Multifunctional PEG Hydrogel Nano/Microparticles for Targeted Treatment of NSCLC

描述（由申请人提供）：拟定研究项目的长期目标是开发一种静脉（IV）给药的肺靶向纳米颗粒（NP）/凝胶微粒（GMP）递送系统，用于治疗非小细胞肺癌（NSCLC）。在初步诊断后，超过一半的局部肺癌患者存活至少5年，这表明限制原发性肺癌转移扩散的方法是有益的。虽然靶向是提高药物浓度和最小化副作用的有效方法，但肺靶向的选择很窄。因此，迫切需要用于治疗NSCLC的靶向肺递送方法。提出了两个层次的目标。第一种是被动瞄准。静脉给药后，GMP选择性地在肺中蓄积。我们令人信服的初步数据表明，被动靶向实现了抗癌药物效力的10倍增加和10倍降低的全身药物浓度峰值。二是主动瞄准。提出了两种类型的NP来实现主动靶向。使用一种新的制造工艺，实现了纳米颗粒的高载药量，克服了疏水性癌症药物的溶解度限制。NP表面用选择性靶向癌细胞的配体官能化。第二NP基团也用细胞表面配体官能化，然而，这些NP被工程化以紧密结合癌细胞表面受体并保持在那里以抑制转移性信号级联，而不是选择性地在癌细胞内递送药物货物。一旦GMP被动地在肺中积累，嵌入GMP中的NP扩散出来并寻找癌细胞，从而导致非常程度的靶向特异性。提出了三个具体目标：目的1：设计和评估一系列GMP，以在正常小鼠和肺癌的正交各向异性小鼠模型中实现（a）最佳的被动肺靶向效率、保留和消除以及（B）最小的肺毒性（结构和功能改变和炎症）。目的2：设计、制备和评价增强喜树碱（CPT）促凋亡作用的纳米粒和颗粒蛋白。将开发主动靶向的NP，其特异性地将CPT和α-硫辛酸（ALA）递送至肺癌细胞，以利用由这两种化疗剂诱导的肿瘤细胞凋亡中的协同作用。目的3：设计、制备和评估CXCR 4/7靶向的NPs和GMP，以减少转移的发生。将研究两种主动靶向方法：（1）直接CXCR 4/7受体结合和（2）抑制下游促转移信号传导因子NF-κ B、ERK和/或MMP-9。如果成功，将产生可注射的肺靶向药物递送系统，其：（1）利用被动靶向以利用肺的天然流动过滤模式来实现高的局部和最小的全身药物浓度;（2）利用化疗诱导的肿瘤细胞凋亡和主动靶向中的协同作用来减少所需的有效药物和MP剂量;和（3）通过干扰CXCR 4/7 -CXCL 12趋化因子途径，利用主动靶向减少转移性病变的发生。 公共卫生相关性：肺癌目前是美国男性和女性癌症死亡的主要原因，非小细胞肺癌（NSCLC）占肺癌病例的绝大多数。迫切需要为这种高度致命的疾病开发新的治疗方法。该项目涉及一种新型靶向递送系统（静脉注射）的开发和评估，该系统使用嵌入微粒的纳米颗粒将化疗药物和其他药物特异性地递送到患者的肺部，以治疗NSCLC并减少治疗限制性副作用。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research program is to develop an intravenously (IV) administered lung- targeted nanoparticle (NP)/gel microparticle (GMP) delivery system for the treatment of non-small cell lung cancer (NSCLC). After the initial diagnosis, greater than half of the patients with localized lung cancer survive at least 5 years suggesting a benefit to an approach that limits metastatic spread from the primary lung cancer. While targeting is an effective approach for improving drug concentrations and minimizing side effects, the options for lung targeting are narrow. Thus, targeted lung delivery approaches for treating NSCLC are urgently needed. Two levels of targeting are proposed. The first is passive targeting. GMPs selectively accumulate in the lung after IV administration. Our compelling preliminary data demonstrates that passive targeting achieves a 10-fold increase in anti-cancer drug potency and 10-fold lower peak systemic drug concentrations. The second is active targeting. Two types of NPs are proposed to achieve active targeting. Using a novel fabrication process, high drug loading into NPs is achieved that overcomes the solubility limitations of hydrophobic cancer drugs. The NP surfaces are functionalized with ligands that selectively target cancer cells. The second NP group is also functionalized with cell surface ligands, however, instead of delivering drug cargo selectively inside the cancer cell, these NPs are engineered to tightly bind to cancer cell surface receptors and remain there in order to inhibit the metastatic signaling cascade. Once the GMPs passively accumulate in the lung, the NPs imbedded in the GMP diffuse out and seek cancer cells resulting in an extraordinary degree of targeting specificity. Three specific aims are proposed: AIM 1: Engineer and evaluate a series of GMPs to achieve (a) optimal passive lung targeting efficiency, retention and elimination and (b) minimal pulmonary toxicity (structural and functional alterations and inflammation) in normal mice and in an orthotropic mouse model of lung cancer. AIM 2: Design, fabricate, and assess NPs and GMPs that enhance the pro-apoptotic effect of camptothecin (CPT). Actively targeted NPs will be developed that specifically deliver CPT and alpha lipoic acid (ALA) to lung cancer cells to exploit synergy in tumor cell apoptosis induced by these two chemotherapeutic agents. AIM 3: Design, fabricate, and assess CXCR4/7-targeted NPs and GMPs that reduce the occurrence of metastasis. Two active targeting approaches will be investigated: (1) direct CXCR4/7 receptor binding and (2) inhibition of downstream pro-metastatic signaling factors NF-kB, ERK and/or MMP-9. If successful, an injectable lung targeted drug delivery system will be produced that: (1) utilizes passive targeting to exploit the natural flow-filtration pattern of the lung to achieve high local and minimal systemic drug concentrations; (2) exploits synergy in chemotherapy-induced tumor cell apoptosis and active targeting to reduce the required effective drug and MP doses; and (3) utilizes active targeting to reduce the occurrence of metastatic lesions by interfering with the CXCR4/7 - CXCL12 chemokine pathway. PUBLIC HEALTH RELEVANCE: Lung cancer is currently the leading cause of cancer deaths in both men and women in the United States and Non-Small Cell Lung Cancer (NSCLC) accounts for the vast majority of lung cancer cases. There is a pressing need to develop new treatment approaches for this highly fatal disease. This project involves the development and evaluation of a novel targeted delivery system (injected intravenously) that uses nanoparticles imbedded into microparticles to deliver chemotherapeutic drugs and other agents specifically to the lungs of patients in order to treat NSCLC and reduce therapy-limiting side effects.