Novel Nanotechnology Platform for Breast Cancer Treatment

 描述（由申请人提供）：乳腺癌是美国女性癌症死亡的第二大原因。在诊断时，不到10%的女性患有转移性疾病。然而，当确定性治疗后复发时，大多数患者最终会出现播散性转移，而不是孤立的局部复发。紫杉烷类（紫杉醇和多西他赛）对于治疗乳腺癌、卵巢癌、前列腺癌和肺癌具有显著的抗癌功效。但其选择性差、毒性大，是影响化疗停药的重要因素。曲妥珠单抗联合化疗通常用作转移性HER-2阳性乳腺癌的一线治疗。患者在数月至数年内出现获得性耐药;而其他患者则表现出内在耐药（从头耐药）。抑制HSP 90有可能同时关闭多种致癌信号通路。随着最近发现的抵消分子靶向药物功效的反馈环，对抗反馈环的一种解决方案是用多模式抑制剂攻击癌症，该多模式抑制剂使用HSP 90抑制剂同时抑制多个信号传导节点，这也可以对抗抗性突变的出现。HSP 90抑制的治疗潜力正在许多临床试验中进行广泛评估，包括17-AAG（目前处于III期临床试验中）。同时联合治疗对于克服HER-2阳性乳腺癌的耐药性至关重要。然而，安全和特异性地递送具有非重叠作用机制的多种药物的能力一直具有挑战性。为了克服这些问题，我们计划开发多功能聚合物纳米颗粒，以测试以下假设：三模式组合纳米颗粒将证明比HER-2阳性乳腺癌的当前护理标准疗法更有效，毒性更低。这些多功能聚合物纳米颗粒将紫杉醇（Taxol）和17-AAG掺入核内，但也将在表面上用曲妥珠单抗作为靶向部分“装饰”，以特异性靶向HER-2受体以及作为分子靶向治疗剂。我们假设这些靶向纳米颗粒将在体外对HER-2阳性乳腺癌细胞系以及HER-2阳性曲妥珠单抗和/或拉帕替尼耐药乳腺癌细胞系具有活性，并且它们将在HER-2阳性耐药肿瘤的小鼠异种移植模型中显示出体内功效。目的1：合成隐形的可水解交联曲妥珠单抗表面靶向P（LLA-HEMA）纳米粒。目标二：我们将制造和表征药物（紫杉醇和17-AAG）负载和罗丹明-123负载隐形水解交联曲妥珠单抗表面标记- P（LLA-HEMA）纳米粒子，并进行内化和细胞毒性研究。目标3：我们将对Bodipy（R）标记的隐形可水解交联曲妥珠单抗表面标记- P（LLA-HEMA）纳米颗粒进行生物分布研究，对药物（紫杉醇和17-AAG）负载的隐形可水解交联曲妥珠单抗表面标记- P（LLA-HEMA）纳米颗粒进行功效研究，以及内化和细胞毒性研究。这项工作一旦成功完成，将带来化疗药物、分子靶向治疗和HSP 90抑制剂的联合作用，以最小的毒性克服HER-2耐药性。

 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.