title: Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.
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.
authors.affiliation: 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;
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Li
authors.affiliation: 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;
authors.forename: Jin-Zhi
authors.initials: JZ
authors.lastname: Du
authors.affiliation: 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;
authors.forename: Xiao-Jiao
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China;
authors.forename: Cong-Fei
authors.initials: CF
authors.lastname: Xu
authors.affiliation: 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;
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Sun
authors.affiliation: 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;
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China;
authors.forename: Zhi-Ting
authors.initials: ZT
authors.lastname: Cao
authors.affiliation: 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;
authors.forename: Xian-Zhu
authors.initials: XZ
authors.lastname: Yang
authors.affiliation: 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;
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Zhu
authors.affiliation: Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30322; jwang699@ustc.edu.cn snie@emory.edu.
authors.forename: Shuming
authors.initials: S
authors.lastname: Nie
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D053758:Nanoparticles; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018874:Spheroids, Cellular
chemical_list: D000970:Antineoplastic Agents
keywords: nanomedicine; particle size; stimuli responsive; tumor extracellular pH; tumor penetration