Selinexor-Loaded Polymeric Micelles for Multiple Myeloma Therapy

Introduction Multiple myeloma (MM) is characterized by the clonal proliferation of abnormal plasma cells in the bone marrow. Selinexor (SEL) is an XPO1 inhibitor, and in a pivotal clinical trial, the SEL and dexamethasone regimen showed a 26% of partial response rate or better, with two patients achieving stringent complete response. However, the single-agent efficacy of SEL was modest, with systemic toxicities including thrombocytopenia and gastrointestinal symptoms that negatively impacted the quality of life. Nanomedicine refers to the ingenious design of nanoscale biomaterials for drug delivery. Polymeric micelles are made up of self-assembled amphiphilic block polymers and act as an effective strategy to address the challenge of free drug administration. To reduce side effects and improve therapeutic efficacy, we reported our work on SEL delivery using mPEG-PCL micelles for the treatment of MM.

Materials and Methods The SEL-loaded micelles were developed through thin-film hydration. The mean particle size, zeta potential, and polydispersity index of micelles were assessed by a Malvern Nano-ZS 90. The release behavior of the mPEG-PCL-SEL micelle was determined by a dialysis method in vitro. The cytotoxicity and apoptosis rate of the mPEG-PCL-SEL micelle were assessed on the RPMI-8226 cell line and the ARD cell line. The ARD orthotopic MM model was developed by intravenous administration of ARD-luc cells into 6-week-old B-NDG mice. Four groups were treated with saline, blank micelles, or mPEG-PCL-SEL micelles (SEL concentrations: 2.5 and 5 mg/kg) via intravenous injection, and the other four groups were given free-SEL via oral gavage (SEL concentrations: 2.5, 5, 10, and 15 mg/kg), respectively. All of the treatments were given twice a week for two weeks. To evaluate the tumor burden, bioluminescence imaging was monitored. Brain samples were collected for assessment of brain penetration ability of the micellar formulation. In addition, the animal weight, peripheral blood counts, and condition of mice were measured to investigate the side effects.

Results The particle size of the mPEG-PCL-SEL micelle was 31.3 nm, the PDI was 0.11-0.16, and the zeta potential was −4.52 mV. The encapsulation efficacy was 90.56%. The micelles remained stable for a long period and exhibited a controlled release behavior. In addition, the mPEG-PCL-SEL micelle exhibited enhanced cellular uptake ability and efficient cytotoxicity toward MM cells. Most importantly, in the orthotopic MM model, this micelle system exhibited impressive therapeutic efficacy. The 5 mg/kg mPEG-PCL-SEL micelle group demonstrated better treatment efficacy than the 10 mg/kg free-SEL group according to the quantitative analysis of tumor bioluminescence, indicating the superior therapeutic activity, although there was no significant difference. Surprisingly, the SEL-loaded micelle efficiently prolonged the survival of myeloma-bearing mice. Besides, the micellar formulation possessed a reduced brain penetration property which may contribute to improved tolerability. And mice in the SEL-micelle groups did not show abnormal situation of hematopoietic cells and weight loss. The micelle demonstrated a favorable safety profile.

Discussion and conclusions In this work, we developed mPEG-PCL-SEL micelles with thin-film hydration. To the best of our knowledge, no relevant studies of SEL delivery have been reported. The micelle formulation showed good stability and controlled release manner. Besides, the mPEG-PCL-SEL micelle induced comparable or even better levels of cytotoxicity compared with the free-SEL in vitro. Most importantly, the mPEG-PCL-SEL micelle exhibited improved therapeutic efficacy compared with the free-SEL at the same dose level and showed similar or better therapeutic outcomes than the high-dose free-SEL, performed with survival benefit. Meanwhile, the micelle formulation possessed acceptable tolerability and safety profile. It is worth noting that none of the treatment groups achieved complete remission. This may be due to the limited treatment efficacy of a single agent. Hence, nanomedicine-based combination therapy containing SEL can be studied to further improve the efficacy of MM treatment.

No relevant conflicts of interest to declare.