Nanoparticle targeting of cathepsin-L inhibitor and doxorubicin in breast cancer

组织蛋白酶-L 抑制剂和阿霉素纳米颗粒靶向治疗乳腺癌

• 批准号: 7394765
• 负责人: SHAKER A MOUSA
• 金额: $ 12.84万
• 依托单位: VASCULAR VISION PHARMACEUTICALS COMPANY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-26 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394765
• 关键词: Address; Aldehydes; Animals; Antibodies; Biodegradation; Biological; Breast Cancer Cell; Breast Cancer Model; Bypass; CTSL gene; Cancer Cell Growth; Cancer Patient; Cathepsin L; Cathepsins; Cell Line; Cells; Chemicals; Clinic; Cytotoxic agent; Data; Development; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug resistance; ERBB2 gene; Effectiveness; Encapsulated; Environment; Exhibits; Exposure to; Female; Gene Targeting; Genetic; Glycolic-Lactic Acid Polyester; Growth; Human; Implant; Integrins; Laboratories; MCF7 cell; Maleimides; Malignant Neoplasms; Mammary gland; Modality; Modeling; Multidrug Resistance Gene; Mus; Neuroblastoma; Nude Mice; Pathway interactions; Patients; Peptides; Performance; Pharmaceutical Preparations; Process; Proliferating; RNA; Relapse; Reporting; Research; Resistance; Resistance development; Role; Site; Stress; Surface; System; Technology; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Failure; Tumor Angiogenesis; Work; Xenograft procedure; angiogenesis; antiangiogenesis therapy; antibody conjugate; base; cancer cell; carbobenzoxyphenylalanine; cell growth; chemotherapeutic agent; chemotherapy; chorioallantoic membrane; concept; drug testing; improved; in vivo; inhibitor/antagonist; longevity gene; malignant breast neoplasm; membrane model; mouse model; multidrug resistance inhibition therapy; nanoparticle; nanoparticulate; neoplastic cell; neovascularization; new technology; polylactic acid-polyglycolic acid copolymer; prevent; research study; response; senescence; success; therapeutic target; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): The development of resistance to chemotherapy represents an adaptive biological response by tumor cells that leads to treatment failure and patient relapse. There is an urgent need to overcome this problem if treatments are to be successful in eradicating tumors. Tumor cell irreversible growth arrest (senescence) is an early cellular response to the stress of exposure to chemotherapeutic agents. Those cells that are able to bypass senescence ultimately exhibit resistance to chemotherapy. Recent reports provide a persuasive rationale for studying the role of cathepsin L in the process of chemotherapeutic drug resistance. We showed that specific targeting of cathepsin L using chemical inhibitors or siRNA to this molecule forced cancer cells into a state of irreversible growth arrest and suppressed development of resistance to drugs. We also demonstrated the ability of cathepsin L inhibitor to reverse drug resistance in vivo utilizing nude mice bearing xenografts of doxorubicin resistant neuroblastoma cell line SKN-SH/R drug resistant tumors. Because many chemotherapeutic agents show systemic toxicities, and because cathepsin L inhibitors to be used in these studies are peptides subject to biodegradation, we will address these limitations by encapsulation of agents using PEG-PLGA nanoparticles targeted to either the sites of tumor neovascularization (1v integrin) or to MCF7 tumor cells via HER2 antibody. Female nude mice will have drug-resistant MCF7 human breast cancer cells implanted orthotopically into the fourth mammary gland. We will study two commercially available Cathepsin L inhibitors, Z-Phe-Try (t-Bu)-diazomethylketone and 1-Naphthalenesulfonyl-Ile-Trp- Aldehyde given either alone or with doxorubicin with respect to their effects on tumor cell growth and drug-resistance. Specific Aim 1: Prior to performance of nanoparticle-targeted therapy studies in nude mice, preliminary experiments to determine optimum formulations of nanoparticles will be performed in vivo in the chick chorioallantoic membrane (CAM) tumor implant model of tumor angiogenesis and growth. This model permits in vivo pre-screening for bioactivity while limiting the use of more sentient and costly murine species. Specific Aim 2: Nanoparticle formulations that show optimum anti-tumor and anti-angiogenesis activity in the CAM model will be tested in the mouse breast cancer model. In these studies, we will evaluate the effectiveness of cathepsin L inhibitors in reducing doxorubicin resistance as evidenced by improved anti-tumor activities. Comparisons will be made between non-targeted and targeted therapies with respect to anti-tumor efficacy and doxorubicin-associated toxicities. Cancer cells have the unique ability to develop resistance to chemotherapeutic drugs, and so research on ways to reverse this phenomenon would have significant value in the treatment of cancer patients. This project will use a combination of two drugs, one of which impairs the cancer cell's ability to develop drug resistance, in a mouse model of breast cancer. A novel technology, the use of nanoparticles to encapsulate the test drugs, will be tested to determine whether these nanoparticles can improve the delivery of drugs and minimize the associated toxicities.

描述(申请人提供)：化疗耐药性的发展代表了肿瘤细胞的适应性生物反应，导致治疗失败和患者复发。如果要在根除肿瘤方面取得成功，就迫切需要克服这个问题。肿瘤细胞不可逆性生长停滞(衰老)是细胞对暴露于化疗药物应激的早期反应。那些能够绕过衰老的细胞最终表现出对化疗的抗药性。最近的报道为研究组织蛋白酶L在化疗耐药过程中的作用提供了有说服力的理论基础。我们发现，利用化学抑制剂或小干扰RNA将组织蛋白酶L特异性地靶向到该分子，使癌细胞进入不可逆转的生长停滞状态，并抑制了耐药性的发展。我们还在荷阿霉素耐药神经母细胞瘤细胞株SKN-SH/R的裸鼠移植瘤实验中证实了组织蛋白酶L抑制剂的体内逆转耐药能力。由于许多化疗药物都显示出全身毒性，并且这些研究中使用的组织蛋白酶L抑制剂都是可生物降解的多肽，因此我们将通过使用聚乙二醇聚乳酸微球包裹靶向肿瘤新生血管部位(1v整合素)或通过HER2抗体靶向MCF7肿瘤细胞的药物来解决这些限制。雌性裸鼠将把具有抗药性的MCF7人乳腺癌细胞原位移植到第四个乳腺。我们将研究两种商业上可用的组织蛋白酶L抑制剂，Z-苯丙氨酸(t-Bu)-重氮甲基酮和1-萘磺酰异色胺醛单独或与阿霉素合用对肿瘤细胞生长和耐药性的影响。具体目标1：在裸鼠体内进行纳米颗粒靶向治疗研究之前，将在鸡绒毛膜尿囊膜(CAM)肿瘤血管生成和生长的移植瘤模型中进行初步实验，以确定纳米颗粒的最佳处方。这种模型允许在体内预先筛选生物活性，同时限制使用更有知觉和更昂贵的小鼠物种。具体目标2：在CAM模型中显示最佳抗肿瘤和抗血管生成活性的纳米颗粒制剂将在小鼠乳腺癌模型中进行测试。在这些研究中，我们将评估组织蛋白酶L抑制剂在改善抗肿瘤活性方面降低阿霉素耐药性的有效性。将在抗肿瘤疗效和阿霉素相关毒性方面对非靶向治疗和靶向治疗进行比较。癌细胞具有对化疗药物产生耐药性的独特能力，因此研究扭转这一现象的方法在癌症患者的治疗中具有重要价值。该项目将在乳腺癌的小鼠模型中使用两种药物的组合，其中一种药物会削弱癌细胞产生耐药性的能力。将对一项新技术进行测试，即使用纳米颗粒包裹测试药物，以确定这些纳米颗粒是否可以改善药物的输送并将相关毒性降至最低。

项目成果

The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor.

• 发表时间: 2009-11
• 期刊: Anticancer research
• 影响因子: 2
• 作者: A. Rebbaa;F. Chu;T. Sudha;C. Gallati;U. Dier;E. Dyskin;M. Yalçın;C. Bianchini;O. Shaker;S. Mousa