Stimuli-responsive crosslinked theranostics against advanced prostate cancer

 描述(申请人提供)：前列腺癌是美国所有癌症相关死亡的第二大原因，也是最常见的男性癌症。去势抵抗前列腺癌(CRPC)是一种无法治愈的致命疾病。多西紫杉醇为主的化疗是CRPC的一线标准治疗方案。然而，全身化疗的疗效受到给药效率低、耐药性和全身毒性的限制。该项目的目标是开发新型的刺激响应型交联剂。 用于图像引导递送基于机制的分子药物以避免晚期前列腺癌的治疗耐药性和全身毒性的Theranostics(SCTS)。SCTS将独特的刺激响应型交联策略和高效的avç3整合素靶向配体(LXW64)集成到具有独特构型依赖成像特性的新型多功能纳米卟啉系统中。目标1的目标是设计和合成一系列分别对肿瘤微环境中的内源性刺激(如酸性pH、还原剂和蛋白酶)做出反应的硼酸盐、二硫化物和蛋白酶可裂解的交联剂。SCT将被LXW64装饰，以增强其对晚期前列腺癌的靶向能力。目的2通过多模式成像(NIRFI、PET和MRI)定量研究SCTS在前列腺癌异种移植模型中的时空分布，包括药代动力学、生物分布、瘤内给药和药物释放。我们将定量测量SCTS在正电子发射计算机断层显像中的~(64)Cu信号，从而确定SCTS的药代动力学和生物分布。MRI和NIRF成像功能的激活与局部刺激的水平相关，可被认为是纳米颗粒解离和药物释放的标志。成像结果将通过电感耦合等离子体质谱(ICP-MS)定量Gd水平、放射自显影和Förster共振能量转移(FRET)药物释放以及蛋白水解酶和整合素水平的免疫组织化学来验证。在目标3中，携带多西他赛耐药前列腺癌异种移植瘤的SCID小鼠将接受SCT治疗，该SCT与新的热休克蛋白90抑制剂(Ganetespib)和多西紫杉醇共负载。这些新的纳米制剂有望通过P-糖蛋白和抑制替代生长途径绕过药物外排，这是多西紫杉醇耐药的两个重要机制。与治疗反应相关的肿瘤消退将通过分子成像进行量化，并与肿瘤微环境的分子变化相关联。建议的治疗药物的成功开发将显著提高监测治疗给药过程的成像灵敏度，并增强基于机制的药物的给药，以克服多西紫杉醇的耐药性。这项研究的结果不仅对于推动新型治疗晚期前列腺癌的治疗纳米平台的开发具有重要意义，而且还将为使用刺激响应型交联治疗药物进行图像导向药物输送提供一个新的框架。

 DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of all cancer-related deaths and the most commonly diagnosed cancer among males in US. Castration-resistant prostate cancer (CRPC) is an incurable and lethal form of the disease. Docetaxel-based chemotherapy is the first-line standard treatment for CRPC. However, the efficacy of systemic chemotherapy is limited by poor efficiency in the delivery, drug resistance and systemic toxicity. The goal of this project is to develop novel stimuli-responsive cross-linked theranostics (SCTs) for image-guided delivery of mechanism-based molecular medicine to circumvent treatment-resistance and systemic toxicity for advanced prostate cancer. SCTs integrate unique stimuli-responsive crosslinking strategies and highly potent avß3 integrin targeting ligand (LXW64) into a novel multifunctional nanoporphyrin system with unique architecture-dependent imaging properties. The goal of Aim 1 is to design and synthesize a series of SCTs with boronate, disulfide and protease-cleavable crosslinkers that are responsive to the intrinsic stimuli at the tumor microenvironment, such as acidic pH, reducing agents and proteases, respectively. SCTs will be decorated with LXW64 to enhance their targeting capability to advanced prostate cancer. In Aim 2, the spatiotemporal distribution of SCTs including pharmacokinetics, biodistribution and intratumoral delivery and drug release, will be quantitatively investigated by multimodal imaging (NIRFI, PET and MRI) in orthotopic prostate cancer xenograft models. The 64Cu signal of SCTs from PET imaging will be measured quantitatively so that the pharmacokinetics and biodistribution of SCTs can be determined. The activation of the MRI and NIRF imaging functions correlates with the level of local stimuli and can be considered as an indication of nanoparticle dissociation and drug release. The imaging results will be validated by inductively coupled plasma mass spectrometry (ICP-MS) for quantitative Gd level, autoradiography and förster resonance energy transfer (FRET) for drug release as well as immunohistochemistry for protease and integrin level. In Aim 3, SCID mice bearing docetaxel-resistance prostate cancer xenograft will be treated with SCTs that are co-loaded with a new heat shock protein 90 inhibitor (ganetespib) and docetaxel. These novel nano-formulations hold promise for circumventing drug efflux through P-glycoprotein and inhibiting alternative growth pathways, two important mechanisms of resistance to docetaxel. Tumor regression associated with response to therapy will be quantified by molecular imaging, and correlated with molecular changes in tumor microenvironment. Successful development of the proposed theranostic agents will significantly improve the imaging sensitivity for monitoring the therapeutic delivery process, and enhance the delivery of mechanism-based drugs to overcome docetaxel resistance. Results from this study will be significant not only in advancing the development of a novel theranostic nano-platform for effective therapy of advanced prostate cancer, but also in providing a new framework of using stimuli-responsive cross-linked theranostics for image-guided drug delivery.