Abstract
Here, we report the synthesis and evaluation of dual drug-loaded nanoparticles as an effective means to deliver carfilzomib and doxorubicin to multiple myeloma tumor cells at their optimal synergistic ratio. First, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines to determine the molar ratio that elicited the greatest synergy using the Chou-Talalay method. The therapeutic agents were then incorporated into liposomes at the optimal synergistic ratio of 1:1 to yield dual drug-loaded nanoparticles with a narrow size range of 115 nm and high reproducibility. Our results demonstrated that the dual drug-loaded liposomes exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. Taken together, this study presents the synthesis and preclinical evaluation of dual drug-loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma. Mol Cancer Ther; 15(7); 1452-9. ©2016 AACR.
Highlights
Multiple myeloma is the second most common hematologic malignancy in the United States, representing approximately 2% of all cancer-related deaths
The synergy of the 1:1 ratio is demonstrated in Fig. 1C, where NCI-H929 and MM.1S cells were incubated with carfilzomib, doxorubicin, or the 1:1 combination at a concentration of 25 nmol/L for each drug
Given the synergy and cytotoxicity observed in multiple myeloma cell lines, the 1:1 molar drug ratio was selected for nanoparticle formulation
Summary
Multiple myeloma is the second most common hematologic malignancy in the United States, representing approximately 2% of all cancer-related deaths. The acquisition of drug resistance by multiple myeloma cells often requires that a combination of two or more drugs be prescribed to effectively promote cell death by synergistically disrupting different cellular mechanisms necessary for growth and survival [1]. The two drugs may be administered at the optimal drug ratio for synergy, this does not ensure that this ratio will be maintained at the tumor site due to differences in injection schedules, pharmacokinetic properties, metabolism, and nonuniform biodistribution [5,6,7]. In order for combination therapies to achieve maximal antitumor effects and improved patient outcomes, it is imperative that the drugs reach the tumor at their optimal molar ratio. One strategy to enable this would be to use nanoparticles as drug delivery vehicles to control the release, biodistribution, and
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