title: Disulfide cross-linked micelles for the targeted delivery of vincristine to B-cell lymphoma.
abstract: Vincristine (VCR) is a potent anticancer drug, but its clinical efficacy is limited by neurotoxicity. The field of drug delivery may provide an opportunity to increase the therapeutic index of VCR by delivering the drug specifically to tumor sites while sparing normal tissue. We have recently developed a telodendrimer (PEG(5k)-Cys(4)-L(8)-CA(8)) capable of forming disulfide cross-linked micelles (DCMs) which can encapsulate a variety of chemotherapeutics. In the present study, we encapsulated VCR into these micelles (DCM-VCR) and used them to treat lymphoma bearing mice. DCM-VCR particles have a size of 16 nm, which has been shown to be optimal for their accumulation into tumor via the enhanced permeability and retention (EPR) effect. Compared to our first-generation non-cross-linked micelles (NCMs), DCM-VCR demonstrated greater stability and slower drug release under physiological conditions. In addition, DCM-VCR exhibited a maximum tolerated dose (MTD) of 3.5 mg/kg while the MTD for conventional VCR was only 1.5 mg/kg. Using a near-infrared cyanine dye (DiD) as the surrogate drug, we showed that DCM-VCR accumulated at the tumor site starting 1 h after injection and persisted up to 72 h in lymphoma xenografted nude mice. In an in vivo efficacy study, high dose (2.5 mg/kg) DCM-VCR produced the greatest reduction in tumor volume. High dose DCM-VCR was well tolerated with no significant changes in complete blood count, serum chemistry and histology of the sciatic nerve. Mice treated with an equivalent dose (1 mg/kg) of conventional VCR and DCM-VCR controlled tumor growth equally; however, in combination with on-demand addition of the reducing agent N-acetylcysteine, DCM-VCR exhibited a superior antitumor effect compared to conventional VCR.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, California 95817, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Kato
authors.forename: Yuanpei
authors.initials: Y
authors.lastname: Li
authors.forename: Kai
authors.initials: K
authors.lastname: Xiao
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Lee
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Tuscano
authors.forename: Robert T
authors.initials: RT
authors.lastname: O'Donnell
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry*; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D014750:Vincristine / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: D004220:Disulfides; D008823:Micelles; D014750:Vincristine