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In Vivo Evaluation of CD38 and CD138 As Targets for Nanoparticle-Based

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In Vivo Evaluation of CD38 and CD138 As Targets for Nanoparticle-Based Omstead et al. J Hematol Oncol (2020) 13:145 https://doi.org/10.1186/s13045-020-00965-4 RESEARCH Open Access 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 benefts in the fght against multiple myeloma; how- ever, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufcient efcacies reported in preclinical studies. Methods: In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are pre- pared from pre-synthesized, purifed 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 efcacy in a month-long in vivo study by tracking tumor size and mouse health. Results: The targeted nanoparticles are frst 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 signif- cantly 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, Efcacy Background afects approximately 500,000 people and causes roughly Multiple myeloma is a plasma cell malignancy that devel- 100,000 deaths annually [5]. While currently treatable, ops solid tumors within the protective microenviron- multiple myeloma remains incurable and has a fve-year ment of the bone marrow [1, 2]. Tese malignant B cells survival rate of 49% [6]. Current treatment of multiple form bone lesions and produce misfolded paraproteins myeloma typically involves high-dose chemotherapy, that result in frequent infections, anemia, amyloido- which is often associated with improved outcomes but sis, and kidney failure [3, 4]. Multiple myeloma globally often comes with major side efects that can limit dos- ages [7]. As a common occurrence, multiple myeloma *Correspondence: [email protected] relapses after treatment, becoming resistant to previously 1 Department of Chemical and Biomolecular Engineering, University efective treatments [8]. Tis relapsed multiple mye- 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 loma typically is treated with other chemotherapy, such © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Omstead et al. J Hematol Oncol (2020) 13:145 Page 2 of 15 as proteasome inhibitors or imide drugs, and recently is incorporated into the bilayer [35]. Liposomes are typi- approved monoclonal antibodies, such as elotuzumab cally modifed with a polyethylene glycol (PEG) coating or daratumumab [9–13]. Te bone marrow microen- to become stealth to an immune response and to reduce vironment causes the recurrent cancer cells to develop clearance by the reticuloendothelial system [36]. Tey cell adhesion-mediated drug resistance (CAM-DR), but can also be functionalized for active targeting with addi- recent animal studies have shown that this resistance can tion of various molecules, such as antibodies, antibody be overcome through the use of actively targeted thera- fragments, small molecules, or peptides [37]. pies [2, 14]. Tus, there has been signifcant recent efort Our group developed a now well-established method of toward the use of ligand-targeted nanoparticles for drug targeted-liposome synthesis to ofer uniquely high con- delivery for multiple myeloma with the main objective of trol over the valency of peptide targeting and increased overcoming drug resistance and improving patient out- reproducibility in production between batches [18, 19, come [14–16]. 38]. Tis is accomplished by synthesizing and purifying Our laboratory has previously researched the use peptide–lipid conjugates individually prior to particle of targeted nanoparticles for treatment for multiple synthesis and then using the pure building blocks at pre- myeloma, particularly in the feld of peptide-targeted cise stoichiometric ratios while incorporating into the liposomes. We have previously identifed overexpressed lipid flm before hydration/extrusion, which allows pre- receptors common to multiple myeloma cells, such as cise control over the valency of the peptide per liposome. VLA-4 and LPAM-1, and developed and optimized tar- We also take advantage of the combined efects of weak geted formulations with which to deliver a drug payload to moderate monovalent afnity of a targeting peptide [17–19]. Tese systems showed signifcantly increased and the simultaneous presentation of multiple copies of uptake over that of nontargeted particles in vitro and it per liposome to provide a multivalent binding efect in vivo. Nevertheless, not every multiple myeloma case that we tune to selectively achieve increased avidity for has overexpressed VLA-4 or LPAM-1 receptors. Tere- the target of cancer cells over healthy cells, consequently fore, developing liposomal nanoparticle formulations reducing of-target efects. that target other receptors of signifcance in this disease Previously, we investigated the efcacy of VLA-4-tar- will increase the available therapies available to fght this geted liposomal nanoparticles and found that they can disease and to improve patient outcomes [20–22]. signifcantly enhance tumor cell uptake in vivo [19]. Fur- Two receptors, CD38 and CD138, have recently gar- thermore, we also described our strategy for optimizing a nered much interest for multiple myeloma. CD38 is the nanoparticle formulation designed for selective targeting target of the recently FDA-approved monoclonal anti- [16]. Using a similar approach for optimization, in this body daratumumab, which makes it an ideal receptor to study, we optimized the uptake and efcacy of two dox- evaluate for targeted drug delivery therapies [9, 11, 23, orubicin-prodrug-loaded nanoparticle formulations that 24]. CD138, also known as Syndecan-1, has also been target two separate receptors using in vitro and in vivo recently investigated as a potential target for antibody- studies. Both biodistribution and efcacy were analyzed conjugated drug therapies for multiple myeloma as well in vivo to determine the delivery profle of the nanopar- as in a wide variety of cancer types, including bladder ticles as well as their anti-tumor efectiveness. CD38-tar- cancer and triple-negative breast cancer due to overex- geted nanoparticles showed signifcantly greater tumor pression in these malignancies [25–28]. While peptide- cell uptake and enhanced efcacy over CD138-targeted targeted nanoparticles have never been used before for nanoparticles in vivo that would not have been expected either of these promising targets, the unique benefts of a from solely the results of the in vitro study. By evaluat- multivalent liposomal targeting system could be efective ing and comparing several formulations, we successfully in treating multiple myeloma. identifed the most potent CD38-targeted formulation Peptide-targeted liposomes hold a variety of benefts that clearly outperformed both free drug- and the non- that make them an ideal nanoparticle system for selec- targeted drug-loaded nanoparticles, making them desir- tive cancer drug delivery [29]. Liposomes are the longest able candidates for clinical testing in multiple myeloma studied and most frequently developed, highly modif- tumors that express CD38. able nanoparticle platform [30–32]. Liposomal delivery systems take advantage of the enhanced permeability and Methods retention (EPR) efect to passively accumulate preferen- Materials tially at a tumor site [33, 34]. Teir lipid bilayer feature N-Fmoc-amino acids, Rink Amide resin, 2-(1H-Ben- also accommodates loading
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