Polymers with time-dependent properties for drug deliver

描述（由申请人提供）：本研究的总体目标是开发一类新的原位形成，可注射和可生物降解的聚合物生物材料，该材料基于时间依赖的摩尔质量和较低的临界溶液温度（LCST）特性，用于局部递送抗癌剂phenstatin。目前正在开发的许多生物可降解、可注射和原位形成的生物材料都有缺点，包括使用与水混溶的有机溶剂进行输送、低分子量有毒副产物、反应性化学反应以及需要外部光源（即光聚合）。用于这些应用的理想替代材料将很容易注入并及时形成，而不会因温度升高、毒性或侵入性技术而对周围组织产生有害影响。使用具有随时间变化的摩尔质量和较低临界溶液温度（LCST）特性的NIPAAm共聚物可以解决许多这些困难。n -异丙基丙烯酰胺（NIPAAm）、甲基丙烯酸酐（MA）和马来酸酐（MAn）的共聚物在水环境中由于马来酸酐侧链转化为马来酸而具有时间依赖性的LCST性质，并且由于甲基丙烯酸酐水解转化为甲基丙烯酸而具有时间依赖性的摩尔质量。将合成NIPAAm、甲基丙烯酸酐和马来酸酐的共聚物，并对初始和最终LCST、初始和最终摩尔质量、凝胶的初始强度和降解时间进行表征。将从选定的材料中评估药物释放概况。这些材料的细胞毒性和生物相容性将通过细胞增殖（MTT）和BALB/c 3T3细胞的活/死试验进行评估。通过体外巨噬细胞和淋巴细胞活化实验来评估这些材料的组织刺激潜能。最后，将选定的材料皮下注射到Sprague Dawley大鼠，以验证可注射性和原位形成。体内相容性将使用选定的组织学技术进行评估。该材料释放的苯他汀的体内疗效将通过SCID小鼠卵巢癌模型进行评估。

DESCRIPTION (provided by applicant): The overall goal of this research is to develop a new class of in situ-forrning, injectable, and biodegradable polymeric biomaterials based on time-dependent molar mass and lower critical solution temperature (LCST) properties for localized delivery of an anti-cancer agent, phenstatin. Many current biodegradable, injectable, and in situ-forming biomaterials under development have disadvantages including the use of water miscible organic solvents for delivery, low molecular weight toxic byproducts, reactive chemistries and the need for external light sources (i.e., for photopolymerization). Ideal replacement materials for these applications would be easily injected and form in a timely fashion without detrimental effects to surrounding tissue from temperature increases, toxicity or invasive techniques. Many of these difficulties can be addressed using NIPAAm copolymers with time-dependent molar mass and lower critical solution temperature (LCST) properties. Copolymers of N-isopropylacrylamide (NIPAAm), methacrylic anhydride(MA) and maleic anhydride (MAn) will possess time-dependent LCST properties in an aqueous environment due to the conversion of maleic anhydride side chains to maleic acid and time-dependent molar mass due to conversion of methacrylic anhydride to methacrylic acid, both by hydrolysis. Copolymers of NIPAAm, methacrylic anhydride, and maleic anhydride will be synthesized and be characterized for initial and final LCST, initial and final molar mass, the initial strength of the gel, and degradation time. Drug release profiles will be evaluated from selected materials. The cytotoxicity and biocompatibility of these materials will be assessed using cell proliferation (MTT) and live/dead assays on BALB/c 3T3 cells. Tissue irritation potential of these materials will be evaluated in vitro by macrophage and lymphocyte activation experiments. Finally, a selected material will be injected subcutaneously into Sprague Dawley rats to verify injectability and in situ formation. In vivo compatibility will be assessed using selected histological techniques. In vivo efficacy of phenstatin released from this material will be evaluated using a SCID mouse ovarian cancer model.