An osteolytic stimuli-responsive nanotherapeutic system for bone metastases

描述（由申请人提供）：骨转移性癌症非常难以治疗，会导致疼痛、骨折、神经压迫、发病率和死亡率。目前骨转移癌的治疗方式通常是姑息性的，显然需要更好的治疗选择，而本提案解决了这一重要的公共卫生需求。本项目拟探索、开发和测试一种新型纳米治疗平台，以提高抗癌药物的骨骼亲和力、选择性和疗效，以期开发出一种有效的骨转移治疗方式。纳米治疗剂是基于合成肽、聚乙二醇和聚三亚甲基碳酸酯（Pep-b-PEG-b-PTMC）的三嵌段共聚物。该功能肽被设计为具有骨趋向性八肽（Asp8）和组织蛋白酶K （CTSK）可切割底物（HPGGPQ）。两亲性共聚物可以自发形成具有核壳结构的胶束纳米颗粒。最初，我们将使用fda批准的抗癌药物阿霉素（DOX）作为模型抗癌药物。两亲共聚物能够通过自组装过程将疏水剂纳入纳米颗粒的核心。除了分享纳米颗粒用于抗癌治疗的共同优势外，我们的策略提供了一种区分健康骨骼和溶骨病变的方法，然后引发治疗行动来攻击病理骨骼区域内的癌细胞，与目前可用的骨转移治疗方法相比，这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一种溶骨刺激反应药物输送系统，并最终提供一种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入侵的癌细胞。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。一旦纳米治疗系统建立起来，它就很容易适应其他候选治疗方法。这可能会为骨转移和其他骨相关疾病提供一个新的骨靶向药物递送平台。

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.