A study of nanoparticle drug carrier for treatment of multidrug-resistant breast cancer with loco-regional involvement.

摘要

The toxicity of anticancer agents to normal tissues, frequent occurrence of multidrug resistance (MDR) that is associated with mechanisms such as P-glycoprotein (P-gp) mediated cellular drug efflux, and metastasis of cancer cells present formidable obstacles to the conventional chemotherapy of breast cancer. To improve the therapeutic index of MDR breast cancer chemotherapy, a novel polymer-lipid hybrid nanoparticle (PLN) system was developed and investigated for the encapsulation and delivery of Ionic, water-soluble anticancer drugs (e.g. doxorubicin HCl (Dox)) alone and with Pgp inhibitors.;PLN loaded with various drugs were prepared using lipids and anionic polymers. The PLN size ranged from 80-400 nm in diameter. The encapsulation efficiencies for Dox and verapamil HCl were both significantly increased with the inclusion of the polymers to lipids. The study of counterion effect and electron microscopy suggested that in addition to drug diffusion, ion-exchange mechanism and lipid erosion contributed to the drug release from PLN.;In vitro cytotoxicity of Dox-loaded PLN (Dox-PLN) was evaluated using murine EMT6 and human MDA435/LCC6 parent and MDR breast cancer cell lines. The PLN formulation enhanced the Dox efficacy and cellular Dox uptake and retention by P-gp-overexpressing cell lines. Fluorescence microscope images confirmed that Dox was transported to intracellular compartment at least partly by the PLN. The results of endocytosis inhibition study suggest that lipid nanoparticles may overcome cellular drug resistance by bypassing the membrane-associated transporters via endocytosis. Overall, the association of Dox with PLN makes the drug molecules more difficult to be cleared from the drug-resistant cells.;To further enhance the effectiveness against MDR cancer, Dox and a novel chemosensitizer GG918 was co-encapsulated in PLN and simultaneously delivered. Dual-agent loaded PLN resulted in the highest anticancer activity against and Dox uptake by P-gp-overexpressing cells when compared to other ways of administering the drug combination.;The in vivo anticancer activity of Dox-PLN was demonstrated using mice bearing solid tumors initiated by inoculating EMT6 cells. Intratumorally administered Dox-PLN were shown able to significantly delay the growth of the tumors and induce necrosis inside the tumors, while causing very low normal tissue toxicity at fairly high doses.;To conclude, the findings described in this thesis demonstrate that by integrating the pharmaceutical (i.e. PLN) and pharmacological (i.e. GG918) means, the chemotherapy of MDR breast cancer may be potentially optimized.