Nanoparticle-mediated treatment for bone metastasis

 描述（由申请人提供）：晚期前列腺癌通常转移至骨，但由于静脉给药的抗癌药物在骨内的生物分布不良而无法治愈。双膦酸盐目前被用于降低骨相关事件的风险和改善骨痛，但它们不能改善生存率。与骨导向剂缀合的注射药物或载药纳米载体在治疗骨转移中仍然是低效的。在这个提议中，作为骨转移的治疗，我们探索了纳米颗粒（NP）介导的药物递送到骨的新途径-骨髓中内皮细胞之间的细胞内裂缝。聚乙二醇化的纳米颗粒，由于其亲水性表面，保持在循环中，而不是有效地通过骨髓毛细血管中的开窗排出。我们的新方法是设计非聚乙二醇化的纳米颗粒，并合理化它们的特性（大小，电荷和表面组成），以便在静脉给药后，这些纳米颗粒通过骨髓窦状毛细血管的开口排出。在使用前列腺癌的PC-3 M-luc细胞诱导的溶骨性骨内小鼠模型的初步研究中，（a）在静脉内注射后，这些NP显示出在转移部位内的骨髓中的局灶性积聚和（B）单剂量的紫杉醇负载的NP显著抑制骨转移的进展并完全防止骨损失。我们的目的是在通过心内注射PC-3 M-luc细胞诱导的骨转移的临床相关模型中评价这些NP。我们将检测地舒单抗在NP（DNmb- nano）中的疗效。DNmb是一种与核因子-κB配体受体激活因子（RANKL）结合的单克隆抗体。RANKL在骨微环境中的过度表达驱动骨转移和骨吸收进展的恶性破坏性循环。我们还将探索DNmb作为RANKL的靶向配体，并使用载于NP（TXT-nano）中的多西他赛，因为TXT已被证明比紫杉醇更有效地治疗前列腺癌。我们假设使用我们的NP，其有效地定位于骨，以及DNmb和TXT与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：在晚期骨转移的前列腺肿瘤模型中，描述将NP有效定位于转移部位的关键参数。目标2：评价多西他赛和地舒单抗负载纳米粒（TXT-nano和DNmb-nano）联合治疗抑制骨转移进展和骨丢失的疗效。目的3：利用纳米粒研究药物的药代动力学和药效学分布及药物耐受性。影响：由于骨是许多人类癌症转移的常见部位，具有破坏性后果，因此有效的药物递送策略可能具有相当广泛的意义。

 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.