The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance

Abstract

Two types of nanoparticles were prepared using the diblock copolymer methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL), with either a short PCL block length, which forms micelles, or with a longer PCL block length, which forms kinetically "frozen core" structures termed nanospheres. Paclitaxel (PTX)-loaded micelles and nanospheres were evaluated for their cytotoxicity, cellular polymer uptake, and drug accumulation in drug-sensitive (Madin-Darby Canine Kidney [MDCK]II) and multidrug-resistant (MDR) P-glycoprotein (P-gp)-overexpressing (MDCKII-MDR1) cell lines. Both types of PTX-loaded nanoparticles were equally effective at inhibiting proliferation of MDCKII cells, but PTX-loaded micelles were more cytotoxic than nanospheres in MDCKII-MDR1 cells. The intracellular accumulation of both PTX and the diblock copolymers were similar for both nanoparticles, suggesting that the difference in cytotoxicity might be due to the different drug-release profiles. Furthermore, the cytotoxicity of these PTX-loaded nanoparticles was enhanced when these systems were subsequently or concurrently combined with a low-molecular-weight MePEG-b-PCL diblock copolymer, which we have previously demonstrated to be an effective P-gp inhibitor. These results suggest that the dual functionality of MePEG-b-PCL might be useful in delivering drug intracellularly and in modulating P-gp in order to optimize the cytotoxicity of PTX in multidrug-resistant cells.

Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy

“…Moreover, Xu et al demonstrated promising results obtained during treatment of drug-resistant A549 lung cancer cell with PLGA-based nanoparticles loaded with cyclosporin A and encapsulated P-gp inhibitor [ 139 ]. These observations are in great agreement with reports demonstrated in previous years [ 140 , 141 ].…”

Acetylated Tubulin (AT) as a Prognostic Marker in Squamous Cell Carcinoma of the Head and Neck

“…Several mechanisms of resistance to taxanes have been described. Overexpression of drug efflux pumps, such as P-glycoprotein and multidrug resistance-associated protein-1 (MRP1), is one of the possible drug resistance mechanisms [15][16][17]. MRP1 can efficiently pump antineoplastic drugs out of cancer cells, thereby lowering intracellular drug concentrations.…”

Mixed Molecular Weight Copolymer Nanoparticles for the Treatment of Drug-Resistant Tumors: Formulation Development and Cytotoxicity

“…c and d). As demonstrated in previously published studies, after an initial incubation with PTX, it was essential to maintain the presence of MePEG 17 ‐b‐PCL 5 in the media to enable inhibition of P‐gp and hence retention of PTX within MDCKII‐MDR cells . Therefore, it is possible that after incubation with the cells and subsequent removal of the formulations, the concentration of MePEG 17 ‐b‐PCL 5 associated with the cells did not remain high enough to prevent efflux by P‐gp.…”

“…As demonstrated in previously published studies, after an initial incubation with PTX, it was essential to maintain the presence of MePEG 17 -b-PCL 5 in the media to enable inhibition of P-gp and hence retention of PTX within MDCKII-MDR cells. 38 Therefore, it is possible that after incubation with the cells and subsequent removal of the formulations, the concentration of MePEG 17 -b-PCL 5 associated with the cells did not remain high enough to prevent efflux by P-gp. In light of the results presented in Figure 5, it was apparent that long-term treatment with the P-gp inhibitor was required to inhibit the growth of MDCKII-MDR cells; therefore, we investigated the effect of continuous 3-day incubation of MDCKII-MDR cells with free drug or drug-loaded nanoparticles with varying concentrations of copolymer ( Fig.…”