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

开发用于骨髓瘤治疗的基于 microRNA (miR) 的细胞靶向聚合物纳米颗粒

基本信息

批准号：
10607998
负责人：
RUBEN D CARRASCO
金额：
$ 53.99万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-09 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607998
关键词：
Adhesions Antisense Oligonucleotide Therapy Apoptosis BCL9 gene Biochemical Biology Blood Bone Marrow Bone Marrow Cells Bortezomib Cell Death Cell Line Cell Proliferation Cell Survival Cell membrane Cell physiology Cell secretion Cell surface Cells Cellular biology Chemicals Complex Data Development Dexamethasone Drug resistance Educational workshop Encapsulated Endothelial Cells Engineering Engraftment Family Formulation Genetic Transcription Goals Growth Hematologic Neoplasms Histologic Human Immune Immune Evasion Immunocompetent Immunocompromised Host Immunologic Markers Immunology In Vitro Individual Inhibition of Apoptosis Libraries Lymphocyte Subset Macrophage Malignant Neoplasms Mediating Methods MicroRNAs Modality Modeling Multiple Myeloma Mus Nanotechnology National Cancer Institute Natural Immunity Oncogenes Oncogenic Organ Patient-Focused Outcomes Patients Persons Pharmaceutical Preparations Plasma Cells Play Polymers Proliferating Proteomics Public Health Recommendation Refractory Disease Regulation Replacement Therapy Resistance Role Signaling Molecule Small Interfering RNA System Testing Therapeutic Toxic effect Transcription Coactivator Treatment Cost Tumor Suppressor Proteins United States Work Xenograft Model advanced disease angiogenesis bone cell cancer therapy cancer type cell growth cellular targeting chemokine clinically relevant design drug resistance development effective therapy efficacious treatment improved in vitro activity in vivo innovation lenalidomide macromolecule migration nanomedicine nanoparticle nanopolymer novel novel therapeutics overexpression preservation submicron therapeutic miRNA tool treatment response tumor

项目摘要

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.

项目摘要多发性骨髓瘤 (MM) 是一种定植于骨髓 (BM) 的浆细胞癌症，尽管如此，仍然无法治愈新的有希望的治疗方式的使用部分是由于 (i) MM 进展和耐药性。 (ii) BM 微环境 (BMME) 保护 MM 细胞，以及 (iii) 免疫逃避。迫切需要创新和更有效的治疗方法，特别是对于晚期疾病患者传统药物难以治疗的 MicroRNA (miR) 在起始、进展和药物中发挥着关键作用。包括 MM 在内的各种人类癌症类型的耐药性，并为我们正在进行的研究提供了令人兴奋的机会我们最近记录了：（i）miR-30-5p 家族。作为一种靶向 BCL9 的 MM 肿瘤抑制因子，BCL9 是一种关键的 Wnt/-连环蛋白共激活剂，在 BM 内皮细胞 (BMEC)，促进 MM 细胞的 BM 定植和增殖，(ii) miR-221/222 该簇在对地塞米松无反应的患者的 MM 细胞中过度表达，并且通过靶向 PUMA 并抑制细胞凋亡发挥 MM 癌基因的作用，以及 (iii) miR-30c-5p 和 miR-221/222 在小鼠免疫细胞中表达，我们可以在移植的 MM 肿瘤中识别小鼠巨噬细胞基于 miR 的治疗的主要挑战是需要安全有效的递送方法。经过化学修饰或物理封装，miR 在血液中不稳定，不易穿过细胞纳米颗粒（NP）包含各种已使用的亚微米大小的大分子。成功地作为各种药物（包括 miR）的载体，使这些药物能够到达细胞靶点兰格实验室已经成功地设计了一个多样化的聚合物库。 NPs，其中一个例子，7C1NP，被证明是无毒的并且可以有效地将 siRNA 传递到 BMEC 我的实验室随后证明 7C1NP 制剂不仅可以向人类传递 siRNA/miR。 BMEC 以及 MM 细胞以及小鼠体内免疫细胞该项目的首要目标是利用 7C1NP 递送系统 (i) 发现 miR-30-5p 可能的新靶点和作用和 miR-221/222 在 MM 进展中的作用；以及 (ii) 探索这些聚合物封装的 miR 在 MM 中的潜力通过 miR-30-5p“替代疗法”靶向 BMEC 中的 BCL9，并抑制 BM 中的 MM 生长，以及 (b) miR-221/222“反义（as）疗法”靶向MM细胞中的PUMA并增强细胞凋亡，同时消除对来那度胺和硼替佐米获得耐药性，并且 (b) 研究这些疗法对其他疗法的影响免疫细胞和 MM 相关巨噬细胞极化所提出的研究对公共健康具有重要意义。因为它们将使用来自患者的 MM 细胞系和 MM 细胞进行，并与临床相关 MM 小鼠异种移植模型考虑了 MM 细胞和 BMME 及其最终目标是通过更有效的疗法来改善患者的治疗结果，从而缓解不仅可以降低多发性骨髓瘤的总体治疗成本，还可以降低其他潜在的血液恶性肿瘤的治疗成本。