Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

• Type of Material: Article
• Authors: Hong-Jun Li, University of Science and Technology of China; Jin-Zhi Du, University of Science and Technology of China; Xiao-Jiao Du, University of Science and Technology of China; Cong-Fei Xu, University of Science and Technology of China; Chung-Yang Sun, University of Science and Technology of China; Hong-Xia Wang, University of Science and Technology of China; Zhi-Ting Cao, University of Science and Technology of China; Xian-Zhu Yang, University of Science and Technology of China; Yan-Hua Zhu, University of Science and Technology of China; Shuming Nie, Emory University; Jun Wang, University of Science and Technology of China
• Language: English
• Date: 2016-04-12
• Publisher: United States National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2016 National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1522080113
• Title of Journal or Parent Work: PNAS
• Volume: 113
• Issue: 15
• Start Page: 4164
• End Page: 4169
• Grant/Funding Information: This work was supported by the National Basic Research Program of China (973 Programs, 2012CB932500, 2015CB932100, and 2013CB933900) and the National Natural Science Foundation of China (51125012, 51390482, and 51503195).
• Keywords: Science & Technology; Design; Multidisciplinary Sciences; Strategies; Nanomedicine; Nanocarriers; Cancer; Tumor extracellular pH; pH; Delivery; Accumulation; Conjugate; Tumor penetration; Size; Photoswitchable nanoparticles; Stimuli responsive; Particle size; Science & Technology - Other Topics
• Research Categories: Engineering, Biomedical; Health Sciences, Oncology; Biology, Microbiology

Abstract

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.