Insufficient oxygenation (hypoxia), acidic pH (acidosis), and elevated levels of reactive oxygen species (ROS), such as H2O2, are characteristic abnormalities of the tumor microenvironment (TME). These abnormalities promote tumor aggressiveness, metastasis, and resistance to therapies. To date, there is no treatment available for comprehensive modulation of the TME. Approaches so far have been limited to regulating hypoxia, acidosis, or ROS individually, without accounting for their interdependent effects on tumor progression and response to treatments. Hence we have engineered multifunctional and colloidally stable bioinorganic nanoparticles composed of polyelectrolyte-albumin complex and MnO2 nanoparticles (A-MnO2 NPs) and utilized the reactivity of MnO2 toward peroxides for regulation of the TME with simultaneous oxygen generation and pH increase. In vitro studies showed that these NPs can generate oxygen by reacting with H2O2 produced by cancer cells under hypoxic conditions. A-MnO2 NPs simultaneously increased tumor oxygenation by 45% while increasing tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor in a murine breast tumor model. Intratumoral treatment with NPs also led to the downregulation of two major regulators in tumor progression and aggressiveness, that is, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to radiation therapy alone. These results suggest great potential of A-MnO2 NPs for modulation of the TME and enhancement of radiation response in the treatment of cancer.

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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 (...

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