Openwork@Dendritic Mesoporous Silica Nanoparticles for Lactate Depletion and Tumor Microenvironment Regulation

• Published in: Angewandte Chemie International Edition Vol. 59; no. 49; pp. 22054 - 22062
• Main Authors: Tang, Jie, Meka, Anand Kumar, Theivendran, Shevanuja, Wang, Yue, Yang, Yannan, Song, Hao, Fu, Jianye, Ban, Wenhuang, Gu, Zhengying, Lei, Chang, Li, Shumin, Yu, Chengzhong
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.12.2020
• Edition: International ed. in English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Anthraquinones - pharmacology; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; cancer therapy; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Dendrimers - chemistry; Dendritic structure; Depletion; Drug Delivery Systems; Female; Growth factors; Hypoxia; Hypoxia - drug therapy; hypoxia prodrugs; Lactate oxidase; Lactic acid; Lactic Acid - metabolism; Liquid oxygen; mesoporous silica nanoparticles; Metastases; Mice; Mixed Function Oxygenases - metabolism; Nanoparticles; Nanoparticles - chemistry; Neovascularization, Pathologic - drug therapy; Particle Size; Pore size; Porosity; Silica; Silicon dioxide; Silicon Dioxide - chemistry; Surface Properties; tumor microenvironment; Tumor Microenvironment - drug effects; Tumors; Vascular endothelial growth factor; hypoxia prodrugs; cancer therapy; mesoporous silica nanoparticles; lactate oxidase; tumor microenvironment
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202001469

The direct depletion of lactate accumulated in the tumor microenvironment holds promise for cancer therapy but remains challenging. Herein, we report a one‐pot synthesis of openwork@ dendritic mesoporous silica nanoparticles (ODMSNs) to address this problem. ODMSNs self‐assembled through a time‐resolved lamellar growth mechanism feature an openworked core and a dendritic shell, both constructed by silica nanosheets of ≈3 nm. With a large pore size, high surface area and pore volume, ODMSNs exhibited a high loading capacity (>0.7 g g−1) of lactate oxidase (LOX) and enabled intratumoral lactate depletion by >99.9 %, leading to anti‐angiogenesis, down‐regulation of vascular endothelial growth factor, and increased tumor hypoxia. The latter event facilitates the activation of a co‐delivered prodrug for enhancing anti‐tumor and anti‐metastasis efficacy. This study provides an innovative nano‐delivery system and demonstrates the first example of direct lactate‐depletion‐enabled chemotherapy. A one‐pot synthesis of openwork@dendritic mesoporous silica nanoparticles (ODMSNs) for depletion of lactase accumulated in the tumor microenvironment is reported. ODMSNs exhibited a high loading capacity of lactate oxidase and enabled intratumoral lactate depletion of over 99.9 %, leading to anti‐angiogenesis, down‐regulation of vascular endothelial growth factor, and increased tumor hypoxia.