Stroma Targeted Theranostic Nanoparticles for Pancreatic Cancer

胰腺癌患者预后极差，五年生存率较低。 超过5%。虽然这种生物攻击性的原因还没有清楚地阐明， 广泛的肿瘤间质和促结缔组织反应的影响，两者都是独一无二的 胰腺癌的特征，已被认为与促进肿瘤进展和 转移。尽管一些研究已经利用受体靶向纳米颗粒来改进 胰腺癌的检测和治疗通常成功率不高，使用 靶向基质的多功能纳米颗粒，可占总纳米颗粒的80% 肿瘤体积，可能会导致改变游戏规则的结果。主动靶向肿瘤间质 胰腺癌，我们的目标是开发一种双间质靶向多功能治疗药物 纳米颗粒将有助于改进对胰腺癌的检测，并提供 脱甲基剂与立体定向小体结合后产生协同治疗 辐射。 在我们成功使用Syndecan-1靶向胰腺癌的基础上，这项提议将 开发和测试一种以使用基质为中心的新的多模式方法 将作为肿瘤特异性光声造影剂的纳米粒(Syndecan-XT) 以及低甲基化药物地西他滨的药物输送载体。改善肿瘤间质 靶向，我们将使用双重方法使用Syndecan-1，它与IV型胶原结合 和纤维连接蛋白基质蛋白，以及升高的肿瘤受体，即胰岛素生长因子 1受体(IGF1-R)和2)明胶覆盖的胶体介孔二氧化硅纳米颗粒，该纳米颗粒 会促进明胶被MMP2和9消化后的药物释放。我们将测试 最重要的假设是基质靶向Syndecan-XT纳米颗粒包裹 去甲基化药物将显著提高胰腺肿瘤的检出和疗效 SBRT治疗的结果是协同杀灭肿瘤，同时减少脱靶 细胞毒性。我们将使用以下目标来检验这一假设：目标1)开发、表征、 优化和评估Syndecan-XT纳米粒子作为放射治疗感受器 靶向胰腺肿瘤间质的纳米粒；目的2)优化治疗方案 Syndecan-XT纳米粒和SBR体内放射治疗；目的3)评估治疗 SBR和Syndecan-XT联合或联合地西他滨治疗的疗效观察 胰腺癌原位模型和KPC模型的放射治疗。成功完成 这些目标将为拟议的Syndecan的最终目标提供坚实的基础- XT+SBR治疗是不能切除的胰腺癌患者转变为 成为手术切除的候选对象。

The prognosis of patients with pancreatic cancer is extremely poor, with 5-yr survival rates lower than 5%. While the reasons for this biological aggressiveness have not been clearly elucidated, the impact of the extensive tumor stroma and desmoplastic reaction, both of which are unique features of pancreatic cancer, have been implicated in the promotion of tumor progression and metastasis. Although several studies have utilized receptor targeted nanoparticles for improved detection and treatment of pancreatic cancer with generally poor success, the use of multifunctional nanoparticles targeted to the stroma, which can comprise up to 80% of the total tumor volume, could result in a game-changing outcome. To actively target the tumor stroma of pancreatic cancer, our objective is to develop a dual stroma targeted multifunctional theranostic nanoparticle which will facilitate improved detection of pancreatic cancer and deliver a demethylating agent to result in a synergistic therapy upon combination with stereotactic body radiation. Building upon our successful targeting of pancreatic cancer using Syndecan-1, this proposal will develop and test a novel multimodal approach centered on the use of a stroma targeted nanoparticle (Syndecan-XT) which will serve as a tumor specific optoacoustic contrast agent and drug delivery vehicle for Decitabine, a hypomethylating agent. To improve tumor stroma targeting, we will utilize a dual approach using 1) Syndecan-1, which binds to the collagen IV and fibronectin matrix proteins as well as elevated tumor receptors, i.e. insulin growth-like factor 1 receptor (IGF1- R), and a 2) gelatin capped, colloidal mesoporous silica nanoparticle, which will facilitate drug release upon digestion of the gelatin by MMPs 2 and 9. We will test the overarching hypothesis that stroma-targeted Syndecan-XT nanoparticles encapsulating hypomethylating agents will significantly improve the detection of pancreatic tumors and efficacy of SBRT therapy to result in synergistic tumor kill while resulting in reduced off-target cytotoxicity. We will test this hypothesis using the following aims: Aim 1) Develop, characterize, optimize, and evaluate Syndecan-XT nanoparticles as theranostic-radiosenisitizing nanoparticles for specific targeting of the stroma of pancreatic tumors; Aim 2) Optimize regimen for Syndecan-XT nanoparticles and SBR radiation therapy in vivo; Aim 3) Assess therapeutic efficacy of SBR therapy and Syndecan-XT with or without Decitabine in combination with radiation therapy in orthotopic and KPC models of pancreatic cancer. Successful completion of these aims will provide a solid foundation for the ultimate goal of the proposed Syndecan- XT+SBR therapy which is the conversion of patients with unresectable pancreatic cancer to become candidates for surgical resection.