Co-delivery of Doxorubicin and Curcumin with Polypeptide Nanocarrier for Synergistic Lymphoma Therapy

Abstract

The traditional chemotherapy, including Adriamycin (Doxorubicin, DOX), is widely used and is part of the first-line chemotherapy of invasive B cell lymphoma. DOX is nonselective cytotoxic drug and has many adverse effects, which limit its clinical application in combination with other anti-cancer drugs. Optimization of the delivery system targeting tumor microenvironment could be a feasible approach that may have significant clinical significance. Further, combination of DOX with other anticancer drugs, such as curcumin, can enhance the synergistic effects, possibly through epigenetic mechanisms. Hence, we evaluated the efficacy and toxicity of novel nanoparticles that enable the co-delivery of DOX and curcumin in the treatment of invasive B cell lymphoma both in vivo and vitro. The polymer nano materials [mPEG-b-P(Glu-co-Phe)] was used to co-load DOX and curcumin (CUR): L-DOX + CUR. DOX signal was measured to determine the ability of the drugs entering the cells by flow cytometry, and the different enrichment areas in the cells were directly observed by confocal microscope. The toxicity of LDOX + CUR was tested by CCK-8 assay in different cells, and the synergistic coefficients were calculated. The cell apoptosis and the possible mechanisms of apoptosis pathways regulation by L-DOX + CUR were examined using flow cytometry and Western Blot. The MTD (maximum tolerable dose) test was performed in mice. Tumor-bearing SCID mice (i.e., BJAB cell) were used to evaluate the in vivo efficacy of L-DOX + CUR. L-DOX + CUR, was prepared successfully, and the mole ratio of DOX and CUR fixed in 1.0:1.2. (DOX loading rate 9.7%, CUR loading rate 8.1%). L-DOX + CUR exhibited increased intracellular delivery and the main enrichment area of DOX was nucleus. L-DOX + CUR increased cytotoxicity, induced higher rates of apoptosis, and had synergistic effect, especially in BJAB cells (min CI 0.019). It even had epigenetic effect and affected miRNA levels favorably by down-regulating miR-21, miR-199a and up-regulating miR-98 and miR-200c. Additionally, L-DOX + CUR increased MTD in Kunming mice (i.e., 25 mg/kg), compared to DOX (10 mg/kg) and L-DOX (20 mg/kg). In BJAB cell bearing SCID mice, L-DOX + CUR treatment suppressed tumor growth compared to DOX or L-DOX alone, and exhibited less weight loss in mice. We developed new polymer nanoparticles-mPEG-b-P (Glu-co-Phe) co-loaded with DOX and DUR. L-DOX + CUR exhibited synergistic cytotoxic and apoptotic effects on invasive B cell lymphoma. Treatment of L-DOX + CUR potentiated tumor killing in xenografts and reduced toxicity in vivo.