Synergistic Nanoparticulate Drug Combination Overcomes Multidrug Resistance, Increases Efficacy, and Reduces Cardiotoxicity in a Nonimmunocompromised Breast Tumor Model

Abstract

Anthracyclines, commonly employed for cancer chemotherapy, suffer from dose-limiting cardiotoxicity and poor efficacy due to multidrug resistance (MDR). We previously demonstrated that simultaneous delivery of the synergistic drugs doxorubicin (DOX) and mitomycin C (MMC) by polymer-lipid hybrid nanoparticles (PLN) circumvented MDR, increased efficacy, and reduced cardiotoxicity in immuncompromised mice superior to poly(ethylene glycol)-coated (PEGylated) lipososmal DOX (PLD). Herein it is shown that the DOX-MMC combination was also synergistic in MDR EMT6/AR1 murine breast cancer cells and that their nanoparticle formulations were able to overcome the MDR phenotype. In contrast PLD exhibited little or no effect on the MDR cells. For the first time, these differences in in vitro efficacy are shown to be strongly correlated with cellular uptake and intracellular distribution of DOX brought about by DOX formulations (e.g., free solution, PLN vs PLD). To take into consideration the role of an intact immune system and tumor stroma in the response of host and tumor to chemotherapy, use was made of nonimmunocomprised mouse models to study the dose tolerance, cardiotoxicity, and efficacy of DOX-MMC coloaded PLN (DMsPLN) compared to PLD. DMsPLN treatment at 50 mg/m(2) DOX and 17 mg/m(2) of MMC singly or once every 4 days for 4 cycles were well tolerated by the mice without elevated systemic toxicity blood markers or myocardial damage. In contrast, PLD was limited to a single treatment due to significant total weight loss. The DMsPLN treatment delayed tumor growth up to 312% and 28% in EMT6/WT and EMT6/AR1 models, respectively. This work supports the translational value of DMsPLN for the aggressive management of either naïve or anthracycline-resistant tumors.

MicroRNA-101 sensitizes hepatocellular carcinoma cells to doxorubicin-induced apoptosis via targeting Mcl-1

“…DOX-based chemotherapy is used against a wide range of cancer types, including ovarian (6), breast (7) and bladder cancer (8) as well as HCC (9). However, the clinical application of DOX is limited due to cardiac toxicity and drug resistance (10). Therefore, it is urgently required to develop novel and efficient approaches to improve the curative effects of DOX for HCC treatment.…”

Strategies for optimizing polymer-lipid hybrid nanoparticle-mediated drug delivery

“…[8] PLN formulations have been shown to circumvent efflux transporter-mediated multidrug resistance (MDR) in cancer cells [1,4,6,9] and increase antitumor efficacy while reducing systemic toxicity of the anticancer drugs. [10,11] It was found that the PLN facilitated drug uptake and retention in P-gp overexpressing cancer cells, provided effective intracellular drug release, transported the drug (e.g. doxorubicin) to the nuclei where drug target (i.e.…”

“…[12] Owing to these unique properties and more desired drug release kinetics than clinically used liposomal doxorubicin (Doxil®/Caelyx®) which has a long release half-life of 118 hours, a PLN formulation with co-encapsulated synergistic anticancer drugs, that is, doxorubicin and mitomycine C, outperformed Doxil®/Caelyx® in MDR cancer cells and in preclinical tumor models. [10][11][12] …”

“…endogenous fatty acids). Up to date, reported PLN formulations can be divided into two major categories as schematically illustrated in Figure 1: type A -monolithic matrix PLN, where polymer and drug(s) are homogeneously distributed in the solid lipid matrix, [1,[3][4][5][6][9][10][11][12] and type Bcore-shell PLN, where drug-containing polymer core is covered by a single layer of phospholipid. [7,8,13] The latter is sometimes called lipid-polymer hybrid nanoparticles (LPN) in literature.…”

“…Moreover, type A PLN can be made 'stealth' for prolonged systemic circulation by introducing PEG-lipid of two different chain lengths. [6,[9][10][11][12] The core-shell (type B) PLN utilize the advantage of hydrophobic polymer core for sustained drug release and lipid (bi) layer to mimic hydrophilic liposomal surface. PEG chains can also be conjugated on the surface to achieve long circulation of the nanoparticles.…”