An osteolytic stimuli-responsive nanotherapeutic system for bone metastases

描述(申请人提供)：骨转移癌很难治疗，会导致疼痛、骨折、神经压迫、发病率，甚至常常死亡。目前骨转移癌的治疗方法通常是姑息性的，显然需要更好的治疗方案，而这项建议满足了这样一个重要的公共卫生需求。该研究项目建议探索、开发和测试一种新型的纳米治疗平台，以提高抗癌药物的骨骼亲和力、选择性和疗效，希望开发一种有效的骨转移治疗方式。纳米疗法是基于合成的多肽、聚乙二醇和聚三亚甲基碳酸酯三嵌段共聚物(PEP-b-PEGb-PTMC)。该功能肽含有八肽成骨蛋白(Asp8)和组织蛋白酶K(CTSK)可裂解底物(HPGGPQ)。两亲性共聚物可以自发形成具有核-壳结构的胶束纳米粒子。最初，我们将使用阿霉素(DOX)，这是FDA批准的一种抗癌治疗药物，作为模型抗癌药物。两亲性共聚物能够通过自组装过程将疏水性试剂结合到纳米颗粒的核心中。除了共享纳米颗粒在提供抗癌治疗药物方面的共同优势外，我们的策略还提供了一种区分健康骨骼和溶骨性病变的方法，然后引发治疗行动，以攻击病理性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响应型药物输送系统，并最终提供一种有效的治疗方式来改进骨转移的治疗。这项拟议的研究项目可能导致一种有效的治疗方法，以攻击骨转移微环境周围侵袭的癌细胞。此外，建议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。一旦建立了纳米治疗系统，它就很容易适应于提供其他候选治疗药物。这可能导致一种新的骨靶向药物传递平台，用于治疗骨转移瘤，可能还包括其他与骨相关的疾病。

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.