Cisplatin Loaded Poly(L-glutamic acid)-g-Methoxy Polyethylene Glycol Complex Nanoparticles Combined with Gemcitabine Presents Improved Safety and Lasting Anti-Tumor Efficacy in a Murine Xenograft Model of Human Aggressive B Cell Lymphoma

Abstract

Cisplatin (CDDP) is a highly effective anti-tumor drug with a broad spectrum of activity. However, the clinical efficacy of CDDP-containing regimens is yet unsatisfactory due to the severe dose-related toxicity of CDDP. In a previous study, CDDP nanoparticles (L-CDDP) forms a complex as CDDP with poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) with improved safety compared to CDDP. Herein, a murine xenograft model of human aggressive B cell lymphoma (BCL) was established to explore anti-lymphoma efficiency of L-CDDP combined with GEM. BJAB cells represent an aggressive BCL, which were utilized to explore the anti-proliferative effect, cell apoptosis via CCK-8 test and flow cytometry technology, respectively. Toxicity experiment and the maximum tolerated dose (MTD) test were conducted in Kunming mice. Tumor inhibition experiment was conducted at the dose of MTD in SCID beige mice-bearing lymphoma. In this study, the loading capacity and encapsulating efficiency of CDDP in the L-CDDP was 18.3% and 89.7%, respectively, and the hydrodynamic diameter of the prepared L-CDDP was 20.6 nm. The CCK-8 data indicated that the anti-proliferative activity of monodrug groups (GEM, CDDP, L-CDDP) was dose- and time-dependent in BJAB cells. The synergistic effects in anti-lymphoma were detected in these two groups (GEM+CDDP, GEM + L-CDDP). Compared to control group, the proportion of apoptotic cells in experimental groups in BJAB cells was significantly higher at 48 h. Toxicity assays revealed that GEM + L-CDDP regimen had low hematological toxicity, hepatotoxicity, and nephrotoxicity. Tumor inhibition experiment demonstrated that GEM + L-CDDP group exhibited significant tumor-suppressing effects. Moreover, tumors continued to shrink in GEM + L-CDDP group, while these appeared to grow in the GEM + CDDP group. Finally, tumor necrosis was most prominent in the GEM + CDDP and GEM + L-CDDP groups, as assessed by hematoxylin-eosin staining. In conclusion, compared to CDDP, L-CDDP combined with GEM seriously induces BJAB cell apoptosis. Also, GEM + L-CDDP exhibits low hematotoxicity, hepatotoxicity, and nephrotoxicity. Importantly, GEM + L-CDDP presents lasting anti-lymphoma efficacy in a SCID beige mice-bearing lymphoma.