"OA02" Peptide Facilitates the Precise Targeting of Paclitaxel-Loaded Micellar Nanoparticles to Ovarian Cancer In Vivo
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale de nanoparticules, sur lesquelles ont été fixées le peptide OA02, pour le traitement d'un cancer de l'ovaire
Micellar nanoparticles (NPs) 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 NPs have been decorated with a high-affinity "OA02" peptide against alpha-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 PEG5k-CA8 telodendrimer (micelle forming unit). The conjugation of OA02 peptide had negligible influence on the physicochemical properties of PEG5k-CA8 NPs and as hypothesized, OA02 peptide dramatically enhanced the uptake efficiency of PEG5k-CA8 NPs in SKOV-3 and ES-2 ovarian cancer cells via receptor-mediated endocytosis, but not in alpha-3 integrin negative K562 leukemia cells. When loaded with paclitaxel (PTX), OA02-NPs had significantly higher in vitro cytotoxicity against both SKOV-3 and ES-2 ovarian cancer cells as compared with non-targeted NPs. Furthermore, the in vivo biodistribution study demonstrated OA02 peptide greatly facilitated tumor localization and the intracellular uptake of PEG5k-CA8 NPs into ovarian cancer cells as validated in SKOV3-luc tumor bearing mice. Finally, PTX-loaded OA02-NPs exhibited superior anti-tumor efficacy and lower systemic toxicity profile in nude mice bearing SKOV-3 tumor xenografts, when compared with equivalent doses of non-targeted PTX-NPs as well as clinical PTX formulation (Taxol®). Therefore, OA02 targeted telodendrimers loaded with PTX have great potential as a new therapeutic approach for ovarian cancer patients.
Cancer Research 2012