通过新型NCI-H929脂质提取物修饰纳米脂质体增强多发性骨髓瘤的靶向递送

Background : Multiple myeloma (MM) is an incurable hematological malignancy characterized by the aberrant proliferation of plasma cells in the bone marrow. Current first line goals of therapy for newly diagnosed symptomatic MM aim to achieve minimal residual disease prior to transplant, a key predictor of overall survival. However, toxicities remain a rate limiting step during induction therapy. Cell membrane lipid-extracted nanoliposomes (CLENs) are a novel drug delivery system that can be optimized to preferentially target MM cells. Prior research involving the use of the multiple myeloma cell line, RPMI-8226, supports the use of lipid extracts (LE) to enhance targeting. This study aims to evaluate whether the inclusion of LE derived from an additional MM cell line, NCI-H929, will also enhance targeting, while decreasing nanoliposome uptake by model off-target and non-target cells. Methods : The MM (target) cell line explored in this study was NCI-H929. K562-GFP was used as the non-target cell line, and normal healthy peripheral blood mononuclear cells (PBMCs) served as the off-target cell control. Cells were seeded at a concentration of 20,000 cells/mL in vented centrifuge tubes and exposed for 1 hour to varying compositions of nanoliposome preparations including: DOPC, NCI-H929 lipid extract (LE), cholesterol (Chol), and DPPE-rhodamine for fluorescence studies. Nanoliposomes were prepared using a modified thin film method. Relative fluorescence intensity was determined using a fluorescence microplate reader. Results : Mean liposome diameters (± deviation) for DOPC formulations containing NCI-H929 LE were: DOPC (100%)- 188.6 ± 2 nm, DOPC/LE- 95/5 212.3 ± 2 nm, 90/10- 230.4 ± 2 nm, 85/15- 200 ± 4 nm, and 80/20- 142 + 1 nm. For formulations including cholesterol, diameters were: DOPC/Chol 90/10- 235 ± 2 nm and DOPC/Chol/LE 80/10/10- 227.4 ± 2 nm. Following 1 hour exposure of the target cell line to different concentrations of DOPC/LE, a statistically significant increase in uptake was observed in DOPC/LE preparations compared to DOPC alone: 95/5 and 90/10 (p < 0.0001), 85/15 (p < 0.001), and 80/20 (p < 0.05), with the highest uptake observed for 90/10. The addition of cholesterol did not further enhance uptake, and no significant uptake was observed in non-target or off-target cells compared to controls. Conclusions : Our preliminary findings support that cellular uptake in MM cells may be increased via NCI-H929-LE modified nanoliposomes, with diminished uptake by non-target and off-target cell populations. Confirmation studies are currently underway, including cytotoxicity studies comparing conventional chemotherapy against NCI-H929 LE-modified nanoliposomal formulations.