title: Neuropilin-1-targeted gold nanoparticles enhance therapeutic efficacy of platinum(IV) drug for prostate cancer treatment.
abstract: Platinum-based anticancer drugs such as cisplatin, oxaliplatin, and carboplatin are some of the most potent chemotherapeutic agents but have limited applications due to severe dose-limiting side effects and a tendency for cancer cells to rapidly develop resistance. The therapeutic index can be improved through use of nanocarrier systems to target cancer cells efficiently. We developed a unique strategy to deliver a platinum(IV) drug to prostate cancer cells by constructing glutathione-stabilized (Au@GSH) gold nanoparticles. Glutathione (GSH) has well-known antioxidant properties, which lead to cancer regression. Here, we exploit the advantages of both the antioxidant properties and high surface-area-to-volume ratio of Au@GSH NPs to demonstrate their potential for delivery of a platinum(IV) drug by targeting the neuropilin-1 receptor (Nrp-1). A lethal dose of a platinum(IV) drug functionalized with the Nrp-1-targeting peptide (CRGDK) was delivered specifically to prostate cancer cells in vitro. Targeted peptide ensures specific binding to the Nrp-1 receptor, leading to enhanced cellular uptake level and cell toxicity. The nanocarriers were themselves nontoxic, but exhibited high cytotoxicity and increased efficacy when functionalized with the targeting peptide and drug. The uptake of drug-loaded nanocarriers is dependent on the interaction with Nrp-1 in cell lines expressing high (PC-3) and low (DU-145) levels of Nrp-1, as confirmed through inductively coupled plasma mass spectrometry and confocal microscopy. The nanocarriers have effective anticancer activity, through upregulation of nuclear factor kappa-B (NF-κB) protein (p50 and p65) expression and activation of NF-κB-DNA-binding activity. Our preliminary investigations with platinum(IV)-functionalized gold nanoparticles along with a targeting peptide hold significant promise for future cancer treatment.
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology , Beijing, 100190, People's Republic of China.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Shuaidong
authors.initials: S
authors.lastname: Huo
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Aaron
authors.initials: A
authors.lastname: Tan
authors.forename: Shengliang
authors.initials: S
authors.lastname: Li
authors.forename: Shubin
authors.initials: S
authors.lastname: Jin
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Xue
authors.forename: YuanYuan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Ji
authors.forename: Lu
authors.initials: L
authors.lastname: Han
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: XiaoNing
authors.initials: X
authors.lastname: Zhang
authors.forename: Jinchao
authors.initials: J
authors.lastname: Zhang
authors.forename: Guozhang
authors.initials: G
authors.lastname: Zou
authors.forename: Tianyou
authors.initials: T
authors.lastname: Wang
authors.forename: Suoqin
authors.initials: S
authors.lastname: Tang
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Liang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000737:chemistry; D006046:Gold / Q000737:chemistry; D006801:Humans; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D016328:NF-kappa B / Q000378:metabolism; D039942:Neuropilin-1 / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry; D000077150:Oxaliplatin; D010455:Peptides / Q000737:chemistry; D010984:Platinum / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D013499:Surface Properties; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D004337:Drug Carriers; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D010455:Peptides; D000077150:Oxaliplatin; D039942:Neuropilin-1; D010984:Platinum; D006046:Gold; D005978:Glutathione