Nanoparticle-mediated treatment for bone metastasis

 描述(申请人提供)：晚期前列腺癌通常转移到骨骼，但由于静脉注射的抗癌药物在骨骼内的生物分布不佳而变得无法治愈。双膦酸盐目前被用于降低骨骼相关事件的风险和缓解骨骼疼痛，但它们并不能提高存活率。注射的药物或载药的纳米载体与骨寻找剂结合在一起，在治疗骨转移方面仍然无效。在这个方案中，作为骨转移的一种治疗方法，我们探索了纳米粒(NP)介导的药物传递到骨的新途径--骨髓内皮细胞之间的裂隙。聚乙二醇化的纳米粒由于其表面亲水性，可以留在循环中，而不是通过骨髓毛细血管的开窗有效地扩张。我们的新方法是设计非聚乙二醇化的纳米粒子，并使其特征合理化(大小、电荷和表面组成)，以便在静脉给药后，这些纳米粒子确实通过骨髓的正弦毛细血管开口过度扩张。在使用PC-3M-Luc细胞诱导的溶骨性小鼠骨内前列腺癌模型的初步研究中，(A)静脉注射这些纳米颗粒后，这些纳米颗粒在转移部位的骨髓中显示出局限性聚集；(B)单剂量加载紫杉醇的纳米颗粒显著抑制了骨转移的进展，完全防止了骨丢失。在本建议中，我们的目的是评估这些纳米颗粒在临床相关的PC-3M-Luc细胞诱导的骨转移模型中的作用。我们将测试Denosumab在NPs(DNmb-Nano)中的疗效。DNMB是一种与核因子受体激活剂κB配体(RANKL)结合的单抗。RANKL在骨微环境中的过度表达会导致骨转移和骨吸收的恶性循环。我们还将探索DNmb作为针对RANKL的靶向配体，并使用载于NPs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。我们推测，利用我们的NPs，有效地定位于骨，结合DNmb和TXT及其互补的作用机制，可以抑制骨转移的进展，防止骨丢失。具体目标是：目标1：在晚期骨转移的前列腺癌模型中，描述有效定位NPs到转移部位的关键参数。目的：评价多西紫杉醇和地诺单抗纳米粒(TXT-Nano和DNmb-Nano)联合应用抑制骨转移和骨丢失的疗效。目的3：利用纳米粒测定药物分布和耐受性的药代动力学和药效学。影响：由于骨骼是许多人类癌症常见的转移部位，具有毁灭性的后果，有效的药物输送策略可能具有相当广泛的影响。

 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.