In vivo evaluation of CD38 and CD138 as targets for nanoparticle-based drug delivery in multiple myeloma
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RESEARCH
In vivo evaluation of CD38 and CD138 as targets for nanoparticle‑based drug delivery in multiple myeloma David T. Omstead1, Franklin Mejia1, Jenna Sjoerdsma1, Baksun Kim1, Jaeho Shin1, Sabrina Khan1, Junmin Wu1, Tanyel Kiziltepe1,3,4, Laurie E. Littlepage2,3 and Basar Bilgicer1,3,4*
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. Keywords: Liposomes, Peptide-targeted, Multiple myeloma, Drug-loaded, Nanoparticle, CD38, CD138, Biodistribution, Efficacy Background Multiple myeloma is a plasma cell malignancy that develops solid tumors within the protective microenvironment of the bone marrow [1, 2]. These malignant B cells form bone lesions and produce misfolded paraproteins that result in frequent infections, anemia, amyloidosis, and kidney failure [3, 4]. Multiple myeloma globally *Correspondence: [email protected] 1 Department of Chemical and Biomolecular Engineering, University of Notre Dame, 205C McCourtney Hall, Notre Dame, IN 46556‑5637, USA Full list of author information is available at the end of the article
affects approximately 500,000 people and causes roughly 100,000 deaths annually [5]. While currently treatable, multiple myeloma remains incurable and has a five-year survival rate of 49% [6]. Current treatment of multiple myeloma typically involves high-dose chemotherapy, which is often associated with improved outcomes but often comes with major side effects that can limit dosages [7]. As a common occurrence, multiple myeloma relapses after treatment, becoming resistant to previously effective treatments [8]. This relapsed multiple myeloma typicall
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