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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

基本信息

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
项目类别：
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

项目摘要

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。而所有的转移