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The effect of P-glycoprotein inhibition and ultrasound exposure on the cytotoxicity of taxane loaded diblock copolymer nanoparticles in multidrug resistant cells

University of British Columbia

One of the major mechanisms of multidrug resistance involves an efflux protein, P-glycoprotein (Pgp), which pumps commonly used anticancer drugs such as taxanes out of cells, leading to a decrease in cellular drug accumulation. The overall goal of this project was to develop strategies to enhance intracellular drug accumulation and cytotoxicity of nanoparticulate taxanes in multi-drug resistant (MDR) cell lines. Paclitaxel (PTX) loaded nanoparticles fabricated from micelle forming MePEG₁₁₄-b-PCL₁₉ and nanosphere forming MePEG₁₁₄-b-PCL₁₀₄ were compared for drug and block copolymer uptake, and cytotoxicity in drug sensitive MDCKII and drug resistant MDCKII-MDR1 cell lines. PTX loaded micelles were more cytotoxic than PTX loaded nanospheres. Co-administration of the known Pgp inhibitor, MePEG₁₇-b-PCL₅, with PTX loaded micelles or nanospheres significantly increased drug cytotoxicity in MDCKII-MDR1 cells. Mixed molecular weight (MW) PCL₂₀₀/PCL₅ nanoparticles composed of long hydrophobic block, MePEG₁₁₄-b-PCL₂₀₀, and MePEG₁₇-b-PCL₅, were developed and characterized for the co-delivery of taxanes and Pgp inhibitor. Both PTX and docetaxel (DTX) loaded mixed MW PCL₂₀₀/PCL₅ nanoparticles were demonstrated to release MePEG₁₇-b-PCL₅ in a controlled release manner and increase drug cytotoxicity in MDR cells as compared to the drug loaded MePEG₁₁₄-b-PCL₂₀₀ nanoparticles in the absence of MePEG₁₇-b-PCL₅. The mixed MW nanoparticles remained in the plasma for longer than the drugs with approximately 3% of the injected dose remaining 24 hrs post injection. Ultrasound irradiation was investigated as a potential strategy to enhance the cytotoxicity of PTX loaded MePEG-b-PDLLA micelles in MDR cells. Using an ultrasound regime of a single 10-second burst of high frequency (4 MHz) and high intensity (32 W/cm²) ultrasound, it was shown that ultrasound irradiation resulted in a two-fold increase in intracellular uptake of PTX in drug sensitive MDCKII and MCF-7 cell lines and their respective Pgp-overexpressing MDCKII-MDR1 and NCI-ADR counterparts as compared to untreated cells (no ultrasound). The enhanced accumulation and retention of PTX resulting from ultrasound treatment translated into greater cytotoxicity in both drug sensitive and resistant cell lines. In conclusion, we have demonstrated two promising strategies for enhancing MDR cellular drug accumulation and effectiveness: the use of mixed molecular weight taxane loaded nanoparticles and ultrasound irradiation.

Text

2015-02-28

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/49957

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/