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The objectives of this study were to evaluate the potential of a polymer-lipid hybrid nanoparticle (PLN) system to enhance cellular accumulation and retention of doxorubicin (Dox), a widely used anticancer drug and an established P-glycoprotein (Pgp) substrate, in Pgp-overexpressing cancer cell lines and to explore the underlying mechanisms. Nanoparticles containing Dox complexed with a novel anionic polymer (Dox-PLN) were prepared using an ultrasound method. Two Pgp-overexpressing breast cancer cell lines (a human cell line, MDA435/LCC6/ MDR1, and a mouse cell line, EMT6/AR1) were used to investigate the effect of nanoparticles on cellular uptake and retention of Dox. Endocytosis inhibition studies and fluorescence microscopic imaging were performed to elucidate the mechanisms of cellular drug uptake. Treatment of Pgp-overexpressing cell lines with Dox-PLNs resulted in significantly enhanced Dox uptake and more substantial increases in drug retention after the end of treatment compared with free Dox solutions (p Ͻ 0.05). Fluorescence microscopic images showed improved nuclear localization of Dox and uptake of lipid when the drug was delivered in the Dox-PLN form to MDA435/LCC6/ MDR1 cells. Endocytosis inhibition studies revealed that phagocytosis is an important pathway in the membrane permeability of the nanoparticles. These findings suggest that some of the Dox physically associated with the nanoparticles bypass the membrane-associated Pgp when delivered as DoxPLNs, and in this form, the drug is better retained within the Pgp-overexpressing cells than the free drug. The present study suggests a new mechanism for overcoming drug resistance in Pgp-overexpressing tumor cells using lipid-based nanoparticle formulations.Chemotherapy with the use of cytotoxic drugs is commonly implemented in the management of many cancer types, e.g., breast cancers (Skeel, 2003;Tack et al., 2004). However, suboptimal therapeutic responses associated with multidrug resistance (MDR) frequently occur (Longley and Johnston, 2005). Overexpression of P-glycoprotein (Pgp) is one of the prominent mechanisms that contribute to the MDR phenotype (Endicott and Ling, 1989;Gottesman, 2002). Pgp is a 170-kDa membrane-associated glycoprotein that may actively extrude several substrates, including a variety of cytotoxic drugs such as doxorubicin (Dox), from cell cytoplasm to outside of plasma membrane, thus lowering the effective drug concentrations within the cells (Endicott and Ling, 1989;Gottesman, 2002). Because cytotoxic drugs typically carry numerous dose-limiting normal tissue side effects (Tipton, 2003), it is generally impractical to overcome this form of drug resistance simply by increasing the drug dose. To improve the therapeutic ratio of cancer chemotherapy, it is critical to establish alternative approaches that may improve accumulation and prolong retention of cytotoxic drugs in drug-resistant cancer cells without causing additional normal tissue side effects.Particulate drug delivery systems such as polymeric microspheres (...

The new polymer-lipid hybrid nanoparticle system is effective for delivery of Dox and enhances its efficacy against MDR breast cancer cells.

Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy.