基于“中和促肿瘤炎症”的新型化学免疫联合治疗策略构建多模式pH敏感“一箭三星”集成胶束用于前列腺癌治疗的研究

Chemoimmunotherapy is now the hot topic in cancer treatment, and it was reported that neutralizing tumor-promoting inflammation would be benefit for improving the efficacy of chemoimmunotherapy. In this project, a novel “three in one” strategy was proposed, in which cytotoxic drugs Docetaxel (DTX) was used to inhibit or kill tumor cells, Indoximod as an immune checkpoint indoleamine 2,3-dioxygenase inhibitor was expected to relieve immune suppression , while Ibrutinib as a Bruton’s tyrosine kinase inhibitor was selected to inhibit the tumor-infiltrating B lymphocytes, thus the immune suppression caused by tumor-promoting inflammation could be relieved. The “one rocket launch three satellites” assembled micelles were creatively designed to accomplish the novel “three in one” strategy. Stepwise-targeting ability is realized due to NGR peptide and GLA could target either tumor tissue or tumor cells, respectively. DTX loaded mini-nanoparticle was firstly prepared by pH sensitive material GLA-CA-PAMAM and achieved the deep penetration into tumor tissue. Meanwhile, Indoximod and Ibrutinib co-loaded hybrid micelles were obtained using pH sensitive materials PLH-PEG-NGR and PLH-PLL as carriers. Subsequently, the creative “one rocket launch three satellites” assembled micelles were formed by combining both mini-nanoparticles and hybrid micelles. All three drugs could be responsively released in sequence in the tumor tissues according to three different pH-sensitive modes, i.e. charge-reverse, protonation and schiff-bond sensitive abscission, respectively. In summary, the creative “one rocket launch three satellites” assembled micelles could integrate the advantages including three drugs co-loading, stepwise-targeting, multi-mode pH-sensitive and deep penetration. Furthermore, the tumor immune inhibitions were relieved in two channels and T cell responses were double reinforced, by means of inhibiting immune checkpoint and neutralizing tumor-promoting inflammation, therefore improve the therapeutic efficacy of prostate cancer. This novel “three in one” strategy would lay the foundation for the clinical development of chemoimmunotherapy.

中和促肿瘤炎症有望提高化学免疫联合治疗效果。本课题据此提出“三位一体”新策略，同时使用DTX杀肿瘤细胞，免疫检验点IDO抑制剂Indoximod解除肿瘤对T细胞的抑制，Bruton酪氨酸激酶抑制剂依鲁替尼解除促肿瘤炎症对T细胞的抑制。拟利用NGR靶向肿瘤部位，GLA靶向前列腺癌细胞，实现逐级靶向；pH敏感GLA-CA-PAMAM为载体制备载DTX纳米小粒，向肿瘤深层渗透；pH敏感PLH-PLL制备双载Indoximod及依鲁替尼混合胶束；纳米小粒与混合胶束组装构建“一箭三星”集成胶束，实现三药共载；利用电荷翻转、质子化、希夫碱键敏感断裂三种pH敏感模式实现三药依序释放。“一箭三星”集成胶束集三药共载、逐级靶向、依序释药、深层渗透等多功能，通过抑制免疫检验点、中和促肿瘤炎症双通道解除肿瘤免疫抑制，双效增强T细胞免疫，有望提高前列腺癌治疗效果，为临床开展“三位一体”化学免疫联合治疗奠定基础。

肿瘤发生发展与肿瘤微环境之间的关系已在临床上获得广泛关注。重塑肿瘤微环境有望提高化学免疫联合治疗效果。基于肿瘤免疫微环境重塑策略，本课题旨在设计合理的逐级靶向、多模式纳米递送系统，通过对肿瘤微环境的干预提高化学免疫治疗的抗肿瘤效果。课题按研究计划顺利进行，完成了预期目标。主要完成的研究包括三部分：1）基于新型化学免疫联合治疗策略构建pH敏感的电荷粒径双转换纳米笼以实现肿瘤的三重协同治疗：基于化学免疫联合治疗，本部分提出pH敏感的电荷和粒径双转变纳米笼策略，构建了共载Abemaciclib和IMD-0354的pH敏感的电荷和粒径双转变纳米笼。该纳米笼具有主动靶向、电荷翻转、粒径转变、共递送和组织深层渗透等多种功能，在化疗协同和免疫协同的基础上，实现化学免疫联合治疗，为药物载体的进一步设计和肿瘤免疫化疗联合治疗模式提供了新的有效策略。2）基于“中和促肿瘤炎症”治疗理念，提出耗竭肿瘤浸润B 细胞的免疫治疗方案，构建多模式pH敏感、重塑肿瘤微环境杂合纳米笼，增强化学免疫联合治疗的抗肿瘤效果：本部分基于“中和促肿瘤炎症”免疫治疗理念，构建了一种肿瘤微环境pH响应型重塑肿瘤微环境杂合纳米笼，用于逐级靶向递送Bruton酪氨酸激酶抑制剂依鲁替尼和化疗药多西他赛分别至TIB和肿瘤细胞。该杂合纳米笼可通过耗竭肿瘤浸润B 细胞（TIB），“中和促肿瘤炎症”，重塑肿瘤免疫微环境，从而提高化疗免疫联合治疗效果，为异靶点递送药物载体的先进设计和基于 TIB 免疫治疗的肿瘤联合治疗模式提供了有效的策略。3）基于“一箭三星”新策略重塑抗肿瘤免疫微环境，构建MMP-2响应集成纳米平台，实现化疗、光疗、免疫治疗联合抗肿瘤：本部分提出了一种抗PD-1抗体偶联化学-光热疗法的集成纳米平台（A/Au@MSMS-P）来重塑免疫对抗癌症。基质金属蛋白酶-2（MMP-2）响应的A/Au@MSMS-P促进负载玻玛西尼的金-硅纳米粒(A/Au@MSMS)和抗PD-1抗体的分离，从而通过“一箭三星”新策略增强检查点阻断剂的治疗效果。