Disulfide Cross-Linked
Micelles for the Targeted Delivery of Vincristine to B-Cell Lymphoma
Jason Kato
Yuanpei Li
Kai Xiao
Joyce
S. Lee
Juntao Luo
Joseph M. Tuscano
Robert
T. O’Donnell
Kit S. Lam
10.1021/mp300128b.s001
https://acs.figshare.com/articles/journal_contribution/Disulfide_Cross_Linked_Micelles_for_the_Targeted_Delivery_of_Vincristine_to_B_Cell_Lymphoma/2517496
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<sup>5k</sup>-Cys<sub>4</sub>-L<sub>8</sub>-CA<sub>8</sub>) 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 <i>in vivo</i> 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 <i>N</i>-acetylcysteine, DCM-VCR exhibited a superior
antitumor effect compared to conventional VCR.
2012-06-04 00:00:00
vivo efficacy study
EPR
dose
DCM
PEG 5k
drug release
16 nm
sciatic nerve
tumor sites
antitumor effect
tumor site
serum chemistry
micelle
encapsulated VCR
tumor growth
72 h
blood count
mg
1 h
anticancer drug
lymphoma xenografted
tumor volume
MTD
Targeted Delivery
drug delivery
NCM