Combinatorial Polymeric Conjugated Micelles with Dual Cytotoxic and Antiangiogenic Effects for the Treatment of Ovarian Cancer

Abstract

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)-block-poly(β-benzyl L-aspartate) using a pHsensitive linker. The micelles release the drug(s) at pH 5.5 indicating preferential release in the acidic endosomal/lysosomal environment. Micelles exhibit anti-proliferative effects in ovarian cell cancer lines (SKOV-3 and ES2) and an endothelial cell line (HUVEC) 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 anti-angiogenic effects, while the MIX-M exhibited both antiangiogenic and apoptotic induction that results in significant tumor volume reduction. Based on our results, MIX-M micelles can be utilized to achieve synergistic apoptotic and anti-angiogenic effects when treated at frequent low doses.

Recent Advances and Impact of Chemotherapeutic and Antiangiogenic Nanoformulations for Combination Cancer Therapy

“… Pictorial representation of individual and mixed micelle polymer-conjugates of paclitaxel (PTX) and rapamycin (RAP): ( A ) synthesis schematic for polymeric-paclitaxel conjugate and polymeric-rapamycin conjugate and their micelles formulation, ( B ) pH-dependent drug release from micelles, ( C ) accessibility and accumulation of micelles for human umbilical vein endothelial cells HUVECs and cancer cells (ovarian) in the tumor environment [ 87 ]. Reprinted with permission from ref.…”

“…No acute toxicity was observed in healthy mice for over 21 days at a dose of 60 mg/kg of the micelles. The individual micelles exhibited only antiangiogenic activity, whereas the mixed micelles demonstrated both antiangiogenic and apoptosis induction activity in an epithelial ovarian cancer xenograft model in efficacy studies at 20 mg/kg/drug dosed every 4 days and assessed after 21 days(Figure 9)[87].…”

Micelles Formed by Polypeptide Containing Polymers Synthesized Via N-Carboxy Anhydrides and Their Application for Cancer Treatment

“…In 2016, Rao et al presented the synthesis of individual and mixed paclitaxel/rapamycin (PTX/RAP) micelles [ 29 ]. These micelles were formed with PTX and/or RAP and poly(ethylene glycol)- b -poly( β -benzyl- l -aspartate) copolymer via a pH-sensitive linker.…”

“… Paclitaxel (PTX) micelles, Rapamycin micelles and mixed micelles conjugated to diblock copolymer poly(ethylene glycol)– b –poly( β -benzyl- l -aspartate) [ 29 ]. …”

Researchers develop drug delivery system to slow and control tumors

“…A new system to slow and control tumors developed by researchers from Oregon and the United Kingdom was recently reported in Chemistry of Materials …”