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Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4164-9. doi: 10.1073/pnas.1522080113. Epub 2016 Mar 28.

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

Author information

1
CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China;
2
CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China; Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30322;
3
Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China;
4
Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30322; jwang699@ustc.edu.cn snie@emory.edu.
5
CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China; Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China; Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China jwang699@ustc.edu.cn snie@emory.edu.

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.

KEYWORDS:

nanomedicine; particle size; stimuli responsive; tumor extracellular pH; tumor penetration

PMID:
27035960
PMCID:
PMC4839420
DOI:
10.1073/pnas.1522080113
[Indexed for MEDLINE]
Free PMC Article

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