Combination Drug Delivery Strategy for the Treatment of Multidrug Resistant Ovarian Cancer

Abstract

The onset of multidrug resistance (MDR) in ovarian cancer is one of the main causes of treatment failure and low survival rates. Inadequate drug exposure and treatment-free periods due to intermittent chemotherapy select for cancer cells overexpressing drug efflux transporters, resulting in resistant disease. The present study examines the sustained administration of the chemotherapeutic agent docetaxel (DTX) alone and in combination with cepharanthine (CEP), a potent drug efflux transporter inhibitor. DTX and CEP were delivered via the intraperitoneal route in a sustained manner using an injectable polymer-lipid formulation. In vitro, the combination strategy resulted in significantly (p < 0.05) more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in ovarian cancer cells showing the MDR phenotype. In vivo, sustained treatment with DTX and CEP showed significantly greater (p< 0.05) tumor inhibition (91 ± 4%) in a murine model of multidrug resistant ovarian cancer compared to sustained DTX treatment (76 ± 6%) and was more than twice as efficacious as intermittent DTX treatment. Overall findings from these studies highlight the impact of sustained delivery of monotherapy and combination therapy in the management of refractory ovarian cancer displaying the MDR phenotype.

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

“…The mRNA expression of mdr1 and mrp7 in HeyA8-MDR cells is 3.1 and 3.3 times greater than that in HeyA8 cells, respectively (33). In addition, the docetaxel IC 50 values of HeyA8-MDR cells were shown to be 200 times greater than those in HeyA8 cells (33). The average tumor burden in nontreated mice bearing HeyA8 (1.59 AE 0.11 g) and HeyA8-MDR (1.60 AE 0.15 g) xenografts was significantly greater than in mice treated continuously, 3Â/wk, and 1Â/wk (HeyA8: 0.10 AE 0.03 g, 0.27 AE 0.04 g, 0.39 AE 0.08 g, respectively; HeyA8-MDR: 0.38 AE 0.03 g, 1.25 AE 0.09 g, 1.05 AE 0.23 g, respectively).…”

“…The mRNA expression of mdr1 and mrp7 in HeyA8-MDR cells is 3.1 and 3.3 times greater than that in HeyA8 cells, respectively (33). In addition, the docetaxel IC 50 values of HeyA8-MDR cells were shown to be 200 times greater than those in HeyA8 cells (33).…”

Nanocarriers for Delivery of siRNA and Co-Delivery of siRNA and Other Therapeutic Agents

“…One important reason is the innately possessed or gradually acquired MDR, which is a phenomenon when cancer cells are resistant to structurally unrelated anticancer drugs. For example, more than 90% of ovarian cancer patients who initially respond to standard regimen of chemotherapy with platinum-based drug and taxane are believed to relapse after a median period of 18 months due to the emergence of MDR [11]. Similarly, MDR is believed to account for treatment failure in more than 90% of metastatic breast cancer patients [12].…”

Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

“…The effect was further enhanced as the amount of CQ increased in PCL. According to the combination index (CI) values measured by the Chou-Talalay method, 26 PTX and CQ showed synergistic action in both cells when co-loaded into one liposome, and a stronger effect was achieved in A549/T cells compared with A2780/T cells. However, a significant difference in cytotoxicity between PTXL+CQL(1:2) and PCL1:2 was observed.…”