Development of microRNA (miR)-based cell-targeted polymeric nanoparticles for myeloma therapy

点击翻译按钮获取中文摘要

Project Abstract Multiple myeloma (MM), a cancer of plasma cells that colonize the bone marrow (BM), remains incurable despite the use of new promising treatment modalities. This is partly due to (i) MM progression and drug resistance development, (ii) protection of MM cells by the BM microenvironment (BMME), and (iii) immune evasion. Thus, there is urgent need for innovative and more effective therapies, particularly for patients with advanced disease refractory to conventional agents. MicroRNAs (miRs) play critical roles in the initiation, progression, and drug resistance of various human cancer types, including MM, and are providing exciting opportunities in our ongoing search for novel and more effective cancer therapies. We recently documented that: (i) the miR-30-5p family serves as an MM-tumor suppressor targeting BCL9, a critical Wnt/-catenin co-activator, highly expressed in BM endothelial cells (BMECs), that promotes BM colonization and proliferation of MM cells, (ii) the miR-221/222 cluster is overexpressed in MM cells from patients who have become unresponsive to dexamethasone, and functions as an MM oncogene by targeting PUMA and inhibiting apoptosis, and (iii) miR-30c-5p and miR-221/222 are expressed in murine immune cells, and we can identify murine macrophages within MM tumors engrafted in mice. The main challenge for miR-based therapy is the need for safe and effective delivery methods. Unless chemically modified or physically encapsulated, miRs are unstable in the blood and do not easily cross the cell membrane. Nanoparticles (NPs) encompass a variety of submicron-sized macromolecules that have been used successfully as vehicles for various agents, including miRs, enabling these agents to reach cellular targets previously considered undruggable. The Langer lab has successfully engineered a diverse library of polymeric NPs, of which one exemplar, 7C1NP, was shown to be non-toxic and effective in delivering siRNAs to BMECs in mice. My lab subsequently showed that the 7C1NP formulation can deliver siRNAs/miRs not only to human BMECs but also to MM cells as well as murine immune cells in vivo. The overarching goal of this project is to take advantage of the 7C1NP delivery system to (i) uncover possible new targets of, and roles for, miR-30-5p and miR-221/222 in MM progression; and (ii) explore the potential of these polymer-encapsulated miRs for MM therapy via miR-30-5p “replacement therapy” to target BCL9 in BMECs, and inhibit MM growth in the BM, and (b) miR-221/222 “antisense (as) therapy” to target PUMA in MM cells and enhance apoptosis while abrogating acquired resistance to Lenalidomide, and Bortezomib, and (b) investigate the effect of these therapies on other immune cells and MM-associated macrophage polarization. The proposed studies are significant to public health in that they will be performed with MM cells lines and MM cells from patients and utilizing clinically relevant mouse xenograft models of MM that take in consideration the heterotypic interactions between MM cells and the BMME and their ultimate goal is to improve patient outcome with more efficacious therapies that alleviate suffering, and reduce the overall treatment cost of not only MM but potentially other hematologic malignancies.