Next Gen Targeted nanoparticles for Inhibiting Gli2 in Bone Metastatic Tumors

用于抑制骨转移肿瘤中 Gli2 的下一代靶向纳米颗粒

• 批准号: 10623705
• 负责人: Craig Lewis Duvall
• 金额: $ 66.79万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623705
• 关键词: Academic Medical Centers; Acrylates; Affect; Alendronate; Allografting; Biodistribution; Biological Availability; Biology; Biomedical Engineering; Bone Density; Bone Diseases; Bone Marrow; Bone Pain; Bone Resorption; Bone necrosis; Bone neoplasms; Breast; Breast Cancer Cell; Cancer Biology; Cancer Model; Cell model; Chemistry; Chemoresistance; Clinical; Collecting Cell; Data; Development; Disease; Disseminated Malignant Neoplasm; Dose; Dose Limiting; Drug Kinetics; Drug Screening; Ensure; Equilibrium; Family; Formulation; Fracture; Generations; Genetic; Glycols; Goals; Grant; Growth; Growth Factor; Hematology; Histopathology; Homeostasis; Human; Hydrophobicity; Hypercalcemia; Immunocompetent; Jaw; Kinetics; Lead; Ligand Binding; Liver; Location; Malignant neoplasm of lung; Maximum Tolerated Dose; Medicine; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Methods; Micrometastasis; Modeling; Modification; Morbidity - disease rate; Neoplasm Metastasis; Oncology; Osteoblasts; Osteoclasts; Paclitaxel; Pain; Patient-Focused Outcomes; Patients; Pharmacodynamics; Pharmacology; Polymer Chemistry; Polymers; Positioning Attribute; Pre-Clinical Model; Preclinical Testing; Primary Neoplasm; Principal Investigator; Proliferating; Property; Prostate; Reactive Oxygen Species; Repression; Running; Serum Markers; Site; Stains; Subgroup; Sulfides; System; Technology; Testing; Toxic effect; Translations; Tumor Burden; Tumor Cell Invasion; Tumor Expansion; Universities; Up-Regulation; Woman; Work; Zoledronic Acid; antagonist; bisphosphonate; bone; cancer stem cell; chemotherapy; clinical translation; clinically relevant; cooking; design; drug candidate; drug efficacy; effective therapy; efficacy evaluation; efficacy study; experience; improved; in vivo; inhibitor; intravenous administration; intravenous injection; malignant breast neoplasm; metastatic process; mouse model; nanoparticle; neoplastic cell; nephrotoxicity; novel; novel therapeutics; parathyroid hormone-related protein; particle; pharmacokinetics and pharmacodynamics; pre-clinical; propylene; protein expression; research clinical testing; side effect; skeletal; skeletal-related events; small molecule; small molecule inhibitor; standard of care; systemic toxicity; transcription factor; treatment effect; tumor; tumor growth; validation studies

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.

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。虽然都是转移性的 部位在临床上很重要，骨骼转移在乳腺癌、前列腺癌、肺癌、 以及其他，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。一旦在骨骼中建立，肿瘤就会破坏正常的骨骼稳态 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 Gli2 因子作为减少肿瘤引起的骨疾病的有希望的靶点。鉴定出小分子后 抑制剂，Gli Antagonist 58 (GANT58)，作为骨转移肿瘤中 Gli2 活性的有前途的抑制剂，我们 发现 GANT58 的生物利用度较差限制了其在全身递送模型中的使用。因此，我们开发了 聚合纳米颗粒可溶解、改善药代动力学 (PK) 并提高 GANT58 的生物利用度 （GANT58-NP）。纳米颗粒包含活性氧 (ROS) 响应性聚(丙烯硫醚-嵌段- 低聚乙二醇丙烯酸酯）（PPS-b-POEGA）。第一代GANT58-NPs静脉注射 (Dh=93 nm) 减少胫骨内和心内乳腺肿瘤细胞接种模型以及肺模型中的 TIBD 癌症模型（3 个独特的模型）。 GANT58-NP 是安全的（不会升高肝脏/肾脏的血清标志物） 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)， 所使用的化学物质能够调节骨结合配体阿仑膦酸钠（ALN）的密度，阿仑膦酸钠是一种 生物活性双膦酸盐（破骨细胞抑制剂）。虽然两种配方都减少了肿瘤对骨的侵袭， 通过 ki67 染色减少肿瘤增殖，但它们没有消除肿瘤，也没有显着减少肿瘤 大量用于已建立的骨转移疾病模型。在这里，我们建议筛选更广泛的聚合物 化学空间重点关注：（1）开发一种没有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 负载、GANT58 可触发释放以及随之而来的 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/ PD。此外，我们将评估共载 GANT58 和紫杉醇 BT-NP 制剂的功效。每一个 将评估这些制剂的详细 PK/PD 和生物分布特性，以确定有前途的制剂 减少肿瘤引起的骨疾病而不引起全身毒性的制剂。我们的初步数据 显示出有希望的结果，包括低毒性和减少骨和骨肿瘤负荷的功效 破坏。该提案将更详细地探讨功效和 PK/PD 特性，以开发一种有前途的药物 最终翻译的治疗。这些研究的结果将有助于确定一种新颖且有前途的策略 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 对这些患者的有效治疗，这些研究的结果可能会影响患者的治疗结果并导致 为骨转移肿瘤患者提供令人兴奋的新疗法。