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: 8792835
• 负责人: Patrick J. Sinko
• 金额: $ 36.96万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792835
• 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; Health; 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; 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。第二个NP基团也被细胞表面配体功能化，然而，这些NP不是选择性地在癌细胞内递送药物货物，而是被设计为与癌细胞表面受体紧密结合并保留在那里，以抑制转移性信号级联。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。

项目成果

Influence of molecular size on the retention of polymeric nanocarrier diagnostic agents in breast ducts.

• DOI: 10.1007/s11095-012-0763-z
• 发表时间: 2012-09
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Singh Y;Gao D;Gu Z;Li S;Rivera KA;Stein S;Love S;Sinko PJ
• 通讯作者: Sinko PJ

Ex vivo and in vivo capture and deactivation of circulating tumor cells by dual-antibody-coated nanomaterials.

• DOI: 10.1016/j.jconrel.2015.04.036
• 发表时间: 2015-07
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Jingjing Xie;Yu Gao;Rongli Zhao;P. Sinko;S. Gu;Jichuang Wang;Yuanfang Li;Yusheng Lu;Suhong Yu-Suhong

Effects of block copolymer properties on nanocarrier protection from in vivo clearance.

块共聚物特性对纳米载体保护免受体内清除的影响。

• DOI: 10.1016/j.jconrel.2012.06.020
• 发表时间: 2012-08-20
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: D'Addio SM;Saad W;Ansell SM;Squiers JJ;Adamson DH;Herrera-Alonso M;Wohl AR;Hoye TR;Macosko CW;Mayer LD;Vauthier C;Prud'homme RK
• 通讯作者: Prud'homme RK

An "off-the-shelf" capillary microfluidic device that enables tuning of the droplet breakup regime at constant flow rates.

• DOI: 10.1039/c3lc50804h
• 发表时间: 2013-12-07
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Benson BR;Stone HA;Prud'homme RK
• 通讯作者: Prud'homme RK

Noninvasive detection of passively targeted poly(ethylene glycol) nanocarriers in tumors.

肿瘤中被动靶向聚乙二醇纳米载体的无创检测。

• DOI: 10.1021/mp2003913
• 发表时间: 2012
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Singh,Yashveer;Gao,Dayuan;Gu,Zichao;Li,Shike;Stein,Stanley;Sinko,PatrickJ
• 通讯作者: Sinko,PatrickJ