Next Gen Targeted nanoparticles for Inhibiting Gli2 in Bone Metastatic Tumors

尽管原发性肿瘤的治疗取得了进展，但转移性疾病仍然无法治愈。虽然所有转移性 在临床上，骨转移在乳腺癌、前列腺癌、肺癌 和其他，大约70%死于转移性乳腺癌的女性经历了严重的 骨转移的并发症。肿瘤一旦在骨中形成，就会破坏正常的骨稳态 导致疼痛、骨折和一般发病率增加。我们之前的工作已经建立了转录 因子Gli2作为减少肿瘤诱导的骨疾病的有希望的靶点。在鉴定出小分子后 抑制剂Gli拮抗剂58（GANT 58）作为骨转移肿瘤中Gli 2活性的有前途的抑制剂，我们 发现GANT58的生物利用度差，限制了其在全身给药模型中的使用。因此，我们开发了 聚合物NP溶解、改善药代动力学（PK）和促进GANT58的生物利用度 （GANT58-NP）。NP包含活性氧物质（ROS）响应性聚（亚丙基硫醚-嵌段-亚丙基硫醚）。 聚乙二醇丙烯酸酯）（PPS-b-POEGA）。静脉注射第一代GANT58-NP (Dh= 93 nm）在胫骨内和心内乳腺肿瘤细胞接种模型中以及在肺中减少TIBD 癌症模型（3种独特模型）。GANT58-NP是安全的（不升高肝/肾的血清标志物 毒性或引起可检测的组织病理学。我们的第二代NP是骨靶向的（BT-GANT58-NP）， 所用的化学物质能够调节骨结合配体阿仑膦酸钠（ALN）的密度， 生物活性双膦酸盐（破骨细胞抑制剂）。虽然两种制剂都减少了肿瘤对骨的侵袭， 通过ki67染色减少肿瘤增殖，它们没有消除肿瘤并且没有显著减少肿瘤 在已建立的骨转移性疾病模型中大量存在。在这里，我们建议筛选更广泛的聚合物 化学空间聚焦于：（1）开发无固有生物活性的替代骨靶向策略; (2)研究NP核心化学如何影响GANT58加载，GANT58可释放，以及随后的 体内PK;（3）定义最大耐受剂量（MTD）、剂量限制性毒性和剂量依赖性PK/ 警局此外，我们将评估共负载GANT58和紫杉醇BT-NP制剂的功效。中的每 将评价这些制剂的详细PK/PD和生物分布特性， 本发明提供了用于减少肿瘤诱导的骨疾病而不诱导全身毒性的制剂。我们的初步数据 显示出有希望的结果，包括低毒性和降低骨和骨中肿瘤负荷的功效， 杀伤性该提案将更详细地探索疗效和PK/PD特性，以开发有前景的 最终翻译的治疗。这些研究的结果将有助于确定一种新的和有前途的战略， 减少骨转移性疾病患者的肿瘤负荷和骨破坏。由于目前缺乏 这些研究的结果可能会影响患者的结局，并导致 骨转移瘤患者的新疗法。

Despite progress in the treatment of primary tumors, metastatic disease remains incurable. While all metastatic sites are important clinically, skeletal metastases are common in patients with breast, prostate, lung cancer, and other, with approximately 70% of women that die from metastatic breast cancer experiencing serious complications from bone metastases. Once established in the bone, tumors disrupt normal bone homeostasis leading to increased pain, fracture, and general morbidity. Our previous work has established the transcription factor Gli2 as a promising target for reducing tumor induced bone disease. After identifying the small molecule inhibitor, Gli Antagonist 58 (GANT58), as a promising inhibitor of Gli2 activity in bone metastatic tumors, we discovered the poor bioavailability of GANT58 limited its use in systemic delivery models. Thus, we developed polymeric NPs to solubilize, improve the pharmacokinetics (PK), and promote bioavailability of GANT58 (GANT58-NPs). The NPs comprised reactive oxygen species (ROS)-responsive poly(propylene sulfide-block- oligoethylene glycol acrylate) (PPS-b-POEGA). Intravenous injection of the 1st generation GANT58-NPs (Dh=93 nm) reduced TIBD in models of intratibial and intracardiac breast tumor cell inoculation and in a lung cancer model (3 unique models). GANT58-NPs were safe (did not elevate serum markers of liver/kidney toxicity or cause detectable histopathology. Our 2nd generation NPs were bone targeted (BT-GANT58-NPs), and the chemistry utilized enabled tuning of the density of the bone binding ligand, alendronate (ALN), a bioactive bisphosphonate (osteoclast inhibitor). While both formulations reduced tumor invasion into bone and reduced tumor proliferation by ki67 staining, they did not eliminate tumor and did not significantly reduce tumor bulk in models of established bone metastatic disease. Here, we propose to screen a broader polymer chemistry space focusing on: (1) Developing an alternative bone targeting strategy without inherent bioactivity; (2) Studying how NP core chemistry affects GANT58 loading, GANT58 triggerable release, and consequent in vivo PK; (3) Defining the maximum tolerated dose (MTD), dose-limiting toxicities, and dose dependent PK / PD. In addition, we will evaluate the efficacy of a co-loaded GANT58 and paclitaxel BT-NP formulation. Each of these formulations will be evaluated for detailed PK/PD and biodistribution properties to identify promising formulations to reduce tumor induced bone disease without inducing systemic toxicity. Our preliminary data show promising results that include low toxicity and efficacy in reducing tumor burden in bone and bone destruction. This proposal will explore the efficacy and PK/PD properties in more detail to develop a promising therapy for eventual translation. The results of these studies will help identify a novel and promising strategy to reduce tumor burden and bone destruction in patients with bone metastatic disease. Due to the current lack of effective therapies for these patients, the results of these studies could impact patient outcomes and lead to exciting new therapies for patients with bone metastatic tumors.