Abstract
Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of β-elemene (βE) in solid lipid nanoparticles (MTO/βE-SLNs) for reversing MDR in leukemia. The MTO/βE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/βE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and βE, the in vitro cytotoxicity study indicated that MTO/βE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/βE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by βE. More importantly, the in vivo studies revealed that MTO/βE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and βE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/βE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia.
Highlights
Multidrug resistance (MDR) accounts for most chemotherapy-related failure in a wide array of malignancies
Mitoxantrone dihydrochloride (MTO), a cell cycle non-specific anticancer drug and P-glycoprotein (P-gp) substrate, is a synthetic anthracenedione that is applied for the treatment of acute leukemia, malignant lymphoma [2,3], breast cancer [4], and hepatocellular carcinoma [5]
The toxicity of the MTO and βE combination toward K562/DOX cells was investigated in different mass ratios (w/w)
Summary
Multidrug resistance (MDR) accounts for most chemotherapy-related failure in a wide array of malignancies. After internalization into the leukemia cells, βE could function as a chemosensitizer for inhibiting P-gp, preventing the MTO efflux, and improving the anticancer effects (Scheme 1). To fulfill these goals, the synergistic anticancer effect of the combination of MTO and βE in different ratios (w/w) was evaluated. Drug efflux and intracellular adenosine triphosphate (ATP)-binding cassette production assays were determined to evaluate the reversal effect of MDR by MTO/βE-SLNs. the in vivo effects and antitumor activity were investigated in K562/DOX xenografts tumor model mice.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.