Hypersensitization of Multidrug Resistant Human Ovarian Carcinoma Cells by Pluronic P85 Block Copolymer

Abstract

The chemosensitizing effect of Pluronic P85 block copolymer were studied using two human ovarian carcinoma sublines: the glycoprotein P (P-gp) multidrug resistant (MDR) SKVLB cells and non-MDR SKOV3 cells. The dramatic increase (up to 700 times) in the daunorubicin cytotoxic activity was observed in the presence of 0.01% (22 microM) to 1% (2.2 mM) copolymer in the case of SKVLB cells. By contrast, the copolymer induced a less than 3-fold increase in the drug activity in SKOV3 cells. As a result, the MDR subline demonstrated much higher response ("hypersensitivity") to the daunorubicin/ Pluronic compared to that of the non-MDR cells. The copolymer increased the cytotoxic effects of other MDR type drugs (doxorubicin, epirubicin, vinblastine, and mitomycin C) by a factor of 20-1000 and non-MDR type drugs (methotrexate and cisplatin) by a factor of 2-5.5. The daunorubicin influx in the cytoplasm and nuclei of SKVLB cells was also increased in the presence of the copolymer, while in SKOV3 cells, it remained practically unchanged. However, the hypersensitization of the MDR cells by the copolymer could not be merely explained by the P-gp modulation. Therefore, the possible role of the copolymer in inhibition of non-P-gp drug resistance is hypothesized, which may also explain the sensitization of MDR cells with respect to non-MDR type drugs as well as sensitization of parental cells. The concentration dependence of the IC50 in MDR cells indicates that just the copolymer unimers are responsible for the hypersensitization effect. The results obtained suggest that Pluronic P85 can be used as a delivery system to enhance the activity of antineoplastic agents against MDR tumors.

Designed amphiphilic peptide forms stable nanoweb, slowly releases encapsulated hydrophobic drug, and accelerates animal hemostasis

“…Because the peptide contains both hydrophobic and hydrophilic segments, we hypothesized that it could interact with the hydrophobic cargo and still have a good solubility in aqueous solution. Previous work showed that pyrene can be a good hydrophobic model drug because of its low water solubility (Ϸ6 ϫ 10 Ϫ7 M), well-defined fluorescence spectra, and well-established method to statistically analyze the transfer rate of pyrene into liposome vesicles (20)(21)(22)(23)(24)(25). We therefore used this system to measure our peptide-mediated delivery of pyrene into liposomes.…”

Cell phenotypic changes of mouse connective tissue fibroblasts (L-929) to poly(ethylene glycol)-based gels

“…12,13 These tri-block copolymers, namely Pluronics ® , are used for drug delivery applications and as emulsion stabilizers in pharmaceutical formulations. 14 In this study, we report on the use of polymeric gels that are cross-linked from such tri-block copolymer precursors bearing telechelic acrylate groups. In order to use polymeric (hydro)gels in biomedical applications, intense nutrient transport to cells as well as free diffusion of waste products are required.…”

Enhancement of the polycation‐mediated DNA uptake and cell transfection with Pluronic P85 block copolymer

“…One approach recently advanced for drug delivery of water insoluble compounds involves the use of micelles of Pluronic block copolymers [9,10]. Recent work on these systems suggests that they enhance the transport of charged molecules across cell membranes [11,12]. This paper reports a significant increase in cell uptake and transfection of mammalian cells using a combination of DNA-PEVP complexes and micelles of Pluronic P85 block copolymer.…”