阻塞MPS靶向肿瘤相关巨噬细胞调控肿瘤免疫微环境

Tumor associated macrophages (TAM) are pivotal for promoting key processes in tumor progression, like angiogenesis, immunosuppression, invasion, and metastasis. Therefore, treatment targeting at TAM has practical implications. Nevertheless, nanotherapeutics targeting at TAM will be sequestered immediately by mononuclear phagocyte system (MPS) in the liver, spleen, lung, lymph nodes, etc., once they are in the blood circulation system. In recent study, we found MPS blockade could enhance the nanotherapeutics delivery and tumor inhibitory efficiencies, and at the meantime reduce side effects. Adopting the same methodology, we plan to deliver metformin, with small D-mannose modified hydroxyethyl starch-graft-polylactic acid (D-Man-HES-PLA) nanoparticles, to TAM by MPS blockade, with large HES-PLA microparticles, so as to repolarize TAM, overcome tumor immune suppression, and inhibit tumor development and metastasis. Inhibited by tumor microenvironment, the microparticles used for MPS blockade have no access to TAM, whereas MPS is blocked with microparticles, nanoparticles loaded with metformin will have higher chance to be uptaken by TAM. This study will reveal the effect of MPS blockade on targeting TAM, having significant implications for both fundamental investigation and clinical translation.

肿瘤相关巨噬细胞(TAM)在促进肿瘤发展关键过程，如新血管生成、免疫抑制、侵袭与转移等，均起到重要作用。因此，靶向TAM治疗意义重大。但是，靶向TAM纳米药物面临着如何逃避单核吞噬细胞系统(MPS)摄取的挑战。本课题组最近证实阻塞MPS可以提高化疗纳米药物靶向肿瘤组织递送效率及抑瘤效果，减少不良反应。本项目拟拓展该策略，在合成一系列羟乙基淀粉-聚乳酸(HES-PLA)基础上，构建大粒径HES-PLA微球和D-甘露糖(Man)修饰的小粒径D-Man-HES-PLA纳米粒；先使用大粒径微球阻塞MPS，然后使用小粒径纳米粒靶向TAM递送二甲双胍，逆极化TAM，解除肿瘤微环境免疫抑制，阻止肿瘤发展与转移。受肿瘤微环境生理屏障所限，阻塞MPS微球无法接近TAM；由于MPS已被微球阻塞，载药纳米粒可以更好地靶向TAM。该项目将为发展靶向TAM新方法提供新线索，具有重要理论意义与临床转化价值。

肿瘤相关巨噬细胞（TAM）在肿瘤发生发展、血管新生、免疫抑制微环境的形成和侵袭转移等方面起重要的作用。靶向TAM对于肿瘤治疗具有重要的意义。然而，靶向TAM的纳米药物容易被单核吞噬细胞系统（MPS）摄取，降低抗肿瘤疗效。采用大粒径的微球阻塞MPS可以使纳米药物逃避MPS的摄取，增强纳米药物在肿瘤部位的蓄积，提高抑瘤效果。我们基于羟乙基淀粉-聚乳酸（HES-PLA）构建了大粒径HES-PLA微球和D-甘露糖(Man)修饰的小粒径D-Man-HES-PLA纳米粒。先使用大粒径微球阻塞MPS，然后使用小粒径纳米粒靶向TAM递送二甲双胍，可以逆极化TAM，解除肿瘤微环境免疫抑制，阻止肿瘤发展与转移。此外，我们基于HES还发展了一系列小粒径的抗肿瘤载药纳米粒，如LY/DOX@HES-PLA，DOX@iRGD-HES-SS-C18，DiR@HES-SS-PTX，ICG@HES-OA和ICG@HES-SS-DOX。这些载药纳米粒与游离的化疗药物相比能在肿瘤部位富集，具有更强的抗肿瘤作用及更低的毒副作用，可以与阻塞MPS的策略联用。