Abstract
With the extensive application of doxorubicin (DOX), DOX resistance has become one of the main obstacles to the effective treatment of breast cancer. In this paper, DOX and resveratrol (RES) were co-encapsulated in a modified PLGA nanoparticle (NPS) to overcome the DOX resistance. CLSM results indicated that DOX and RES were simultaneously delivered into the nucleus of DOX-resistant human breast cancer cells by DOX/RES-loaded NPS. Consequently, DOX/RES-loaded NPS showed significant cytotoxicity on MDA-MB-231/ADR cells and MCF-7/ADR cells. Furthermore, DOX/RES-loaded NPS could overcome DOX resistance by inhibiting the expression of drug resistance-related protein such as P-gp, MRP-1 and BCRP, and induce apoptosis through down-regulating the expression of NF-κB and BCL-2. In tumor-bearing mice, DOX/RES-loaded NPS mainly delivered DOX and RES to tumor tissue. Compared with free DOX, DOX/RES-loaded NPS significantly inhibited the DOX-resistant tumor growth in tumor-bearing mice without causing significant systemic toxicity. In a word, DOX/RES-loaded NPS could overcome the DOX resistance and had the potential in the treatment of DOX-resistant breast cancer.
Highlights
IntroductionAn important method to overcome DOX resistance is to use two or more chemotherapeutic drugs with different anti-tumor mechanisms[5]
In recent years, numerous strategies were proposed to reverse DOX resistance
DOX and RES were co-encapsulated in poly(lactic-co-glycolic acid) (PLGA) based nanoparticles to prolong the half-life of DOX and RES, increase the concentration of DOX and RES in tumor tissue, overcome DOX resistance, and reduce the toxicity of DOX in healthy organs
Summary
An important method to overcome DOX resistance is to use two or more chemotherapeutic drugs with different anti-tumor mechanisms[5]. Just using two or more free chemotherapeutic drugs without controlling their delivery and release characteristic can not effectively overcome DOX resistance or enhance the anticancer effects of the drugs[6,7]. Mixture of free DOX and free RES without controlling their pharmacokinetic characteristic can not overcome DOX resistance and enhance the anticancer effects of DOX. DOX and RES were co-encapsulated in poly(lactic-co-glycolic acid) (PLGA) based nanoparticles to prolong the half-life of DOX and RES, increase the concentration of DOX and RES in tumor tissue, overcome DOX resistance, and reduce the toxicity of DOX in healthy organs. The anti-tumor activity of DOX/RES-loaded nanoparticles on DOX-resistant tumor and its molecular mechanisms were deeply investigated in vitro and in vivo
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