Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: Evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer

Abstract

Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET imaging, and overall survival. 18F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles.

Multifunctional Nanoparticles for Prostate Cancer Therapy

“…The release of cyclopamine was found to be higher than paclitaxel in both types of nanoparticles in spite of cyclopamine having higher log p value. Similar results were reported by Cho et al (28). The relative rapid release of cyclopamine as compared to paclitaxel could possibly be because of the higher affinity of paclitaxel toward both the polymeric systems over cyclopamine.…”

Colloidal stability of nano-sized particles in the peritoneal fluid: Towards optimizing drug delivery systems for intraperitoneal therapy

“…In the past few years, different DDSs were evaluated for IP administration [21,22], Among them are targeted nanocarriers [23], nanoparticles for intraperitoneal gene delivery [24], micelles [25], microparticle [26,27] and hydrogels for sustained release in the peritoneal cavity [28][29][30].…”

Poly(ethylene glycol)-block-poly(ε-caprolactone)– and phospholipid-based stealth nanoparticles with enhanced therapeutic efficacy on murine breast cancer by improved intracellular drug delivery

“…Most importantly, we hypothesized that the hybrid nanoparticles may combine the advantages of liposomes and polymeric micelles, such as safety and stability and improve cargo cellular uptake and tumor accumulation. Poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) diblock copolymer has been widely used to prepare PEGcoated micelles 2,4,[14][15][16][17] and is a promising PEG modification tool for stealth nanoparticles for the following reasons: 1) the synthesis of PEG-b-PCL is facile and is adaptable to mass manufacture; 18 2) PEG-b-PCL micelles can stay in the bloodstream for a prolonged time and are capable of efficient cell entry; 19,20 and 3) PEG-b-PCL is biocompatible, since PEG and PCL are both FDA-approved for use in humans. Moreover, PEG-b-PCL micelles carrying PTX (Genexol-PM) are approved in several Asian countries for cancer therapy and are in Phase III clinical trials in the US.…”