PLA-PEG嵌段共聚物在药物释放系统中的应用

介绍PLA-PEG嵌段共聚物的合成和性质,综述其作为胶束、微球、纳米粒等的载体在药物释放系统中的应用。聚乳酸-聚乙二醇嵌段共聚物因具备良好的生物可降解性和相容性而得到广泛应用。     

化学合成的生物降解聚合物在医药领域的应用进展

系统综述了化学合成的生物降解聚合物作为缓控释注射剂,如微球、嵌段共聚物胶束、凝胶等和埋植剂骨架材料的应用进展,并简要介绍了其在医用器械中的应用.     

氟维司群PLA-block-mPEG微球在大鼠体内的药动学研究

分别以嵌段共聚物(聚乳酸-单甲氧基聚乙二醇,分子量比为40 000:2 000)和非嵌段共聚物(聚乳酸-聚羟乙酸,分子量均为40 000,摩尔比分别为75:25、50:50)作为载体材料,采用乳化-液中干燥法制备包载氟维司群的微球.大鼠单剂量(50 mg/kg)皮下注射3种氟维司群微球,采用LC-MS/MS法测定血药浓度,计算药动学参数.结果表明,使用嵌段共聚物制备的微球,药-时曲线较平稳,释放效果较好.     

聚乙二醇-聚乳酸嵌段共聚物及其微粒给药系统的研究进展

 综述可生物降解嵌段共聚物聚乙二醇-聚乳酸（PEG-PLA）及其微粒给药系统在药剂学中的研究与应用。该嵌段共聚物微球能提高蛋白、多肽的稳定性,有利于难溶性药物释放。纳米粒可降低网状内皮吞噬系统的识别与吞噬,改变药物体内分布及清除率,连接识别配体后脑靶向作用显著,具有温敏性和pH敏感性,增加难溶性药物溶解度,且生物相容性良好。PEG-PLA嵌段共聚物微粒给药系统将有广阔的发展和应用前景。     

三嵌段共聚物作为给药系统载体的研究进展

简要综述了三嵌段共聚物的分类以及其作为给药系统载体如胶束、纳米粒、微球、水凝胶、乳剂的研究进展。     

嵌段共聚物在药学中的应用

嵌段共聚物属于两亲类共聚物 ,在水中能自发生成多分子聚集的胶束 ,这些胶束主要以疏水的嵌段为内核 ,亲水嵌段环绕在外构成外壳 ,这种胶束可以有效地增溶油溶性药物。嵌段共聚物无毒、无刺激、无免疫原性 ,胶束尺寸和病毒相仿 ,其大小适合在体内传输。此文综述了嵌段共聚物胶束在药用载体、药物输送、分离和释放等方面的应用。     

温度敏感型聚酯/聚乙二醇三嵌段生物可降解共聚物的降解性能及药物释放的影响因素研究进展

温度敏感型生物可降解水凝胶作为一种注射缓释给药系统的新型载体己受到越来越多的关注,聚酯(A嵌段)/聚乙二醇(B嵌段)三嵌段共聚物是目前最常用的温度敏感型聚合物,具有良好的生物相容性和生物降解性.本文综述了聚乙二醇嵌段含量、聚酯嵌段种类、共聚物凝胶水溶液浓度、处方中添加剂、药物与共聚物分子间的作用力、载药量及制剂形状、介质pH及温度等因素对聚酯/聚乙二醇三嵌段共聚物降解速率及药物释放速率的影响,为聚酯/聚乙二醇三嵌段共聚物水凝胶注射剂开发过程中共聚物降解速率和药物释放速率的调节提供有价值的思路与科学依据.     

嵌段共聚物胶束作为抗肿瘤药物载体的研究进展

嵌段共聚物胶束作为抗肿瘤药的载体，可降低网状内皮系统对抗肿瘤药物的识别和摄取、减少药物的肾排泄及其在正常组织的积蓄；增加了药物在血中的稳定性和在肿瘤组织的积蓄量，是一种长效、高效、安全的抗肿瘤药物载体。嵌段共聚物胶束在肿瘤治疗中的应用具有广阔的发展前景，为肿瘤治疗带来了新的曙光。     

mPEG-PLA的合成及吡喹酮聚合物胶束的制备

目的 合成聚乙二醇单甲醚-聚乳酸(mPEG-PLA)嵌段共聚物,制备吡喹酮mPEG-PLA嵌段共聚物胶束,提高吡喹酮在水中的溶解度.方法 采用开环聚合反应合成mPEG-PLA嵌段共聚物,并通过IR、1H-HMR确证其结构;采用溶剂蒸发法制备共聚物胶束,分别用扫描电镜观察其形态,激光散射法测定其粒径,HPLC法测定其载药量、包封率及饱和溶解度.结果 制备了3种不同嵌段组成的共聚物胶束,扫描电镜下观察为近球形;共聚物胶束的粒径和载药量受有机溶剂种类和用量、共聚物嵌段比例等因素的影响;通过筛选得到有机溶剂为丙酮,油水比为1:4,共聚物嵌段组成为mPEG2000-PLA5000为最适条件;得到胶束的平均粒径为(34.5±5.1) nm,载药量为(19.6±1.8)％,包封率为(74.2±1.6)％.结论 mPEG-PIA聚合物胶束可作为疏水性药物吡喹酮的载体,具有较高的载药性能,能一定程度提高吡喹酮在水中的溶解度.     

pH及温度敏感型生物可降解嵌段共聚物的研究进展

pH及温度敏感型生物可降解嵌段共聚物是指生物可降解材料与pH敏感单体聚合或其本身按照一定序列聚合而成的一种高分子材料，对环境的pH及温度变化产生应答。本文结合近年的研究报道，阐述了各种pH及温度敏感型生物可降解嵌段共聚物的作用机制和应用特点。目前，对pH及温度敏感型生物可降解嵌段共聚物的研究备受关注，其能较好的控制药物释放速度，并具有良好的生物相容性，在智能给药系统研究领域有着广阔的应用前景。     

Sustained release of bovine serum albumin using implantable wafers prepared by MPEG-PLGA diblock copolymers

MPEG-PLGA diblock copolymers, consisting of methoxy polyethylene glycol (MPEG) and poly(L-lactic-co-glycolic acid) (PLGA), were synthesized by ring-opening polymerization of L-lactide and glycolide in the presence of MPEG as an initiator. Implantable wafers, using diblock copolymers as a drug carrier, were fabricated by direct compression method after freeze milling of the diblock copolymers and bovine serum albumin-fluorescein isothiocyanate (BSA-FITC) as a model protein drug. The wafers prepared with MPEG-PLGA diblock copolymers exhibited initial burst in the release of BSA. The BSA release profiles from the wafers depended on MPEG-PLGA diblock copolymer compositions. The in vitro release of the BSA also correlated with the degradation rate of the PLGA part in the diblock polymers. The wafers prepared from diblock copolymers with an increased MPEG segment showed the more structural metamorphosis of crack form due to higher water absorption of MPEG inside the wafer, and induced faster BSA release. The wafers prepared by using MPEG-PLGA diblock copolymers in the presence of small intestinal submucosa (SIS) as a drug carrier additive exhibited controlled BSA release profiles, although the wafers exhibited release patterns with a lag time at the initial stage as the MPEG segment in diblock copolymer compositions increased. Thus, we confirmed that the MPEG-PLGA diblock copolymers could be used as a protein delivery carrier in implantable wafer form.     

Assessment of new biocompatible poly(N-(morpholino)ethyl methacrylate)-based copolymers by transfection of immortalized keratinocytes

Skin carcinomas are among the most commonly diagnosed tumors in the world. In this study, we investigated the transfection of immortalized keratinocytes, used as an in vitro model for skin carcinoma, using the antisense technology and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA)-based copolymers. In order to improve the transfection efficiency of the classic PDMAEMA polymers, copolymers were synthesized including a poly(N-morpholino)ethylmethacrylate) (PMEMA) moiety for an improved proton-sponge effect, intended to favour the release of the oligonucleotide from the acidic endosome. These copolymers were synthesized either statistically (with alternating PDMAEMA and PMEMA fragments) or in blocks (one PDMAEMA block followed by one PMEMA block). MTT assays were performed using the PDMAEMA-PMEMA copolymers and revealed no significant cytotoxicity of these polymers at an N/P ratio of 7.3. Using fluorescent oligonucleotides and analyzing transfection efficiency by flow cytometry, we noticed no significant differences between the two kinds of copolymers. However copolymers with a higher DMAEMA content and a higher Mn were also those displaying the highest vectorization efficiency. Confocal microscopy showed that these copolymers induced a fine granular distribution of the transfected antisense oligonucleotides inside the cells. We also assessed the functionality of the transfected antisense oligonucleotide by transfecting immortalized GFP expressing keratinocytes with a GFP antisense oligonucleotide using these copolymers. A significant silencing was achieved with a PDMAEMA-PMEMA in block copolymer (Mn=41,000, 89 % PDMAEMA). Together, these results suggest that PDMAEMA-PMEMA copolymers combining low toxicity, vectorization and proton sponge properties, can be efficiently used to transfect immortalized keratinocytes and so open new perspectives in the therapy of skin carcinomas as well as of other skin diseases of genetic or immunological origin.     

Technetium-99m-Labeled N-(2-Hydroxypropyl) Methacrylamide Copolymers: Synthesis,Characterization, and in Vivo Biodistribution

PURPOSE: To synthesize novel technetium-99m (99mTc)-labeled N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers and characterize the effect of charge and molecular weight on their biodistribution in SCID mice. METHODS: Electronegative and neutral 7-kDa, 21-kDa, and 70-kDa HPMA copolymers containing a 99mTc chelating comonomer, bearing N-omega-bis(2-pyridylmethyl)-L-lysine (DPK), were synthesized by free-radical precipitation copolymerization. The copolymers were labeled via 99mTc tricarbonyl chelation to DPK-bearing comonomer. They were characterized by side-chain content, molecular weight, molecular weight distribution, radiochemical purity, and labeling stability. Scintigraphic images were obtained during the first 90 min and at 24 h postintravenous injection in SCID mice. At 24 h, organ radioactivity was determined from necropsy tissue counting. RESULTS: 99mTc-labeled HPMA copolymers showed greater than 90% stability over a 24-h challenge with cysteine and histidine. Scintigraphic images and the necropsy data showed that the negatively charged copolymers were eliminated from the body significantly faster than the neutral copolymers in a size-dependent manner. CONCLUSIONS: To facilitate clinical scintigraphic imaging, stable chelation of 99mTc may be achieved by incorporation of a DPK-bearing comonomer into the HPMA backbone. Electronegative and neutral 99mTc-labeled HPMA copolymers of 7, 21, and 70 kDa show significant variation in organ biodistribution in SCID mice. 99mTc-labeled HPMA copolymers could be used as diagnostic agents and to study pharmacokinetics of delivery systems based on these copolymers.     

The influence of carbohydrate nature and drying methods on the compaction properties and pore structure of new methyl methacrylate copolymers

Methyl methacrylate (MMA) copolymers have recently been proposed as an alternative in controlled-release matrix tablets. The aims of this study were to assess the potential value of these copolymers as direct compression excipients and to investigate relationships between the physical and structural properties of the polymers and the compression behaviour of the powders and the microstructural properties of the tablets. Copolymers were synthesised by free radical copolymerisation of MMA with starch or cellulose derivatives and were alternatively dried by oven or freeze-drying techniques. Thus, the present study focuses on the influence of the carbohydrate nature and the drying process on the mechanical and compaction properties of MMA copolymers. Particle size, shape and surface texture of the copolymers have been studied in detail and Heckel treatment has been chosen for discriminating the densification behaviour of powdered materials. Total pore volume and pore size distribution of MMA copolymer tablets were investigated with mercury porosimetry. Oven drying gave less porous particles with more homogenous surfaces than those freeze-dried. Differences in morphology between the MMA copolymers were demonstrated by increasing apparent particle densities, smaller flow rates and higher binding capacities for freeze-dried products. The porousness and mean pore radius of the tablets obtained from freeze-dried copolymers were higher than those of tablets obtained from oven-dried ones.     

Assessment of new biocompatible Poly(N-(morpholino)ethyl methacrylate)-based copolymers by transfection of immortalized keratinocytes

Skin carcinomas are among the most commonly diagnosed tumors in the world. In this study, we investigated the transfection of immortalized keratinocytes, used as an in vitro model for skin carcinoma, using the antisense technology and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA)-based copolymers. In order to improve the transfection efficiency of the classic PDMAEMA polymers, copolymers were synthesized including a poly(N-morpholino)ethylmethacrylate) (PMEMA) moiety for an improved proton-sponge effect, intended to favour the release of the oligonucleotide from the acidic endosome. These copolymers were synthesized either statistically (with alternating PDMAEMA and PMEMA fragments) or in blocks (one PDMAEMA block followed by one PMEMA block). MTT assays were performed using the PDMAEMA-PMEMA copolymers and revealed no significant cytotoxicity of these polymers at an N/P ratio of 7.3. Using fluorescent oligonucleotides and analyzing transfection efficiency by flow cytometry, we noticed no significant differences between the two kinds of copolymers. However copolymers with a higher DMAEMA content and a higher Mn were also those displaying the highest vectorization efficiency. Confocal microscopy showed that these copolymers induced a fine granular distribution of the transfected antisense oligonucleotides inside the cells. We also assessed the functionality of the transfected antisense oligonucleotide by transfecting immortalized GFP expressing keratinocytes with a GFP antisense oligonucleotide using these copolymers. A significant silencing was achieved with a PDMAEMA-PMEMA in block copolymer (Mn?=?41 000, 89 % PDMAEMA). Together, these results suggest that PDMAEMA-PMEMA copolymers combining low toxicity, vectorization and proton sponge properties, can be efficiently used to transfect immortalized keratinocytes and so open new perspectives in the therapy of skin carcinomas as well as of other skin diseases of genetic or immunological origin.     

Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: Physicochemical and technological characterisation

Nowadays, graft copolymers are being used as an interesting option when developing a direct compression excipient for controlled release matrix tablets. New graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS) were synthesised by free radical polymerization and alternatively dried in a vacuum oven (OD) or freeze-dried (FD). This paper evaluates the performance of these new macromolecules and discusses the effect of the carbohydrate nature and drying process on their physicochemical and technological properties. Grafting of EMA on the carbohydrate backbone was confirmed by IR and NMR spectroscopy, and the grafting yields revealed that graft copolymers present mainly a hydrophobic character. The graft copolymerization also leads to more amorphous materials with larger particle size and lower apparent density and water content than carbohydrates (MS, MHS). All the products show a lack of flow, except MHSEMA derivatives. MSEMA copolymers underwent much plastic flow and less elastic recovery than MHSEMA copolymers. Concerning the effect of drying method, FD derivatives were characterised by higher plastic deformation and less elasticity than OD derivatives. Tablets obtained from graft copolymers showed higher crushing strength and disintegration time than tablets obtained from raw starches. This behaviour suggests that these copolymers could be used as excipients in matrix tablets obtained by direct compression and with a potential use in controlled release.     

Binding of 3-isobutyl-1-methylxanthine into copolymers of N-isopropylacrylamide

Linear and crosslinked copolymers based on N-isopropylacrylamide, NIPAAm, containing aromatic esters, have been synthesised. Vinyl benzoate and cinnamoyloxyethyl methacrylate have been used as aromatic comonomers. Certain aromatic esters are known of their capability to form molecular complexes with xanthines and thus, the purpose was to build up thermally responsive copolymers which specifically bind certain xanthines in aqueous solutions and release those under an influence of an environmental stimulus. The solutions of the linear copolymers have been studied in water in the presence of 3-isobutyl-1-methylxanthine, IBMX, as a function of drug concentration and temperature. The synthesised linear copolymers exhibited sensitivity to IBMX concentration in aqueous solutions above and below LCST, observed by viscosimetry and dynamic light scattering. The results are indicative of complex formation between the copolymers and IBMX. The crosslinked copolymers showed an increased IBMX binding capacity with an increasing amount of aromatic ester groups in the polymer network. IBMX release rates from the crosslinked gels were slowed down by the increasing degree of aromatic substitution, especially above LCST.     

Investigation of the cytotoxicity and insulin transport of acrylic-based copolymer protein delivery systems in contact with Caco-2 cultures.

Microparticles or nanospheres of hydrogels of crosslinked poly(methacrylic acid) grafted with poly(ethylene glycol) as well as crosslinked poly(acrylic acid) grafted with poly(ethylene glycol) were prepared for use as oral insulin delivery carriers. The copolymer carriers were synthesized by precipitation/dispersion polymerization that led to gel nanospheres or by bulk polymerization and subsequent size reduction of thin films to obtain gel microparticles. The cytotoxicity of these copolymers was investigated in contact with Caco-2 cell cultures using a metabolic assay to measure the effect of the presence of copolymers on the cell viability. The copolymers were found to exhibit no cytotoxic effect on the cell cultures. Insulin-loaded formulations were also tested for cytotoxicity and insulin transport studies across cell monolayers. The copolymers were shown to open the tight junctions between cells, increasing the available area for diffusion across the cell monolayer, and thus increasing the permeability of insulin across the monolayer.     

Complexes of aminoglycoside antibiotics with copolymers of acrylamide with acrylic and methacrylic acids

Polymer complexes of aminoglycoside antibiotics as bases with low molecular weight water-soluble copolymers of acrylamide (ACR) with acrylic (AA) and methacrylic (MA) acids containing 15 – 20 mol% carboxyl groups were synthesized. Complexes of antibiotics with ACR-MA copolymers were found to be more stable in aqueous and aqueous salt solutions and to have less toxicity in vitro than complexes based on ACR-AA copolymers. All polymer complexes retained high levels of antibacterial activity.