Multifunctional PEG Hydrogel Nano/Microparticles for Targeted Treatment of NSCLC

多功能PEG水凝胶纳米/微粒靶向治疗NSCLC

• 批准号: 8403721
• 负责人: Patrick J. Sinko
• 金额: $ 34.77万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403721
• 关键词: Accounting; Adherence; Adverse effects; Affinity; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Breathing; CXCL12 gene; CXCR4 gene; Camptothecin; Cancer Etiology; Cancer Patient; Caring; Caspase; Cell Surface Receptors; Cell surface; Cessation of life; Data; Development; Diagnosis; Diffuse; Disease; Dose; Doxycycline; Drug Delivery Systems; Engineering; Evaluation; Filtration; Gel; Gelatinase B; Goals; Hydrogels; Inflammation; Inflammatory; Injectable; Life; Ligands; Lung; Lung Neoplasms; Malignant neoplasm of lung; Metastatic Lesion; Mus; NF-kappa B; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Paclitaxel; Pathway interactions; Patients; Pattern; Peptide Fragments; Pharmaceutical Preparations; Pharmacodynamics; Platinum; Process; Research; Resistance; Respiratory physiology; Series; Signal Transduction; Solubility; Specificity; Staging; Structure; Surface; System; Thioctic Acid; Time; Tissues; Toxic effect; United States; Viral; Woman; absorption; cancer cell; chemokine; chemotherapeutic agent; chemotherapy; cytotoxic; design; improved; macrophage; men; metastasis prevention; migration; mouse model; nano; nanoparticle; natural flow; neoplastic cell; novel; outcome forecast; programs; public health relevance; receptor binding; residence; targeted delivery; vMIP-II

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.

描述（由申请人提供）：拟议的研究计划的长期目标是开发静脉内（IV）施用的肺靶向纳米颗粒（NP）/凝胶微粒（GMP）递送系统，以治疗非小细胞细胞肺癌（NSCLC）。最初诊断后，至少5年的局部肺癌患者中，超过一半的患者对限制原发性肺癌转移性传播的方法有好处。靶向是提高药物浓度和最小化副作用的有效方法，但肺靶向的选择却很狭窄。因此，迫切需要采用针对性的肺输送方法来治疗NSCLC。提出了两个级别的目标。第一个是被动定位。静脉内给药后，GMPS在肺中有选择地积累。我们引人注目的初步数据表明，被动靶向抗癌药物效力和较低峰值全身药物浓度的10倍增加了10倍。第二个是主动靶向。提出了两种类型的NP来实现主动靶向。使用新的制造过程，可以实现高药物载入NP，从而克服了疏水性癌症药物的溶解度限制。 NP表面与选择性靶向癌细胞的配体功能化。第二个NP组还可以用细胞表面配体功能化，但是，这些NP不是在癌细胞内选择性地输送药物，而是设计为与癌细胞表面受体紧密结合并留在那里以抑制转移性信号级联。 GMP被动地积累在肺中，NP嵌入了GMP中，并寻求癌细胞，从而产生了极大程度的靶向特异性。提出了三个具体目的：目标1：工程师和评估一系列GMP，以实现（a）正常小鼠和正常小鼠的肺毒性（结构和功能改变以及炎症）的最佳无源肺靶向效率，保留和消除以及（b）在正常小鼠的肺毒性（结构和功能改变以及炎症）中。 AIM 2：设计，制造和评估NP和GMP，从而增强了Camptothecin（CPT）的促凋亡作用。将开发积极靶向的NP，该NPS专门将CPT和α脂酸（ALA）传递到肺癌细胞中，以利用这两种化学治疗剂诱导的肿瘤细胞凋亡中的协同作用。 AIM 3：设计，制造和评估CXCR4/7靶向的NP和GMP，以减少转移的发生。将研究两种主动的靶向方法：（1）直接CXCR4/7受体结合和（2）抑制下游促丙旋转信号传导因子NF-KB，ERK和/或MMP-9。如果成功，将产生一种可注射的肺靶向药物输送系统：（1）利用被动靶向利用肺的自然流通效率模式，以达到高局部和最小的全身药物浓度； （2）利用化学疗法诱导的肿瘤细胞凋亡和主动靶向的协同作用，以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性病变的发生。