Key Laboratory for Organic Electronics and Information Displays and Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials, Jiangsu National Synergetic Innovation Centre for Advanced Materials, Nanjing University of Posts and Telecommunications, Nanjing, Jiangsu 210023, P. R. China.
Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, Jiangsu 210008, P. R. China.
J Mater Chem B. 2024 Aug 14;12(32):7837-7847. doi: 10.1039/d4tb00894d.
The dense extracellular matrix (ECM) in the tumor microenvironment forms an abnormal physical barrier, which impedes the delivery and penetration of nanomedicines and hinders their therapeutic efficacy. Herein, we synthesize matrix-degrading soft-nanocapsules composed of human serum albumin (HSA) and hyaluronidase (HAase) for overcoming the obstruction of ECM in the tumor microenvironment. The matrix-degrading human serum albumin/hyaluronidase soft-nanocapsules, referred to as HSA/HAase SNCs, possess a uniform diameter, inward hollow structure, and wrinkled morphology. biocompatibility results indicate that the HSA/HAase SNCs display no adverse effects on the viability of human umbilical vein endothelial cells (HUVECs), smooth muscle cells (SMCs), and mouse breast cancer (4T1) cells and do not induce hemolysis towards red blood cells (RBCs). The HSA/HAase SNCs exhibit a 1.4-fold increase in tumor cellular uptake compared to the stiff-counterparts and enhanced penetration in 4T1-, mouse colon carcinoma 26- (CT26-), and mouse pancreatic cancer- (PanO-) multicellular spheroids. Thanks to the advanced biological properties, a photodynamic platform prepared by loading Ce6 in the HSA/HAase SNCs (HSA/HAase@Ce6) shows improved reactive oxygen species production, a stronger killing effect for cancer cells, and deeper penetration in tumor tissues. experiments show that HSA/HAase@Ce6 effectively inhibits tumor growth in breast cancer mouse models. RNA-seq analysis of the mice that received the treatment of HSA/HAase@Ce6 shows enrichment of signaling pathways associated with ECM-degradation, which demonstrates that the matrix-degrading nanocapsules overcome the ECM-induced physical barriers in tumors. Overall, the matrix-degrading soft-nanoplatform represents a highly promising strategy to overcome ECM-induced physical barriers and enhance the therapeutic efficacy of nanomedicines.
肿瘤微环境中密集的细胞外基质 (ECM) 形成异常的物理屏障，阻碍纳米药物的传递和渗透，从而抑制其治疗效果。在此，我们合成了由人血清白蛋白 (HSA) 和透明质酸酶 (HAase) 组成的降解细胞外基质的软纳米胶囊，以克服肿瘤微环境中 ECM 的阻碍。这种降解细胞外基质的人血清白蛋白/透明质酸酶软纳米胶囊，简称 HSA/HAase SNCs，具有均匀的直径、内部中空的结构和褶皱的形态。生物相容性结果表明，HSA/HAase SNCs 对人脐静脉内皮细胞 (HUVECs)、平滑肌细胞 (SMCs) 和小鼠乳腺癌 (4T1) 细胞的活力没有不良影响，也不会引起红细胞 (RBCs) 的溶血。与刚性对照物相比，HSA/HAase SNCs 使肿瘤细胞摄取增加了 1.4 倍，并增强了在 4T1、小鼠结肠癌细胞 26 (CT26) 和小鼠胰腺癌 (PanO-) 多细胞球体中的渗透。由于具有先进的生物学特性，在 HSA/HAase SNCs 中装载 Ce6 制备的光动力平台 (HSA/HAase@Ce6) 显示出增强的活性氧物质产生、更强的杀伤癌细胞效果以及在肿瘤组织中的更深渗透。实验表明，HSA/HAase@Ce6 有效地抑制了乳腺癌小鼠模型中的肿瘤生长。接受 HSA/HAase@Ce6 治疗的小鼠的 RNA-seq 分析显示，与 ECM 降解相关的信号通路富集，这表明降解细胞外基质的纳米胶囊克服了肿瘤中 ECM 诱导的物理屏障。总的来说，降解细胞外基质的软纳米平台代表了一种很有前途的策略，可以克服 ECM 诱导的物理屏障，增强纳米药物的治疗效果。
