Purpose: Combined chemotherapeutic drug and protein drug has been a widely employed strategy for tumor treatment. To realize both tumor accumulation and deep tumor penetration for drugs with different pharmacokinetics, we propose a structure-transformable, thermo-pH dual responsive co-delivery system to co-load granzyme B/docetaxel (GrB/DTX).
Methods: Thermo-sensitive hydrogels based on diblock copolymers (mPEG-b-PELG) were synthesized through ring opening polymerization. GrB/DTX mini micelles (GDM) was developed by co-loading these two drugs in pH-sensitive mini micelles, and the GDM-incorporated thermo-sensitive hydrogel (GDMH) was constructed. The thermo-induced gelation behavior of diblock copolymers and the physiochemical properties of GDMH were characterized. GDMH degradation and deep tumor penetration of released mini micelles were confirmed. The pH-sensitive disassembly and lysosomal escape abilities of released mini micelles were evaluated. In vitro cytotoxicity was studied using MTT assays and the in vivo antitumor efficacy study was evaluated in B16-bearing C57BL/6 mice.
Results: GDMH was gelatinized at body temperature and can be degraded by proteinase to release mini micelles. The mini micelles incorporated in GDMH can achieve deep tumor penetration and escape from lysosomes to release GrB and DTX. MTT results showed that maximum synergistic antitumor efficacy of GrB and DTX was observed at mass ratio of 1:100. Our in vivo antitumor efficacy study showed that GDMH inhibited tumor growth in the subcutaneous tumor model and in the post-surgical recurrence model.
Conclusion: The smart-designed transformable GDMH can facilitate tumor accumulation, deep tumor penetration, and rapid drug release to achieve synergistic chemo-protein therapy.

Keywords: structure-transformable, thermo-pH dual responsive, hydrogel, chemo-protein combination therapy


中文翻译：

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工程热-pH 双重响应水凝胶，用于增强肿瘤蓄积、渗透和化学-蛋白质联合治疗。

目的：联合化疗药物和蛋白质药物已被广泛用于肿瘤治疗。为了实现不同药代动力学药物的肿瘤蓄积和肿瘤深度穿透，我们提出了一种结构可转化、热-pH双重响应的共递送系统来共载颗粒酶B/多西他赛（GrB/DTX）。
方法：基于二嵌段共聚物 (mPEG- b ) 的热敏水凝胶-PELG) 通过开环聚合合成。GrB/DTX 微型胶束 (GDM) 是通过将这两种药物共同负载在 pH 敏感的微型胶束中来开发的，并构建了 GDM 结合的热敏水凝胶 (GDMH)。表征了二嵌段共聚物的热诱导凝胶行为和GDMH的理化性质。证实了释放的微型胶束的GDMH降解和深度肿瘤穿透。评估了释放的微型胶束的 pH 敏感分解和溶酶体逃逸能力。使用 MTT 测定法研究体外细胞毒性，并在携带 B16 的 C57BL/6 小鼠中评估体内抗肿瘤功效研究。
结果：GDMH在体温下凝胶化，可被蛋白酶降解，释放出微胶束。GDMH中掺入的微型胶束可以实现深度肿瘤穿透并从溶酶体中逃脱以释放GrB和DTX。MTT结果显示GrB和DTX的最大协同抗肿瘤功效在质量比为1:100时观察到。我们的体内抗肿瘤功效研究表明，GDMH 在皮下肿瘤模型和术后复发模型中抑制肿瘤生长。
结论：智能设计的可转化GDMH可促进肿瘤蓄积、肿瘤深度穿透、快速药物释放，实现化学-蛋白协同治疗。

关键词：结构可转化，热-pH双重响应，水凝胶，化学-蛋白质联合治疗