In vivo evaluation of CD38 and CD138 as targets for nanoparticle-based drug delivery in multiple myeloma

Abstract

Background Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies. Methods In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells. Finally, drug-loaded nanoparticles are tested for long-term efficacy in a month-long in vivo study by tracking tumor size and mouse health. Results The targeted nanoparticles are first optimized in vitro and show increased uptake and cytotoxicity over nontargeted nanoparticles, with CD138-targeting showing superior enhancement over CD38-targeted nanoparticles. However, biodistribution and tumor suppression studies established CD38-targeted nanoparticles to have significantly increased in vivo tumor accumulation, tumor cell uptake, and tumor suppression over both nontargeted and CD138-targeted nanoparticles due to the latter’s poor selectivity. Conclusion These results both highlight a promising cancer treatment option in CD38-targeted nanoparticles and emphasize that targeting success in vitro does not necessarily translate to success in vivo.

Density of Conjugated Antibody Determines the Extent of Fc Receptor Dependent Capture of Nanoparticles by Liver Sinusoidal Endothelial Cells

“…The underlying mechanism, however, was not assessed. In another study, liposomal formulations decorated with various densities of CD38 and CD138 receptor binding peptides, respectively, for engagement of myeloma cells showed a density-dependent increase (CD38) or decrease (CD138) in tumor cell binding as compared to nontargeting liposomes . Accumulation of these formulations in other organs, including the liver, was not affected by the density of either peptide.…”

Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9

“…Mice were intravenously injected with B16 tumor cells, 4 days after tumor injection, nanoparticles containing 50 µg control or Il9r siRNA (Ambion in vivo siRNA) were injected intravenously in the tumor-bearing mice every 72 h. Targeted liposomal nanoparticles were prepared using the extrusion method detailed in previous reports 32 , 33 , 55 . All lipid, and lipid-conjugate components were individually prepared and purified, then combined at the desired stoichiometric ratios in chloroform and dried to form a lipid film.…”

Pathogenesis and treatment of multiple myeloma

“…Although the binding ability of CD138‐targeted liposomes was better than that of CD38‐targeted liposomes in vitro, CD138‐targeted liposomes were prone to accumulate in the nontumor site and bind to normal cells, leading to worse performance in vivo. In addition, a long‐lasting period of in vivo study verified the superior efficacy of CD38‐targeted liposomes 178 . A high targeting rate in vitro may not represent success in vivo, and utilization of the multivalent low‐affinity property may contribute to better binding.…”

“…In addition, a long-lasting period of in vivo study verified the superior efficacy of CD38-targeted liposomes. 178 A high targeting rate in vitro may not represent success in vivo, and utilization of the multivalent low-affinity property may contribute to better binding. Chang et al established dioleoyl phosphatidic acid (DOPA)-based liposomes with two surface modifications, alendronate and transferrin (Tf).…”