Stroma Targeted Theranostic Nanoparticles for Pancreatic Cancer

胰腺癌患者的预后极差，5年生存率较低 超过5%。虽然这种生物侵略性的原因还没有明确阐明， 广泛的肿瘤间质和促纤维增生反应的影响，这两者都是独特的 胰腺癌的特征，已经涉及促进肿瘤进展， 转移尽管几项研究已经利用受体靶向纳米颗粒来改善 胰腺癌的检测和治疗通常成功率很低，使用 靶向基质的多功能纳米颗粒，其可占总纳米颗粒的高达80 肿瘤的体积，可能会导致一个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重基质靶向多功能治疗诊断 纳米颗粒，其将有助于改善胰腺癌的检测，并递送 在与立体定向体组合时产生协同治疗的去甲基化剂 辐射 在我们成功利用Syndecan-1靶向胰腺癌的基础上，该提案将 开发和测试一种新的多模式方法，以使用靶向基质为中心， 纳米颗粒（Syndecan-XT），其将用作肿瘤特异性光声造影剂 和地西他滨（一种低甲基化剂）的药物递送载体。改善肿瘤间质 靶向，我们将利用双重方法，使用1）Syndecan-1，其结合胶原IV 以及升高的肿瘤受体，即胰岛素生长样因子 1受体（IGF1-R），和2）明胶封端的胶态介孔二氧化硅纳米颗粒，其 将促进明胶被MMP 2和9消化后的药物释放。我们将测试 总体假设是，基质靶向Syndecan-XT纳米颗粒包封 低甲基化剂将显著改善胰腺肿瘤的检测和疗效 SBRT治疗的协同作用，以产生协同肿瘤杀伤，同时减少脱靶 细胞毒我们将使用以下目标来测试这一假设：目标1）开发，表征， 优化并评估Syndecan-XT纳米颗粒作为治疗诊断-放射增敏剂 胰腺肿瘤间质特异性靶向纳米颗粒;目的2）优化方案 用于Syndecan-XT纳米颗粒和SBR放射治疗的体内研究;目的3）评估治疗效果 SBR疗法和Syndecan-XT联合或不联合地西他滨与 胰腺癌的原位和KPC模型中的放射治疗。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治疗是将不可切除的胰腺癌患者转换为 成为手术切除的候选者。

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.