Shi Yang, van Nostrum Cornelus F, Hennink Wim E
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The Netherlands.
ACS Biomater Sci Eng. 2015 Jun 8;1(6):393-404. doi: 10.1021/acsbiomaterials.5b00006. Epub 2015 May 12.
Polymeric micelles are widely studied as drug carriers, but their poor in vivo stability and, as a consequence, premature drug release hampers their use for targeted drug delivery. Reversible cross-linking of polymeric micelles to achieve stability in the circulation and triggered de-cross-linking/drug release at their site of action is a highly attractive approach to design effective targeted nanomedicines. In this study, the synthesis and RAFT polymerization of a reactive ketone-containing methacrylamide monomer, 1-(acetonylamino)-2-methyl-2-propen-1-one (AMPO), was investigated. A triblock thermosensitive polymer p(HPMAm)--p(AMPO)--p(HPMAm-Bz--HPMAm-Lac) was synthesized by sequential RAFT polymerization of HPMAm for the permanently hydrophilic block, AMPO for the cross-linkable middle block, and HPMAm-Bz with HPMAm-Lac for the thermosensitive block. The triblock copolymer self-assembled into polymeric micelles with size of 52 nm (PDI of 0.03) by increasing the temperature of an aqueous polymer solution above its critical micelle temperature (3 °C). The micelles were subsequently cross-linked after addition of adipic acid dihydrazide, which reacts with the ketone groups of p(AMPO) located at the interfacial region of the micelles. The cross-linked micelles displayed substantially increased thermal and hydrolytic stability as compared to non-cross-linked micelles. The hydrazone bonds in the cross-links were, however, prone to hydrolysis at mild acidic condition (pH 5.0). A chemotherapeutic drug, paclitaxel, was encapsulated in the polymeric micelles with a high loading capacity (29 wt %). The retention of paclitaxel in the micelles at pH 7.4 was substantially increased by interfacial cross-linking, while the release of the drug was triggered at acidic condition (pH 5.0, pH of late endosomes and lysosomes).
聚合物胶束作为药物载体已得到广泛研究，但其体内稳定性较差，导致药物过早释放，这阻碍了它们在靶向药物递送中的应用。聚合物胶束的可逆交联以实现循环稳定性并在其作用部位触发去交联/药物释放，是设计有效的靶向纳米药物的极具吸引力的方法。在本研究中，对含反应性酮的甲基丙烯酰胺单体1-(丙酮基亚氨基)-2-甲基-2-丙烯-1-酮（AMPO）的合成及可逆加成-断裂链转移（RAFT）聚合进行了研究。通过依次对用于永久亲水嵌段的HPMAm、用于可交联中间嵌段的AMPO以及用于热敏嵌段的HPMAm-Bz与HPMAm-Lac进行RAFT聚合，合成了三嵌段热敏聚合物p(HPMAm)--p(AMPO)--p(HPMAm-Bz--HPMAm-Lac)。通过将聚合物水溶液的温度升高至其临界胶束温度（3℃）以上，三嵌段共聚物自组装成尺寸为52nm（多分散指数为0.03）的聚合物胶束。在加入己二酸二酰肼后，胶束随后发生交联，己二酸二酰肼与位于胶束界面区域的p(AMPO)的酮基反应。与未交联的胶束相比，交联胶束的热稳定性和水解稳定性显著提高。然而，交联中的腙键在温和酸性条件（pH 5.0）下易于水解。一种化疗药物紫杉醇以高载药量（29 wt%）包封在聚合物胶束中。通过界面交联，紫杉醇在pH 7.4时在胶束中的保留率显著提高，而药物在酸性条件（pH 5.0，晚期内体和溶酶体的pH）下释放。
