State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
College of Chemistry and Chemical Engineering, Inner Magnolia University, Huhhot, 010021, China.
Adv Mater. 2020 Mar;32(12):e1907210. doi: 10.1002/adma.201907210. Epub 2020 Feb 12.
Prodrug nanoparticles that codeliver the immune modulators to the tumor site are highly recommendable for cancer immunotherapy yet remain challenging. However, effective stimuli-responsive strategies that exploit the endogenous hallmarks of the tumor have paved the way for cancer immunotherapy. For the first time, the development of the Boolean logic prodrug nanoparticles (BLPNs) for tumor-targeted codelivery of immune modulators (e.g., immune activator and immune inhibitor) and combination immunotherapy is reported herein. A library of stimuli-activatable BLPNs is fabricated yielding YES/AND logic outputs by adjusting the input combinations, including extracellular matrix metalloproteins 2/9 (MMP-2/9), intracellular acidity (pH = 5.0-6.0), and reduction (glutathione) in the tumor microenvironment. Tunable and selective control over BLPNs dissociation and prodrug activation is achieved by specifying the connectivity of orthogonal stimuli-labile spacers while exploiting the endogenous signals at the tumor sites. The tumor-specific distribution of the BLPNs and stimuli-activation of the immune modulators for highly efficient cancer immunotherapy are further demonstrated. The results reported in this study may open a new avenue for tumor-specific delivery of immune therapeutics and precise cancer immunotherapy.
前药纳米粒向肿瘤部位共递送免疫调节剂对于癌症免疫治疗是非常值得推荐的，但仍然具有挑战性。然而，利用肿瘤内源性特征的有效刺激响应策略为癌症免疫治疗铺平了道路。本文首次报道了用于肿瘤靶向共递送免疫调节剂（例如免疫激活剂和免疫抑制剂）和联合免疫治疗的布尔逻辑前药纳米粒（BLPNs）的开发。通过调整输入组合，包括细胞外基质金属蛋白酶 2/9（MMP-2/9）、细胞内酸度（pH=5.0-6.0）和肿瘤微环境中的还原（谷胱甘肽），构建了一系列刺激激活的 BLPNs，产生 YES/AND 逻辑输出。通过指定正交刺激不稳定间隔物的连接性，同时利用肿瘤部位的内源性信号，实现了对 BLPNs 解离和前药激活的可调且选择性控制。进一步证明了 BLPNs 的肿瘤特异性分布和免疫调节剂的刺激激活，以实现高效的癌症免疫治疗。本研究的结果可能为免疫治疗药物的肿瘤特异性递送和精确的癌症免疫治疗开辟新途径。
