Tumor penetration is a critical determinant of the therapy efficacy of nanomedicines. However, the dense extracellular matrix (ECM) in tumors significantly hampers the deep penetration of nanomedicines, resulting in large drug-untouchable areas and unsatisfactory therapy efficacy. Herein, we synthesized a third-generation PAMAM-cored multiarm copolymer and modified the polymer with collagenase to enhance its tumor penetration. Each arm of the copolymer was a diblock copolymer of poly(glutamic acid)-b-poly(carboxybetaine), in which the polyglutamic acid block with abundant side groups was used to link the anticancer agent doxorubicin through the pH-sensitive acylhydrazone linkage, and the zwitterionic poly(carboxybetaine) block provided desired water solubility and anti-biofouling capability. The collagenase was conjugated to the ends of the arms via the thiol-maleimide reaction. We demonstrated that the polymer-bound collagenase could effectively catalyze the degradation of the collagen in the tumor ECM, and consequently augmented the tumor penetration and antitumor efficacy of the drug-loaded polymers.

中文翻译：

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通过胶原酶修饰增强多臂聚合物的肿瘤渗透

肿瘤渗透是纳米药物治疗效果的关键决定因素。然而，肿瘤中致密的细胞外基质（ECM）严重阻碍了纳米药物的深度渗透，导致药物无法触及的区域较大，治疗效果不理想。在此，我们合成了第三代PAMAM核多臂共聚物，并用胶原酶修饰该聚合物以增强其肿瘤渗透性。该共聚物的每个臂都是聚（谷氨酸）-b-聚（羧基甜菜碱）的二嵌段共聚物，其中具有丰富侧基的聚谷氨酸嵌段用于通过pH敏感的酰基腙键连接抗癌剂阿霉素，并且两性离子聚（羧基甜菜碱）嵌段提供了所需的水溶性和抗生物污垢能力。胶原酶通过硫醇-马来酰亚胺反应结合到臂的末端。我们证明，聚合物结合的胶原酶可以有效催化肿瘤 ECM 中胶原蛋白的降解，从而增强载药聚合物的肿瘤渗透和抗肿瘤功效。