Polymers with time-dependent properties for drug deliver

描述(申请人提供)：这项研究的总体目标是开发一种新型的原位成型、可注射和可生物降解的聚合物生物材料，该材料基于随时间变化的摩尔质量和较低的临界溶液温度(LCST)特性，用于局部传递抗癌药物苯伐他汀。目前正在开发的许多可生物降解、可注射和原位形成的生物材料都存在缺点，包括使用水可混溶的有机溶剂进行传递、使用低分子有毒副产品、反应化学反应和需要外部光源(即光聚合)。这些应用的理想替代材料将易于注射并及时形成，而不会因温度升高、毒性或侵入性技术而对周围组织产生不利影响。使用具有随时间变化的摩尔质量和较低的临界溶液温度(LCST)特性的NIPAAm共聚物可以解决其中的许多困难。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将具有随时间变化的LCST性质，这是由于马来酸酐侧链转化为马来酸，以及随着时间变化的摩尔质量由甲基丙烯酸酐转化为甲基丙烯酸，两者都是通过水解的方式实现的。将合成NIPAAm、甲基丙烯酸酐和马来酸酐的共聚物，并对其初始和最终的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。药物释放情况将从选定的材料中进行评估。这些材料的细胞毒性和生物相容性将通过BALB/c 3T3细胞的细胞增殖和活/死实验来评估。这些材料的组织刺激性将通过巨噬细胞和淋巴细胞激活实验在体外进行评估。最后，一种选定的材料将被注射到SpragueDawley大鼠的皮下，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。从该材料释放的苯抑素的体内疗效将使用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.