细菌富集的肿瘤人造微环境响应性的高分子纳米药物载体用于抗癌药物的选择性传输

Differential anti-cancer drug delivery that selectively releases a drug within a tumor represents an ideal cancer therapy strategy. Herein, our project proposes a new strategy for differential drug delivery to tumor through the fabrication of a special bacteria-accumulated tumor environment that is responded by polymeric nanoparticles. This project utilizes the tumor accumulation property of bacteria. By intravenous administration of attenuated bacteria into tumor-bearing mice, the bacteria preferentially enrich in the tumor. Subsequent administrated anti-cancer drug-loaded nanoparticles led to the selectively degradation in the bacteria-accumulated tumor environment after its accumulation in tumors, triggering differential drug release and selectively killing tumor cells. Our project will develop a bacteria-sensitive triple-layered nanogel for the encapsulation of doxorubicin, and polymer-drug conjugates obtained from the conjugation of anticancer drugs with functional poly(ethylene glycol)-b-polyphosphoester block polymer through a bacteria-sensitive bond. We will prove that the ant-cancer drug loaded nanoparticles show little drug release prior to reaching bacterial infection sites but rapidly releases drug once bacteria are sensed due to the degradation of the nanoparticles by the activity of bacterial enzymes both in vitro and at the cellular level. What's more, the concept will be studied in mouse tumor model, and we will verify that the bacteria and anti-cancer drug-loaded nanoparticles preferentially distribute in the tumor, nanoparticles differentially release anti-cancer drug in bacteria-infected tumors, and bacteria enhance the anti-cancer efficacy of anti-cancer drug-loaded nanoparticles.

肿瘤药物治疗的重大挑战是在杀伤肿瘤细胞的同时如何更好保护正常的细胞。本项目提出选择性输送抗癌药物新策略。通过人为构建细菌富集肿瘤微环境，发展对细菌敏感的聚合物纳米颗粒，实现抗癌药物选择性传输。项目利用细菌在肿瘤部位富集的特性，通过尾静脉注射减毒细菌到荷瘤小鼠体内，细菌富集到肿瘤后，注射细菌敏感的载药纳米颗粒；通过细菌分泌的酶对纳米颗粒的降解，实现药物选择性在肿瘤组织释放的目的，进而选择性杀死肿瘤细胞。项目拟通过聚磷酸酯开环聚合，合成可控的三层结构纳米颗粒，用于阿霉素的包载。或利用细菌敏感化学键，将抗癌药物键合到聚乙二醇-聚磷酸酯嵌段聚合物，得到高分子键合药物。从体外及细胞水平证明，在不存在细菌的情况下，不发生药物的暴释，而在细菌存在情况下药物快速释放。并进一步在荷瘤小鼠体内，研究抗癌药物和细菌在肿瘤部位的富集，药物在细菌存在的肿瘤组织中的释放，以及载药纳米颗粒与细菌联合给药对肿瘤的治疗效果。

肿瘤化疗的重大挑战是在杀伤肿瘤细胞的同时如何更好的保护正常细胞。我们提出了选择性输送抗癌药物的新策略。我们构建了分泌脂肪酶的减毒株细菌SBY1，证明了该减毒株能够选择性在肿瘤部位富集，并在正常组织被快速清除，从而人为构建了细菌富集的肿瘤微环境。同时我们构建了对细菌脂肪酶敏感的三层结构纳米凝胶作为抗癌药物的载体，该药物载体可通过高渗透长滞留效应在肿瘤组织聚集，并对细菌富集的肿瘤微环境响应，实现药物选择性在肿瘤组织释放，从而选择性杀伤肿瘤细胞。该策略显著的提高了药物的选择性，增加药物的疗效并降低药物的副作用，为选择性抗癌药物输送治疗癌症提供了一种新的、有效的思路。