Department of Biomaterials, Key Laboratory of Biomedical Engineering of Fujian Province, College of Materials , Xiamen University , Xiamen 361005 , China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience , National Center for Nanoscience and Technology (NCNST) , 11 Beiyitiao , Zhongguancun, Beijing 100190 , China.
Nano Lett. 2018 May 9;18(5):3250-3258. doi: 10.1021/acs.nanolett.8b01071. Epub 2018 Apr 26.
Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (PPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and PPA-1, was synthesized and coassembled with NLG919. The nanostructure swelled when it encountered the weakly acidic tumor niche where DEAP molecules were protonated, and further collapsed due to the cleavage of the peptide substrate by MMP-2 that is highly expressed in tumor stroma. The localized release of PPA-1 and NLG919 created an environment which favored the survival and activation of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth and increase of overall survival. Together, this study offers new opportunities for dual-targeted cancer immunotherapy through functional peptide assembling nanoparticles with design features that are sequentially responsive to the multiple hallmarks of the tumor microenvironment.
联合治疗方案正成为当前癌症免疫治疗的主要方向，以扩大抗肿瘤反应。功能纳米材料为各种药物（尤其是小分子、治疗性肽和核酸）的稳定共递供提供了巨大的潜力，从而实现了可控的药物释放、提高药物生物利用度和降低不良反应。本文设计了一种治疗性肽组装纳米颗粒，该纳米颗粒可以在肿瘤细胞外基质中双重刺激下依次响应，用于肿瘤靶向递药和按需释放短肽拮抗剂程序性死亡配体 1（PPA-1）和色氨酸 2,3-双加氧酶抑制剂（NLG919）。通过同时阻断免疫检查点和色氨酸代谢，纳米制剂增加了肿瘤浸润细胞毒性 T 细胞的水平，从而有效地抑制了黑色素瘤的生长。为了实现这一目标，合成了一种两亲性肽，由功能 3-二乙氨基丙基异硫氰酸酯（DEAP）分子、基质金属蛋白酶-2（MMP-2）的肽底物和 PPA-1 组成，并与 NLG919 共组装。纳米结构在遇到质子化的弱酸性肿瘤微环境时会膨胀，然后由于 MMP-2 高度表达于肿瘤基质中的肽底物的裂解而进一步坍塌。PPA-1 和 NLG919 的局部释放创造了有利于细胞毒性 T 淋巴细胞存活和激活的环境，导致黑色素瘤生长放缓和总生存时间延长。总之，这项研究通过具有对肿瘤微环境多个特征依次响应的设计特征的功能性肽组装纳米颗粒，为双重靶向癌症免疫治疗提供了新的机会。
