Nanoparticle-mediated treatment for bone metastasis

纳米颗粒介导的骨转移治疗

• 批准号: 10163753
• 负责人: VINOD D LABHASETWAR
• 金额: $ 26.84万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163753
• 关键词: Acute; Antineoplastic Agents; Area; Binding; Biodistribution; Blood Circulation; Blood capillaries; Body Weight decreased; Bone Marrow; Bone Pain; Bone Resorption; Cardiac Output; Cells; Characteristics; Charge; Chronic; Data; Discontinuous Capillary; Dose; Drug Delivery Systems; Drug Tolerance; Drug toxicity; Encapsulated; Endothelial Cells; Event; Extravasation; FDA approved; Feedback; Formulation; Goals; Human; Impairment; Injections; Intravenous; 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; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Quality of life; Research; Risk; Role; Route; Site; Skeleton; Soft Tissue Neoplasms; Surface; Survival Rate; Testing; Therapeutic; Time; Treatment Side Effects; base; bisphosphonate; bone; bone cell; bone loss; cancer cell; clinically relevant; cremophor EL; design; docetaxel; drug distribution; effective therapy; efficacy evaluation; efficacy testing; hydrophilicity; intravenous administration; intravenous injection; malignant breast neoplasm; mortality; mouse model; nano; nanocarrier; nanoparticle; nanoparticle delivery; novel strategies; pharmacokinetics and pharmacodynamics; prevent; prostate cancer cell; prostate cancer model; public health relevance; receptor; receptor expression; 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。双磷酸盐目前用于降低骨骼相关事件的风险并减轻骨痛，但它们并不能提高生存率。注射药物或与骨寻找剂缀合的载药纳米载体在治疗骨转移方面仍然无效。在本提案中，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——骨髓内皮细胞之间的细胞内裂隙。聚乙二醇化纳米颗粒由于其亲水性表面，保留在循环中，而不是有效地通过骨髓毛细血管的开窗溢出。我们的新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），以便在静脉注射后，这些纳米颗粒确实会通过骨髓正弦毛细血管的开口溢出。在一项使用 PC-3M-luc 细胞诱导的溶骨性前列腺癌骨内小鼠模型的初步研究中，(a) 静脉注射后，这些 NP 在转移部位的骨髓中表现出局部聚集，(b) 单剂量的紫杉醇负载的 NP 显着抑制骨转移的进展并完全防止骨丢失。在本提案中，我们的目标是评估 这些 NP 在临床相关的骨转移模型中，由心内注射 PC-3M-luc 细胞诱导。我们将测试狄诺塞麦在纳米粒子 (DNmb-nano) 中的功效。 DNmb 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的过度表达驱动骨转移和骨吸收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 中的多西紫杉醇 (TXT-nano)，因为 TXT 已被证明比紫杉醇更有效地治疗前列腺癌。我们假设，使用有效定位于骨的纳米粒子，以及 DNmb 和 TXT 及其互补作用机制的组合，可以抑制骨转移的进展并防止骨丢失。具体目标是： 目标 1：描绘在晚期骨转移的前列腺肿瘤模型中将纳米粒子有效定位到转移部位的关键参数。目标 2：评估负载多西紫杉醇和地诺单抗的纳米粒子（TXT-nano 和 DNmb-nano）组合抑制骨转移进展和由此产生的骨丢失的功效。目标 3：利用 NP 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。影响：由于骨是许多人类癌症转移的常见部位，会造成毁灭性后果，因此有效的药物输送策略可能会产生更广泛的影响。

项目成果

Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer.

• DOI: 10.1016/j.jconrel.2016.04.019
• 发表时间: 2016-06-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Adjei IM;Sharma B;Peetla C;Labhasetwar V
• 通讯作者: Labhasetwar V