Multifunctional PEG Hydrogel Nano/Microparticles for Targeted Treatment of NSCLC

描述(由申请人提供)：拟议研究计划的长期目标是开发一种静脉(IV)给药的肺靶向纳米微粒(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，超过一半的局限性肺癌患者存活至少5年，这表明采用一种限制原发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将副作用降至最低的有效方法，但肺靶向的选择范围很窄。因此，迫切需要靶向肺给药治疗非小细胞肺癌。提出了两个层次的目标定位。第一种是被动瞄准。静脉给药后，GMP选择性地在肺内蓄积。我们令人信服的初步数据表明，被动靶向在抗癌药物效力方面实现了10倍的提高，并将全身药物峰值浓度降低了10倍。二是主动瞄准。提出了两种实现主动靶向的NPs。利用一种新的制备工艺，实现了纳米粒的高载药量，克服了疏水性抗癌药物的溶解性限制。NP表面被选择性靶向癌细胞的配体功能化。第二个NP组也具有细胞表面配体的功能，然而，这些NP被设计成与癌细胞表面受体紧密结合并留在那里，以抑制转移信号级联，而不是选择性地将药物运送到癌细胞内。一旦GMP在肺内被动积聚，嵌入在GMP中的NPs就会扩散出去并寻找癌细胞，从而产生非凡的靶向特异性。提出了三个具体目标：目的1：设计和评价一系列GMPs，以达到(A)最佳的被动肺靶向效率、滞留和消除，以及(B)在正常小鼠和正交异性肺癌小鼠模型中最小的肺毒性(结构和功能改变以及炎症)。目的2：设计、制造和评估可增强喜树碱促细胞凋亡作用的纳米粒和GMP。将开发主动靶向的NPs，将CPT和α-硫辛酸(ALA)特异性地运送到肺癌细胞，以利用这两种化疗药物诱导肿瘤细胞凋亡的协同作用。目的3：设计、制造和评估以CXCR4/7为靶点的NPs和GMP，以减少转移的发生。将研究两种主动靶向方法：(1)直接结合CXCR4/7受体和(2)抑制下游促转移信号因子NF-kB、ERK和/或MMP-9。如果成功，将产生一种可注射的肺靶向给药系统，该系统将：(1)利用被动靶向利用肺的自然流动-滤过模式实现高局部和最低全身药物浓度；(2)利用化疗诱导的肿瘤细胞凋亡和主动靶向的协同作用，减少所需的有效药物和MP剂量；(3)利用主动靶向通过干扰CXCR4/7-CXCL12趋化因子途径来减少转移病变的发生。 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。该项目涉及开发和评估一种新型的靶向给药系统(静脉注射)，该系统使用嵌入到微粒中的纳米颗粒将化疗药物和其他药物专门输送到患者的肺部，以治疗非小细胞肺癌并减少限制治疗的副作用。

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.