title: "OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo.
abstract: Micellar nanoparticles based on linear polyethylene glycol (PEG) block dendritic cholic acids (CA) copolymers (telodendrimers), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers, are reported. The micellar nanoparticles have been decorated with a high-affinity "OA02" peptide against α-3 integrin receptor to improve the tumor-targeting specificity which is overexpressed on the surface of ovarian cancer cells. "Click chemistry" was used to conjugate alkyne-containing OA02 peptide to the azide group at the distal terminus of the PEG chain in a representative PEG(5k)-CA(8) telodendrimer (micelle-forming unit). The conjugation of OA02 peptide had negligible influence on the physicochemical properties of PEG(5k)-CA(8) nanoparticles and as hypothesized, OA02 peptide dramatically enhanced the uptake efficiency of PEG(5k)-CA(8) nanoparticles (NP) in SKOV-3 and ES-2 ovarian cancer cells via receptor-mediated endocytosis, but not in α-3 integrin-negative K562 leukemia cells. When loaded with paclitaxel, OA02-NPs had significantly higher in vitro cytotoxicity against both SKOV-3 and ES-2 ovarian cancer cells as compared with nontargeted nanoparticles. Furthermore, the in vivo biodistribution study showed OA02 peptide greatly facilitated tumor localization and the intracellular uptake of PEG(5k)-CA(8) nanoparticles into ovarian cancer cells as validated in SKOV3-luc tumor-bearing mice. Finally, paclitaxel (PTX)-loaded OA02-NPs exhibited superior antitumor efficacy and lower systemic toxicity profile in nude mice bearing SKOV-3 tumor xenografts, when compared with equivalent doses of nontargeted PTX-NPs as well as clinical paclitaxel formulation (Taxol). Therefore, OA02-targeted telodendrimers loaded with paclitaxel have great potential as a new therapeutic approach for patients with ovarian cancer.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California 95817, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Xiao
authors.forename: Yuanpei
authors.initials: Y
authors.lastname: Li
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Lee
authors.forename: Abby M
authors.initials: AM
authors.lastname: Gonik
authors.forename: Tiffany
authors.initials: T
authors.lastname: Dong
authors.forename: Gabriel
authors.initials: G
authors.lastname: Fung
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sanchez
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Holland R
authors.initials: HR
authors.lastname: Cheng
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D010455:Peptides / Q000138:chemical synthesis / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D039001:Integrin alpha Chains; D008823:Micelles; D010455:Peptides; D011092:Polyethylene Glycols; D017239:Paclitaxel