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（由申请人提供）：化学疗法的抵抗力的发展代表了肿瘤细胞的适应性生物学反应，从而导致治疗衰竭和患者复发。如果要成功地消除肿瘤，迫切需要克服这个问题。肿瘤细胞不可逆生长停滞（衰老）是对暴露于化学治疗剂的压力的早期细胞反应。那些能够绕过衰老的细胞最终表现出对化学疗法的抗性。最近的报告为研究组织蛋白酶L在化学治疗耐药性过程中的作用提供了有说服力的理由。我们表明，使用化学抑制剂或siRNA将组织蛋白酶l的特异性靶向该分子将癌细胞迫使癌细胞变为不可逆转的生长停滞状态，并抑制了对药物的耐药性的发展。我们还证明了组织蛋白酶L抑制剂在体内逆转耐药性的能力，该裸鼠具有抗毒素耐药性神经母细胞瘤细胞系SKN-SKN-SH/R耐药性肿瘤的异种移植。 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.雌性裸小鼠将抗药性MCF7人类乳腺癌细胞原位植入第四个乳腺。我们将研究两个商业可用的组织蛋白酶L抑制剂，Z-Phe-try（T-BU） - 二唑甲基酮和1-萘甲磺酰基 - Ile-trp-醛 - 单独或单独给予阿无氨基甲醛，或与阿霉素相对于其对肿瘤细胞生长和药物抗药性的影响。具体目的1：在裸鼠进行纳米颗粒靶向治疗研究之前，将在鸡绒毛膜膜膜（CAM）肿瘤植入物的肿瘤血管生成和生长的鸡绒毛膜膜（CAM）肿瘤植入物模型中在体内进行初步实验。该模型允许体内预筛查生物活性，同时限制了使用更有意义和昂贵的鼠类。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抑制剂在降低阿霉素耐药性中的有效性，这是通过改善的抗肿瘤活性所证明的。相对于抗肿瘤功效和阿霉素相关的毒性，将进行比较。癌细胞具有发展对化学治疗药物的耐药性的独特能力，因此对扭转这种现象的方法进行研究将在癌症患者的治疗中具有重要价值。该项目将使用两种药物的组合，其中一种会损害癌细胞在乳腺癌的小鼠模型中损害癌细胞发展耐药性的能力。将测试一种新型技术，即使用纳米颗粒封装测试药物的技术，以确定这些纳米颗粒是否可以改善药物的递送并最大程度地减少相关的毒性。

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