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Tumor microenvironment-activated therapeutic peptide-conjugated prodrug nanoparticles for enhanced tumor penetration and local T cell activation in the tumor microenvironment
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2020-11-06 , DOI: 10.1016/j.actbio.2020.11.008
Xianghui Zhu , Chao Li , Yan Lu , Yijia Liu , Dong Wan , Dunwan Zhu , Jie Pan , Guilei Ma

Nanomedicine-based chemoimmunotherapy has shown a great potential for cancer therapies application in recent years. However, most nanoparticles still face a problem of low accumulation and limited penetration of chemotherapeutic drugs and immunotherapeutic drugs into solid tumors. Here, we developed a tumor microenvironment (TME)-activable therapeutic peptide-conjugated prodrug nanoparticle for enhanced tumor penetration and synergistic antitumor effects of chemotherapy and immune checkpoint blockade therapy. The prodrug nanoparticle is composed of a short D-peptide antagonist of PD-L1 (DPPA) conjugated doxorubicin (DOX) prodrug and a PEGylated DOX prodrug, which can dissociate into small DOX nanoparticles (<30 nm) and release DPPA antagonist in TME. The prodrug nanoparticles could co-deliver DOX and DPPA antagonist by one nanocarrier and improve tumor accumulation and penetration of the prodrug nanoparticels via a transcytosis process. It is demonstrated that co-delivery of DOX and DPPA antagonist directly killed tumor cells, promoted the tumor-infiltrating cytotoxic T lymphocytes, reduced the tumor-infiltrating regulatory T cells, and elicited a long-term immune memory effect to prevent tumor recurrence and metastasis. This TME-activable prodrug nanoparticle holds promise as a co-delivery nanoplatform for the improved chemoimmunotherapy of solid tumors.



中文翻译:

肿瘤微环境激活的治疗性肽缀合的前药纳米颗粒,可增强肿瘤微环境中的肿瘤渗透和局部T细胞活化

近年来,基于纳米药物的化学免疫疗法已显示出巨大的潜力可用于癌症治疗。然而,大多数纳米颗粒仍面临化学药物和免疫治疗药物向实体瘤的低累积和渗透受限的问题。在这里,我们开发了一种可与肿瘤微环境(TME)结合的治疗性肽共轭前药纳米颗粒,可增强化疗和免疫检查点封锁疗法的肿瘤渗透性和协同抗肿瘤作用。前药纳米颗粒由PD-L1(D PPA)共轭阿霉素(DOX)前体的短D肽拮抗剂和PEG化DOX前药组成,后者可以分解成小的DOX纳米颗粒(<30 nm)并释放DTME中的PPA拮抗剂。前药纳米颗粒可以通过一种纳米载体共同递送DOX和D PPA拮抗剂,并通过转胞吞作用过程改善前药纳米颗粒的肿瘤积累和渗透。证明DOX和D PPA拮抗剂共同给药可直接杀死肿瘤细胞,促进肿瘤浸润的细胞毒性T淋巴细胞,减少肿瘤浸润的调节性T细胞,并引起长期的免疫记忆效应,以防止肿瘤复发和转移。这种TME激活的前药纳米颗粒有望作为共同交付的纳米平台,用于改善实体瘤的化学免疫疗法。

更新日期:2020-12-11
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