2 research outputs found
Combinatorial polymeric conjugated micelles with dual cytotoxic and antiangiogenic effects for the treatment of ovarian cancer
Emerging treatment paradigms like
targeting the tumor microenvironment
and/or dosing as part of a metronomic regimen are anticipated to produce
better outcomes in ovarian cancer, but current drug delivery systems
are lacking. We have designed and evaluated paclitaxel (PTX) and rapamycin
(RAP) micellar systems that can be tailored for various dosing regimens
and target tumor microenvironment. Individual and mixed PTX/RAP (MIX-M)
micelles are prepared by conjugating drugs to a poly(ethylene glycol)-<i>block</i>-poly(β-benzyl l-aspartate) using a
pH-sensitive linker. The micelles release the drug(s) at pH 5.5 indicating
preferential release in the acidic endosomal/lysosomal environment.
Micelles exhibit antiproliferative effects in ovarian cell cancer
lines (SKOV-3 (human caucasian ovarian adenocarcinoma) and ES2 (human
ovarian clear cell carcinoma)) and an endothelial cell line (HUVEC;
human umbilical vein endothelial cells) with the MIX-M being synergistic.
The micelles also inhibited endothelial migration and tube formation.
In healthy mice, micelles at 60 mg/kg/drug demonstrated no acute toxicity
over 21 days. ES2 xenograft model efficacy studies at 20 mg/kg/drug
dosed every 4 days and evaluated at 21 days indicate that the individual
micelles exhibit antiangiogenic effects, while the MIX-M exhibited
both antiangiogenic and apoptotic induction that results in significant
tumor volume reduction. On the basis of our results, MIX-M micelles
can be utilized to achieve synergistic apoptotic and antiangiogenic
effects when treated at frequent low doses