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

• 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
• Journal Title: PNAS
• Volume: Volume 113, Number 15
• Publisher: United States National Academy of Sciences | 2016-04-12, Pages 4164-4169
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.1522080113
• Subjects: Biology, Microbiology; Engineering, Biomedical; Health Sciences, Oncology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; Nanomedicine; Particle size; Tumor penetration; Tumor extracellular pH; Stimuli responsive; Photoswitchable nanoparticles; Cancer; Size; pH; Accumulation; Delivery; Design; Nanocarriers; Strategies; Conjugate

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.