Novel Nanotechnology Platform for Breast Cancer Treatment

用于乳腺癌治疗的新型纳米技术平台

• 批准号: 8793606
• 负责人: EMMANUEL O AKALA
• 金额: $ 37.75万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793606
• 关键词: Adriamycin PFS; Biodistribution; Breast Cancer Cell; Breast Cancer Treatment; Breast Cancer cell line; Cancer Etiology; Cardiotoxicity; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical Research; Clinical Trials; Combined Modality Therapy; Confocal Microscopy; Diagnosis; Disease; Drug resistance; Dyes; ERBB2 gene; Feedback; Fluorescent Dyes; HSP 90 inhibition; Heat-Shock Proteins 90; In Vitro; Kinetics; Label; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Molecular Target; Mus; Nanotechnology; Neoplasm Metastasis; Oncogenic; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Recurrence; Regimen; Relapse; Resistance; Rhodamine 123; Signal Pathway; Signal Transduction; Skin; Solutions; Surface; Taxane Compound; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Trastuzumab; Ursidae Family; Variant; Woman; Work; Xenograft Model; base; chemotherapeutic agent; chemotherapy; combat; crosslink; cytotoxicity; docetaxel; drug efficacy; in vivo; inhibitor/antagonist; lapatinib; malignant breast neoplasm; nanoparticle; novel; public health relevance; receptor; resistance mutation; response; standard of care; targeted treatment; taxane; tumor; uptake

 DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death among women in the US. At the time of diagnosis, less than 10% of women are presented with a metastatic disease. However, when relapse occurs after definitive therapy, the majority of patients end up with disseminated metastases rather than an isolated local recurrence. Taxanes (paclitaxel and docetaxel) have remarkable anticancer efficacy for the treatment of breast, ovarian, prostate and lung cancers. However, they have poor selectivity and high toxicity which are the most important factors for discontinuation of cancer chemotherapy. Trastuzumab in combination with chemotherapy is often used as first line therapy for metastatic HER-2 positive breast cancers. Patients develop acquired resistance within months to years; while other patients demonstrate intrinsic resistance (de novo resistance). Inhibition of HSP90 has the potential to shut down multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that counteract the efficacy of molecularly targeted agents, one solution to combat feedback loops is to attack cancers with a multimodal inhibitor that simultaneously inhibits multiple signaling nodes using HSP90 inhibitors which can also combat the emergence of resistance mutations. The therapeutic potential of HSP90 inhibition is being evaluated extensively in a number of clinical trials, including 17-AAG (now in phase III clinical trials). Simultaneous combination therapy is critical in circumventing drug resistance for the treatment of HER-2-positive breast cancers. However, the ability to safely and specifically deliver multiple drugs with non-overlapping mechanisms of action has been challenging. To overcome these issues, we plan to develop multifunctional polymeric nanoparticles to test the hypothesis that tri-modal combination nanoparticles will prove more effective with less toxicity than current standard of care therapies for HER-2 positive breast cancers. These multi-functional polymeric nanoparticles will incorporate paclitaxel (Taxol) and 17-AAG within the core, but will also be "decorated" on the surface with trastuzumab as a targeting moiety to specifically target HER-2 receptors as well as function as a molecular targeted therapeutic agent. We hypothesize that these targeted nanoparticles will be active in vitro against HER-2 positive breast cancer cell lines as well as HER-2 positive trastuzumab and/or lapatinib resistant breast cancer cell lines, and that they will show in vivo efficacy in mouse xenograft models of HER-2 positive drug resistant tumors. Aim 1: We will synthesize stealth hydrolysable crosslinked trastuzumab surface-targged- P (LLA-HEMA) nanoparticles. Aim 2: We will fabricate and characterize drug (paclitaxel and 17-AAG)- loaded and rhodamine-123-loaded stealth hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and carry out internalization and cytotoxicity studies. Aim 3: We will carry out biodistribution studies on Bodipy(R)-labeled stealth hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and efficacy studies on drug (paclitaxel and 17-AAG)- loaded stealth hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and internalization and cytotoxicity studies. This work will, when successfully completed, bring to bear the combined power of a chemotherapeutic agent, molecular targeted therapy and HSP90 inhibitor, to overcome HER-2 resistance with minimal toxicity.

 描述（由适用提供）：乳腺癌是美国女性癌症死亡的第二大原因。在诊断时，只有不到10％的女性出现转移性疾病。但是，当继电器在确定治疗后发生时，大多数患者最终会出现传播转移，而不是孤立的局部复发。紫杉烷（紫杉醇和多西他赛）具有显着的抗癌效率，可用于治疗乳房，卵巢，前列腺和肺癌。但是，它们的选择性差和高毒性，这是停用癌症化学疗法的最重要因素。曲妥珠单抗与化学疗法结合使用，通常用作转移性HER-2阳性乳腺癌的第一线治疗。患者在数月到几年内发展出获得的抵抗；而其他患者表现出内在的抵抗力（从头耐药性）。 HSP90的抑制有可能简单地关闭多个致癌信号通路。随着最近发现反馈分子靶向剂有效性的反馈回路，一种打击反馈回路的解决方案是用多模式抑制剂攻击癌症，该抑制剂简单地使用HSP90抑制剂抑制多个信号节点，该抑制剂也可以使用抗电阻突变的出现。 HSP90抑制的理论潜力在许多临床试验（包括17-AAG）（现在正在III期临床试验中）进行了广泛的评估。同时组合疗法对于规避耐药性对于治疗HER-2阳性乳腺癌至关重要。但是，挑战了使用不重叠的作用机制安全，专门提供多种药物的能力。为了克服这些问题，我们计划开发多功能的聚合物纳米颗粒，以检验以下假设：三模式组合纳米颗粒比目前的HER-2阳性乳腺癌的护理标准疗法更为有效，而毒性较小。这些多功能聚合物纳米颗粒将在核心内掺入紫杉醇（紫杉醇）和17-AAG，但也将以曲妥珠单抗作为靶向部分在表面上“装饰”，以特异性地靶向HER-2受体，并用作分子靶向疗法剂的功能。我们假设这些靶向的纳米颗粒的目标1：我们将合成钢丝水解的交联曲妥珠单抗表面 - p（lla-hema）纳米颗粒。 AIM 2：我们将制造和表征药物。 （Paclitaxel和17-AAG） - 负载和若丹明123的蒸汽水解型曲妥珠单抗表面标签-P（LLA-HEMA）纳米颗粒并进行内部化和细胞毒性研究。 Aim 3: We will carry out biodistribution studies on Bodipy(R)-labeled steam hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and effective studies on drug (paclitaxel and 17-AAG)- Loaded steam hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and internalization and细胞毒性研究。成功完成后，这项工作将带来化学治疗剂，分子靶向疗法和HSP90抑制剂的合并能力，以克服Her-2的耐药性。