Nanoparticle-mediated treatment for bone metastasis

纳米颗粒介导的骨转移治疗

• 批准号: 9115900
• 负责人: VINOD D LABHASETWAR
• 金额: $ 31.26万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-04 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115900
• 关键词: Acute; Adverse effects; Antineoplastic Agents; Area; Binding; Biodistribution; Blood Circulation; Blood capillaries; Body Weight decreased; Bone Marrow; Bone Pain; Bone Resorption; Cardiac Output; Cells; Characteristics; Charge; Chronic; Cleaved cell; Data; Diagnostic Neoplasm Staging; Discontinuous Capillary; Dose; Drug Delivery Systems; Drug Kinetics; Drug Tolerance; Drug toxicity; Encapsulated; Endothelial Cells; Environment; Event; Extravasation; FDA approved; Feedback; Formulation; Goals; Human; Injection of therapeutic agent; Ligands; Liver; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Metastatic to; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Neoplasm Metastasis; Nuclear; Organ; Osteoblasts; Osteoclasts; Osteolytic; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Quality of life; Research; Risk; Role; Route; Site; Skeleton; Soft Tissue Neoplasms; Staging; Surface; Survival Rate; TNFSF11 gene; Testing; Therapeutic; Time; base; bisphosphonate; bone; bone cell; bone loss; cancer cell; capillary; clinically relevant; cremophor EL; design; docetaxel; drug distribution; effective therapy; efficacy testing; improved; intravenous administration; intravenous injection; malignant breast neoplasm; mortality; mouse model; nano; nanocarrier; nanoparticle; novel strategies; overexpression; prevent; prostate cancer cell; prostate cancer model; public health relevance; receptor; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): Advanced-stage prostate cancer often metastasizes to bone but becomes incurable due to poor biodistribution of intravenously administered anticancer drugs within bone. Bisphosphonates are currently used to reduce the risk of skeleton-related events and to ameliorate bone pain, but they do not improve survival. Injected drugs or drug-loaded nanocarriers conjugated to bone-seeking agents remain inefficient in treating bone metastasis. In this proposal, as a therapy for bone metastasis, we explore a new route for nanoparticle (NP)-mediated drug delivery to bone - the intracellular clefts between endothelial cells in bone marrow. PEGylated NPs, because of their hydrophilic surface, remain in the circulation rather than efficiently extravagating through the fenestrations in bone-marrow capillaries. Our novel approach has been to design non-PEGylated NPs and rationalize their characteristics (size, charge, and surface composition) so that following their intravenous administration, these NPs do extravagate through the openings of the marrow's sinusoidal capillaries. In a preliminary study using a PC-3M-luc cell-induced osteolytic intraosseous mouse model of prostate cancer, (a) after intravenous injection, these NPs demonstrated focal accumulation in bone marrow within metastatic sites and (b) a single dose of paclitaxel-loaded NPs significantly inhibited the progression of bone metastasis and completely prevented bone loss In this proposal, our objective is to evaluate these NPs in a clinically relevant model of bon metastasis, induced by intracardiac injection of PC-3M-luc cells. We will test the efficacy of denosumab in NPs (DNmb- nano). DNmb is a monoclonal antibody that binds to receptor activator of nuclear factor-κB ligand (RANKL). Over expression of RANKL in the bone microenvironment drives the vicious destructive cycle of progression of bone metastasis and bone resorption. We will also explore DNmb as a targeting ligand against RANKL and use docetaxel loaded in NPs (TXT-nano), as TXT has proven more potent than paclitaxel for treating prostate cancer. We hypothesize that using our NPs, which effectively localize to bone, and the combination of DNmb and TXT with their complementary mechanism of action could inhibit progression of bone metastasis and prevent bone loss. The specific aims are: AIM 1: Delineate the parameters critical for efficient localization of NPs to metastatic sites in a prostate tumor model of advanced-stage bone metastasis. AIM 2: Evaluate the efficacy of the combination of docetaxel- and denosumab-loaded NPs (TXT-nano and DNmb-nano) to inhibit progression of bone metastasis and the resulting bone loss. AIM 3: Determine the pharmacokinetics and pharmacodynamics of drug distribution and tolerance to drug treatment by use of NPs. Impact: Since bone is a common site for metastasis in a number of human cancers, with devastating consequences, an effective drug-delivery strategy could potentially have considerably broader implications.

 描述（由申请人提供）：晚期前列腺癌经常转移至骨骼，但由于静脉内施用的抗癌药物在骨骼内的生物分布不良而变得无法治愈，双膦酸盐目前用于降低骨骼相关事件的风险并改善骨骼疼痛。但注射药物或与骨寻找剂结合的载药纳米载体在治疗骨转移方面仍然无效。作为骨转移的治疗方法，我们探索了一种纳米颗粒（NP）介导的药物递送至骨的新途径——骨髓中内皮细胞之间的细胞内裂隙，因为它们的亲水性表面，保留在循环中而不是有效地。我们的新颖方法是设计非聚乙二醇化纳米颗粒并合理化其特性（尺寸、电荷和表面组成），从而在一项使用 PC-3M-luc 细胞诱导的骨内前列腺癌小鼠模型的初步研究中，静脉注射后，这些 NP 确实会通过骨髓窦毛细血管的开口溢出。 (b) 单剂量负载紫杉醇的 NP 显着抑制骨转移的进展并完全阻止骨转移在本提案中，我们的目标是在心内注射 PC-3M-luc 细胞诱导的临床相关骨转移模型中评估这些 NP（DNmb-nano）的功效。是一种单克隆抗体，可与核因子 κB 配体受体激活剂 (RANKL) 结合，骨微环境中 RANKL 的过度表达可驱动骨进展的恶性破坏循环。我们还将探索 DNmb 作为 RANKL 的靶向配体，并使用负载在 NP 中的多西他赛 (TXT-nano)，因为 TXT 已被证明比紫杉醇更有效地治疗前列腺癌，我们使用我们的 NP 维持了这一点。 DNmb 和 TXT 的结合及其互补的作用机制可以抑制骨转移的进展并防止骨丢失。描绘晚期骨转移前列腺肿瘤模型中 NP 定位至转移部位的关键参数 AIM 2：评估负载多西他赛和地诺单抗的 NP（TXT-nano 和 DNmb-nano）组合的功效。抑制骨转移的进展和由此产生的骨丢失 目的 3：通过使用确定药物分布的药代动力学和药效学以及对药物治疗的耐受性。 NPs. 影响：由于骨是许多人类癌症的常见转移部位，会造成毁灭性的后果，因此有效的药物输送策略可能会产生更广泛的影响。