型 ,以反义EGFR(表皮生长因子受体 )为基因药物模型 ,构建与评价了同载抗癌药物与基因的复合功能纳米药物载体系统。同载超微粒子的平均粒径为 2 5 8 7nm ,粒径分布指数为 0 14 2 ,粒子表面 ξ电位为 - 10 6 7eV。同载超微粒子在PBS中的释药行为研究表明 :超微粒子中 5_FU和基因均具有零级缓慢释放特性。体外肿瘤细胞存活率实验和免疫组化实验均证实同载超微粒子能高效抑制TJ90 5人脑胶质瘤细胞的增殖。最后用荧光共聚焦显微镜动态监测了超微粒子进入瘤细胞的转染过程 ,发现粒子可在不同时间内进入细胞浆和细胞核。     

Interfacial properties of hydrophilized poly(lactic-co-glycolic acid) layers with various thicknesses

Biodegradable polyesters such as poly(lactic-co-glycolic acid) copolymers (PLGA) are preferred materials for drug carrier systems although their surface hydrophobicity greatly limits their use in controlled drug delivery. PLGA thin films on a solid support blended with PEG-containing compound (Pluronic) were used as model systems to study the interfacial interactions with aqueous media. Degree of surface hydrophilization was assessed by wettability, and X-ray photoelectron spectroscopy (XPS) measurements. Protein adsorption behavior was investigated by in situ spectroscopic ellipsometry. The degree of protein adsorption showed a good correlation with the hydrophilicity, and surface composition. Unexpectedly, the layer thickness was found to have a great impact on the interfacial characteristics of the polymer films in the investigated regime (20-200 nm). Thick layers presented higher hydrophilicity and great resistance to protein adsorption. That special behavior was explained as the result of the swelling of the polymer film combined with the partial dissolution of Pluronic from the layer. This finding might promote the rational design of surface modified biocompatible nanoparticles.     

PLGA/TiO2纳米药物缓释载体的研究

首先利用硅烷偶联剂(KH550)对纳米二氧化钛表面进行预处理,得到氨基改性的二氧化钛,然后与带有高活性端基的丙交酯-乙交酯共聚物(PLGA)反应,制备纳米药物缓释载体PLGA/TiO2有机-无机杂化材料.通过核磁(1H-NMR)、傅里叶变换红外光谱仪(FTIR)、热重分析(TGA)、扫描电子显微镜(SEM)、透射电子显...     

Disulfide-crosslinked Poly(L-glutamic acid) Grafted Mesoporous Silica Nanoparticles and Their Potential Application in Drug Delivery

Poly(L-glutamic acid)(PLGA) was grafted onto the surface of mesoporous silica nanoparticles(MSN) via the ring opening polymerization of γ-benzyl-L-glutamate N-carboxyanhydride(BLG-NCA) and its subsequent deprotection of benzyl groups. The PLGA chains were cross-linked with cystamine, and thus forming a type of redox responsive drug delivery system(MSN-cPLGA). The structures were characterized by Fourier transform infrared spectrometry(FTIR), transmission electron microscopy(TEM) and energy disperse spectrometry(EDS), demonstrating that disulfide groups existed on the surfaces of MSN-cPLGA particles. The thermal gravimetric analysis(TGA) results show that the PLGA mass fraction is about 33.4% in the MSN-cPLGA hybrid. The in vitro drug release experiments showed that the MSN-cPLGA hybrid can realize the controlled release of model drugs(5-fluorouracil) in response to redox environment. Even 0.1 mmol/L dithiothreitol(DTT) can accelerate the drug release speed, and a concentration of 10.0 mmol/L DTT is higher enough to trigger the open of cross-linked PLGA network so as to realize rapid release of drugs. All the results demonstrate that the cross-linked PLGA chains on the surface of MSN could act as efficient gatekeepers to control the on-off of the pores, showing potential application in drug delivery system.