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Disulfide Cross-Linked Micelles for the Targeted Delivery of Vincristine to B-Cell Lymphoma
journal contribution
posted on 2012-06-04, 00:00 authored by Jason Kato, Yuanpei Li, Kai Xiao, Joyce
S. Lee, Juntao Luo, Joseph M. Tuscano, Robert
T. O’Donnell, Kit S. LamVincristine (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 (PEG5k-Cys4-L8-CA8) 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.