An osteolytic stimuli-responsive nanotherapeutic system for bone metastases

用于骨转移的溶骨刺激响应纳米治疗系统

• 批准号: 8504628
• 负责人: XULI WANG
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-10 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504628
• 关键词: Address; Affinity; Animals; Antineoplastic Agents; Aspartic Acid; Binding; Biological Availability; Bone Density; Bone Growth; Bone Regeneration; Bone Resorption; Carbonates; Charge; Cleaved cell; Cysteine Protease; Disease; Disseminated Malignant Neoplasm; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Ensure; Environment; Ethylene Glycols; Evaluation; Event; FDA approved; Fracture; Goals; In Vitro; Invaded; Lead; Lytic Metastatic Lesion; Maximum Tolerated Dose; Mediating; Metastatic Neoplasm to the Bone; Minerals; Modality; Modeling; Molecular Biology; Monitor; Morbidity - disease rate; Multiple Myeloma; Mus; Nature; Nerve compression syndrome; Osteolytic; Pain; Patients; Peptides; Permeability; Pharmaceutical Preparations; Procedures; Process; Property; Public Health; Quality of life; Research; Research Project Grants; Safety; Skeleton; Stimulus; Structure; Surface; Survival Rate; System; Testing; Therapeutic; Tissues; Treatment Efficacy; Tropism; United States; anti-cancer therapeutic; base; bone; bone strength; bone turnover; cancer cell; cathepsin K; cell growth; copolymer; cyclopropane; design; drug efficacy; efficacy testing; ethylene glycol; improved; in vivo; indexing; innovation; interest; mortality; nanoparticle; nanotherapeutic; novel; novel therapeutic intervention; overexpression; palliative; preclinical efficacy; prevent; public health relevance; self assembly; skeletal; skeletal tissue; trafficking; tumor; tumor microenvironment; uptake; zeta potential

DESCRIPTION (provided by applicant): Metastatic cancers in bone are very difficult to treat and result in pain, bone fractures, nerve compression, morbidity, and often mortality. Current therapeutic modalities for bone-metastatic cancers are usually palliative in nature and there is a clear need for better treatment options, and this proposal addresses such an important public health need. The research project proposes to explore, develop and test a novel nanotherapeutic platform to improve the skeletal affinity, selectivity and efficacy of anti-cancer agents, in hopes of developing an effective therapeutic modality for bone metastases. The nanotherapeutics are based on a synthetic tri-block copolymers of peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC). The functional peptide is designed to possess bone tropism octapeptide (Asp8) and cathepsin K (CTSK)-cleavable substrate (HPGGPQ). The amphiphilic copolymers can spontaneously form micellar nanoparticles with core-shell structures. Initially we will use doxorubicin (DOX), a FDA-approved anti-cancer therapeutics as a model anti-cancer agent. Amphiphilic copolymers are able to incorporate hydrophobic agents into the core of nanoparticles through a self-assembly process. Besides sharing common advantages of nanoparticles for delivery of anti-cancer therapeutics, our strategy offers an approach to differentiate healthy skeletons and osteolytic lesions and then elicit therapeutic actions to attack cancer cells within pathological skeletal domains, which is a substantial innovative feature in comparison with current available therapeutic approaches for bone metastases. The long-term goal of the project is to develop and validate an osteolytic stimuli-responsive drug delivery system and ultimately provide an effective therapeutic modality to improve the treatment of bone metastases. The proposed research project could lead to an effective therapeutic approach to attack invading cancer cells around bone metastatic microenvironments. In addition, the proposed therapeutic approach has considerable adaptability to accommodate different tissue-targeting moieties and therapeutic compounds. Once the nanotherapeutic system is established, it is easily adaptable for delivering other candidate therapeutics. This may lead to a new bone-targeted drug delivery platform for bone metastases and possibly other bone-related diseases.

描述（由申请人提供）：骨转移性癌症非常难以治疗，并导致疼痛、骨折、神经压迫、发病率和死亡率。 目前骨转移性癌症的治疗方式通常是姑息性的，显然需要更好的治疗方案，这项建议解决了这样一个重要的公共卫生需求。该研究项目旨在探索，开发和测试一种新型纳米药物平台，以提高抗癌药物的骨骼亲和力，选择性和有效性，以期开发一种有效的骨转移治疗方法。纳米治疗剂基于肽、聚（乙二醇）和聚（三亚甲基碳酸酯）的合成三嵌段共聚物（Pep-b-PEG-b-PTMC）。该功能肽被设计为具有亲骨性八肽（Asp 8）和组织蛋白酶K（CTSK）-可切割底物（HPGGPQ）。两亲性共聚物可自发形成具有核壳结构的胶束纳米粒子。最初，我们将使用多柔比星（DOX），一种FDA批准的抗癌疗法作为模型抗癌剂。两亲性共聚物能够通过自组装过程将疏水剂引入纳米颗粒的核中。除了共享用于递送抗癌治疗剂的纳米颗粒的共同优点之外，我们的策略提供了一种区分健康骨骼和溶骨性病变的方法，然后引发治疗作用以攻击病理性骨骼域内的癌细胞，这与目前可用的骨转移治疗方法相比是一个实质性的创新特征。该项目的长期目标是开发和验证溶骨性刺激响应药物递送系统，并最终提供有效的治疗方式来改善骨转移的治疗。拟议的研究项目可能会导致一种有效的治疗方法来攻击骨转移微环境周围的入侵癌细胞。此外，所提出的治疗方法具有相当大的适应性，以适应不同的组织靶向部分和治疗化合物。一旦纳米系统建立，它很容易适应于递送其他候选治疗剂。这可能导致一种新的骨靶向药物输送平台，用于骨转移和其他可能的骨相关疾病。