聚砜与丙烯酸的紫外光辐射接枝共聚及其表征

在均相溶液体系下,运用紫外光辐射引发合成了聚砜与丙烯酸的接枝共聚物。用化学滴定、漫反射傅立叶变换红外光谱和热分析等技术对接枝聚合物进行了表征。结果表明:丙烯酸被接枝在聚砜链上;光照时间、单体浓度和光引发剂浓度对接枝率均有较大影响。膜表面接触角的研究表明,接枝共聚物膜的亲水性比改性前有所提高。     

固定化青霉素酰化酶在光敏感可再生两水相体系中催化青霉素G为6-APA

在一种光敏感可再生高聚物(PNBC 300000)与葡聚糖20000(Dextran 20000)形成的两水相体系中进行固定化青霉素酰化酶的相转移催化青霉素G产生6-APA的反应。在这个两水相体系中,当pH为7.8,底物浓度为62 mmol/L,反应温度为20℃,在50 mmol/L KCl存在下,6-APA的分配系数可达8.4。催化动力学显示,达到平衡的时间近6 h,PG(Na)转化率约82.6%。3批半连续反应转化率为60%~70%,较相近条件下的单水相反应得率提高近20%。在两水相中,底物及产物主要分配在上相,固定化酶分配在下相,底物青霉素G进入下相经酶催化产生的6-APA及苯乙酸又转入上相,从而解除了青霉素酰化酶催化反应的底物及产物抑制作用,达到提高产物得率的效果。形成两水相的高聚物通过488 nm的激光照射可实现循环利用,高聚物的光照回收率在95%~98%。     

可降解聚酯型聚氨酯(PE-U)的合成、表征及降解行为研究

目的本文旨在合成一种新型的可降解生物医用材料。方法以ε-己内酯、1,6-己二酸、1,6-己二醇、2,4-甲苯二异氰酸酯（TDI）为原料,采用本体熔融聚合法合成了一种可降解的聚酯型聚氨酯共聚物（PE-U）。结果采用1H-NMR、DSC、WAXD、TGA/DTG等对所得共聚物进行表征,确认了共聚物的分子结构,而其降解行为表明所得材料的降解速度可控。结论本文所合成的聚酯型聚氨酯共聚物（PE-U）,具有可控降解行为,其降解速度、吸水率等受PE-U结构的影响。     

PDEPT: polymer-directed enzyme prodrug therapy. I. HPMA copolymer-cathepsin B and PK1 as a model combination

Polymer-directed enzyme prodrug therapy (PDEPT) is a novel two-step antitumour approach using a combination of a polymeric prodrug and polymer-enzyme conjugate to generate cytotoxic drug selectively at the tumour site. In this study the polymeric prodrug N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Gly-Phe-Leu-Gly-doxorubicin conjugate PK1 (currently under Phase II clinical evaluation) was selected as the model prodrug, and HPMA copolymer-cathepsin B as a model for the activating enzyme conjugate. Following polymer conjugation (yield of 30-35%) HPMA copolymer-cathepsin B retained approximately 20-25% enzymatic activity in vitro. To investigate pharmacokinetics in vivo,(125)I-labelled HPMA copolymer-cathepsin B was administered intravenously (i.v.) to B16F10 tumour-bearing mice. HPMA copolymer-cathespin B exhibited a longer plasma half-life (free cathepsin B t(1/2alpha)= 2.8 h; bound cathepsin B t(1/2alpha)= 3.2 h) and a 4.2-fold increase in tumour accumulation compared to the free enzyme. When PK1 (10 mg kg(-1)dox-equiv.) was injected i.v. into C57 mice bearing subcutaneously (s.c.) palpable B16F10 tumours followed after 5 h by HPMA copolymer-cathepsin B there was a rapid increase in the rate of dox release within the tumour (3.6-fold increase in the AUC compared to that seen for PK1 alone). When PK1 and the PDEPT combination were used to treat established B16F10 melanoma tumour (single dose; 10 mg kg(-1)dox-equiv.), the antitumour activity (T/C%) seen for the combination PDEPT was 168% compared to 152% seen for PK1 alone, and 144% for free dox. Also, the PDEPT combination showed activity against a COR-L23 xenograft whereas PK1 did not. PDEPT has certain advantages compared to ADEPT and GDEPT. The relatively short plasma residence time of the polymeric prodrug allows subsequent administration of polymer-enzyme without fear of prodrug activation in the circulation and polymer-enzyme conjugates have reduced immunogenicity. This study proves the concept of PDEPT and further optimisation is warranted.     

聚乙二醇-聚乙烯亚胺共聚物介导体外基因传递

【目的】研究非病毒基因载体聚乙二醇（PEG）-聚乙烯亚胺（PEI）共聚物的组成对体外介导基因传递的影响。【方法】将含PEG不同分子量和接枝量的PEG-PEI共聚物,与DNA形成复合物。考察带正电荷的PEI与带负电荷的DNA的相互作用,测定了PEG-PEI/DNA复合物的粒径和Zeta电位,及对Hela细胞的毒性和转染率。【结果】PEG侧链并未明显影响PEI与DNA形成复合物的能力;连接PEG5000能够明显降低复合物的粒径;复合物的Zeta电位随着PEG接枝量的增加而降低;细胞毒性不依赖于PEG的分子量的变化,而是取决于PEG的接枝量;共聚物PEG-PEI（2-25-1）被证实为较有效的介导体外基因传递的复合物。【结论】共聚物的结构组成对DNA复合物的理化性质、毒性和转染率都产生较大的影响。     

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。     

生物降解聚合物PLGA-PEG-PLGA的合成及表征

目的对生物降解聚合物PLGA-PEG-PLGA进行合成及表征。方法以丙交酯、乙交酯及PEG为原料,用开环聚合法合成生物降解聚合物PLGA-PEG-PLGA,并用DSC、GPC和1H-NMR对其结构进行表征。结果合成的聚合物为嵌段聚合物。由1H-NMR可知聚合物数均相对分子质量为6 400~8 000,重均相对分子质量为7 100~9 200。上述制备的聚合物的水溶液具有反向热敏性质。质量分数为30%的PLGA-PEG-PLGA(3)水溶液的胶凝(由溶胶变为凝胶)温度为33℃,符合人体生理温度。结论提供了一种新的生物降解性药物载体材料。     

Pluronic-g-poly(acrylic acid) copolymers as novel excipients for site specific, sustained release tablets

Potential utility of copolymers comprising Pluronic^® (PEO–PPO–PEO) surfactants covalently conjugated with poly(acrylic acid) (PAA) as excipients for sustained-release tablets was explored. Apparent particle density, particle size distribution, Carr index, thermal stability, and compression behavior of the Pluronic–PAA copolymers were characterized. Tablets prepared by direct compression of blends of Pluronic–PAA copolymers were evaluated on the basis of their thermomechanical profile, crushing strength, friability, and drug release properties. Small molecular weight drugs of aqueous solubility decreasing in the order theophylline > hydrochlorothiazide > nitrofurantoin were incorporated to the tablets. For comparison purposes, tablets were also prepared from PAA of Carbopol^® 71G (C71G), and mixtures of C71G and Pluronic^® F127, with each of the above three drugs. The Pluronic–PAA aggregates are stabilized by hydrophobic associations between poly(propylene oxide) (PPO) segments in aqueous solutions, and thus require higher ionization of the carboxylic groups to overcome the associations and swell. The swelling pattern of the Pluronic–PAA copolymers is more dramatically pH-dependent than that of Carbopol lacking any hydrophobic associations. The drug retention in and release from the Pluronic–PAA based tablets is profoundly pH-dependent and hence specific to the pH exceeding that of the pK_a > 5 of these copolymers. Theophylline- and hydrochlorotiazide-containing tablets made with Pluronic–PAA copolymers showed a reduced release rate under acidic conditions compared to the neutral or alkaline conditions, while the opposite pattern was observed with the Carbopol-based tablets due to the different pH-dependent swelling behavior of the polymers. Nitrofurantoin-containing tablets showed a remarkably low drug release rate owing to the strong hydrophobic character of nitrofurantoin and of its complexes with the copolymers. Integrity of the nitrofurantoin-containing tablets was maintained during the 24 h release test. Zero-order kinetics of the cumulative release profile of all drugs under study was observed with the Pluronic–PAA as a tablet excipient. Adequate mechanical properties, the self-assembling behavior, and the pH-sensitiveness of the Pluronic–PAA copolymers make them promising excipients for tablets with preferential delivery into a neutral to alkaline pH environment.     

An epidemic of allergic contact dermatitis due to epilating products

Over a period of 19 months, 33 cases of acute allergic contact dermatitis from Veet epilating waxes and/or the accompanying tissue (Reckitt Benckiser, Massy, France) were observed in France and Belgium. The lesions started on the legs and spread to other parts of the body, especially the face, and were sometimes so severe that hospitalization and/or systemic corticosteroids were required. Primary sensitization occurred as early as after the first application in several patients. Patch tests were performed in 26 of the patients and produced strong positive reactions to the tissue (25 times) and/or the wax (13 times). The allergenic culprits in the wax were modified-colophonium derivatives (colophonium in the standard series testing negatively in all except 4 patients), while methoxy PEG-22/dodecyl glycol copolymer and to a lesser degree lauryl alcohol turned out to be the main causal allergens in the tissue.     

Thermosensitive Hydrogel as a Tgf-β1 Gene Delivery Vehicle Enhances Diabetic Wound Healing

PURPOSE: To accelerate diabetic wound healing with TGF-beta1 gene delivery system using a thermosensitive hydrogel made of a triblock copolymer, PEG-PLGA-PEG. METHODS: Two 7 x 7 mm full thickness excisional wounds were created in parallel at the back of each genetically diabetic mouse. The hydrogel containing plasmid TGF-beta1 was administered to the wound and formed an adhesive film in situ. Controls were either untreated or treated with the hydrogel without DNA. We used a commercial wound dressing, Humatrix, either with or without DNA, to compare the therapeutic effect with the thermosensitive hydrogel. RESULTS: We found that thermosensitive hydrogel alone is slightly beneficial for reepithealization at early stage of healing (day 1-5), but significantly accelerated repithelializaion, increased cell proliferation, and organized collagen were observed in the wound bed treated with thermosensitive hydrogel containing plasmid TGF-beta1. The accelerated reepithelialization was accompanied with enhanced collagen synthesis and more organized extracellular matrix deposition. Humatrix alone or with plasmid TGF-beta1, had little effect. CONCLUSIONS: Thermosensitive hydrogel made of PEG-PLGA-PEG triblock copolymer provides excellent wound dressing activity and delivers plasmid TGF-beta1 to promote wound healing in a diabetic mouse model.