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A pH and thermosensitive choline phosphate-based delivery platform targeted to the acidic tumor microenvironment

机译：针对酸性肿瘤微环境的基于pH和热敏胆碱磷酸盐的递送平台

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Solid tumors generally exhibit an acidic microenvironment which has been recognized as a potential route to distinguishing tumor from normal tissue for purposes of drug delivery or imaging. To this end we describe a pH and temperature sensitive polymeric adhesive that can be derivatized to carry drugs or other agents and can be tuned synthetically to bind to tumor cells at pH 6.8 but not at pH 7.4 at 37°C. The adhesive is based on the universal reaction between membrane phosphatidyl choline (PC) molecules and polymers derivatized with multiple copies of the inverse motif, choline phosphate (CP). The polymer family we use is a linear copolymer of a CP terminated tetraethoxymethacrylate and dimethylaminoethyl (DMAE) methacrylate, the latter providing pH sensitivity. The copolymer exhibits a lower critical solution temperature (LCST) just below 37°C when the DMAE is uncharged at pH 7.4 but the LCST does not occur when the group is charged at pH 6.8 due to the ionization hydrophilicity. At 37°C the polymer binds strongly to mammalian cells at pH 6.8 but does not bind at pH 7.4, potentially targeting tumor cells existing in an acidic microenvironment. We show the binding is strong, reversible if the pH is raised and is followed rapidly by cellular uptake of the fluorescently labeled material. Drug delivery utilizing this dually responsive family of polymers should provide a basis for targeting tumor cells with minimal side reactions against untransformed counterparts.
机译：实体瘤通常表现出酸性微环境，该酸性微环境已被认为是将肿瘤与正常组织区分开以用于药物递送或成像的潜在途径。为此，我们描述了一种pH和温度敏感的聚合物粘合剂，该粘合剂可以衍生化以携带药物或其他试剂，并且可以进行合成调节以在37℃下在pH 6.8但在pH 7.4下不与肿瘤细胞结合。该胶粘剂是基于膜磷脂酰胆碱（PC）分子与聚合物的聚合反应而产生的，该聚合物经多拷贝的反向基序磷酸胆碱（CP）衍生。我们使用的聚合物家族是CP封端的四乙氧基甲基丙烯酸酯和甲基丙烯酸二甲基氨基乙酯（DMAE）的线性共聚物，后者可提供pH敏感性。当DMAE在pH 7.4不带电时，该共聚物的临界溶液温度（LCST）低于37°C，但由于离子化亲水性，当该基团在pH 6.8时，LCST不会发生。在37°C下，该聚合物在pH 6.8时与哺乳动物细胞牢固结合，但在pH 7.4时不结合，从而潜在地靶向酸性微环境中存在的肿瘤细胞。我们显示，如果pH升高，则结合是牢固的，可逆的，随后迅速被荧光标记材料吸收。利用这种双重反应性聚合物家族的药物递送应为靶向肿瘤细胞的针对未转化的对应物的最小副反应提供基础。

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