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.