Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy
Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy
复制标题
用于双靶点癌症免疫治疗的顺序响应治疗性肽组装纳米颗粒
DOI：
10.1021/acs.nanolett.8b01071
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发表时间：
2018-05-01
期刊：
影响因子：
10.8
通讯作者：
Nie, Guangjun
中科院分区：
文献类型：
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作者：
Cheng, Keman;Ding, Yanping;Nie, Guangjun
联合治疗方案正在成为当前肿瘤免疫治疗的主要方向，以扩大抗肿瘤反应。功能纳米材料在药物的稳定共递送方面具有巨大的潜力，特别是小分子药物、治疗性多肽和核酸等，从而实现药物的可控释放，提高药物的生物利用度，减少不良反应。在本文中，设计了可以顺序响应肿瘤细胞外基质中的双重刺激的治疗性肽组装纳米颗粒，用于程序性细胞死亡配体1（（D）PPA-1）的短D-肽拮抗剂和吲哚胺2，3-双加氧酶（NLG 919）的抑制剂的肿瘤靶向递送和按需释放。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的细胞毒性T细胞的水平，进而有效抑制黑色素瘤生长。为了实现这一点，合成了由功能性3-二乙基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（D）PPA-1组成的两亲性肽，并与NLG 919共组装。当纳米结构遇到弱酸性肿瘤小生境（其中DEAP分子被质子化）时，纳米结构膨胀，并且由于在肿瘤基质中高度表达的MMP-2对肽底物的切割而进一步塌陷。（D）PPA-1和NLG 919的局部释放创造了有利于细胞毒性T淋巴细胞存活和活化的环境，导致黑色素瘤生长减缓和总存活率增加。总之，这项研究为双靶向癌症免疫治疗提供了新的机会，通过功能性肽组装纳米颗粒，其设计特征依次响应肿瘤微环境的多个标志。
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 ((D)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 (D)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 (D)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.