PMID- 27035960 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20181113 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 113 IP - 15 DP - 2016 Apr 12 TI - Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy. PG - 4164-9 LID - 10.1073/pnas.1522080113 [doi] AB - 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 approximately 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 approximately 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. FAU - Li, Hong-Jun AU - Li HJ AD - 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; FAU - Du, Jin-Zhi AU - Du JZ AD - 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; FAU - Du, Xiao-Jiao AU - Du XJ AD - 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; FAU - Xu, Cong-Fei AU - Xu CF AD - Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China; FAU - Sun, Chun-Yang AU - Sun CY AD - 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; FAU - Wang, Hong-Xia AU - Wang HX AD - 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; FAU - Cao, Zhi-Ting AU - Cao ZT AD - Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China; FAU - Yang, Xian-Zhu AU - Yang XZ AD - 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; FAU - Zhu, Yan-Hua AU - Zhu YH AD - 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; FAU - Nie, Shuming AU - Nie S AD - Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30322; jwang699@ustc.edu.cn snie@emory.edu. FAU - Wang, Jun AU - Wang J AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160328 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antineoplastic Agents) SB - IM MH - Antineoplastic Agents/administration & dosage/pharmacokinetics/*therapeutic use MH - Apoptosis MH - Cell Line, Tumor MH - Humans MH - *Nanoparticles MH - Neoplasm Metastasis MH - Neoplasms/*drug therapy/pathology MH - Spheroids, Cellular PMC - PMC4839420 OTO - NOTNLM OT - nanomedicine OT - particle size OT - stimuli responsive OT - tumor extracellular pH OT - tumor penetration COIS- The authors declare no conflict of interest. EDAT- 2016/04/02 06:00 MHDA- 2016/12/15 06:00 PMCR- 2016/10/12 CRDT- 2016/04/02 06:00 PHST- 2016/04/02 06:00 [entrez] PHST- 2016/04/02 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] PHST- 2016/10/12 00:00 [pmc-release] AID - 1522080113 [pii] AID - 201522080 [pii] AID - 10.1073/pnas.1522080113 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4164-9. doi: 10.1073/pnas.1522080113. Epub 2016 Mar 28.