Nanoscience Initiative, Advanced Science Research Center at The Graduate Center of the City University of New York (CUNY), 85 Saint Nicholas Terrace, New York, NY 10031, USA.
Department of Biomedical Engineering, The City College of New York, CUNY, 160 Convent Avenue, New York, NY 10031, USA.
Biomater Sci. 2023 Sep 26;11(19):6457-6479. doi: 10.1039/d3bm00840a.
Matrix metalloproteinases (MMP) are enzymes that degrade the extracellular matrix and regulate essential normal cell behaviors. Inhibition of these enzymes has been a strategy for anti-cancer therapy since the 1990s, but with limited success. A new type of MMP-targeting strategy exploits the innate selective hydrolytic activity and consequent catalytic signal amplification of the proteinases, rather than inhibiting it. Using nanomaterials, the enzymatic chemical reaction can trigger the temporal and spatial activation of the anti-cancer effects, amplify the associated response, and cause mechanical damage or report on cancer cells. We analyzed nearly 60 literature studies that incorporate chemical design strategies that lead to spatial, temporal, and mechanical control of the anti-cancer effect through four modes of action: nanomaterial shrinkage, induced aggregation, formation of cytotoxic nanofibers, and activation by de-PEGylation. From the literature analysis, we derived chemical design guidelines to control and enhance MMP activation of nanomaterials of various chemical compositions (peptide, lipid, polymer, inorganic). Finally, the review includes a guide on how multiple characteristics of the nanomaterial, such as substrate modification, supramolecular structure, and electrostatic charge should be collectively considered for the targeted MMP to result in optimal kinetics of enzyme action on the nanomaterial, which allow access to amplification and additional levels of spatial, temporal, and mechanical control of the response. Although this review focuses on the design strategies of MMP-responsive nanomaterials in cancer applications, these guidelines are expected to be generalizable to systems that target MMP for treatment or detection of cancer and other diseases, as well as other enzyme-responsive nanomaterials.
基质金属蛋白酶（MMP）是能够降解细胞外基质并调节基本正常细胞行为的酶。自 20 世纪 90 年代以来，抑制这些酶一直是癌症治疗的一种策略，但效果有限。一种新型的 MMP 靶向策略利用了蛋白酶的固有选择性水解活性和随后的催化信号放大，而不是抑制它。使用纳米材料，酶的化学反应可以触发抗癌效果的时间和空间激活，放大相关反应，并导致机械损伤或报告癌细胞。我们分析了近 60 项文献研究，这些研究采用了化学设计策略，通过四种作用模式：纳米材料收缩、诱导聚集、形成细胞毒性纳米纤维和通过去 PEG 化激活，实现了抗癌效果的时空和机械控制。从文献分析中，我们得出了化学设计指南，以控制和增强各种化学成分（肽、脂质、聚合物、无机）的纳米材料的 MMP 激活。最后，该综述还提供了一个指南，说明如何共同考虑纳米材料的多个特性，如基底修饰、超分子结构和静电荷，以针对 MMP 进行靶向，从而使纳米材料上酶的作用达到最佳动力学，从而实现对反应的放大和额外水平的时空和机械控制。虽然本综述重点介绍了 MMP 响应性纳米材料在癌症应用中的设计策略，但预计这些指南将可推广到针对 MMP 用于癌症和其他疾病的治疗或检测以及其他酶响应性纳米材料的系统中。
