Novel Nanotechnology Platform for Breast Cancer Treatment

用于乳腺癌治疗的新型纳米技术平台

基本信息

批准号：
9265808
负责人：
EMMANUEL O AKALA
金额：
$ 2.73万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265808
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 Modality Molecular Target Mus Nanotechnology Neoplasm Metastasis Oncogenic Outcome Paclitaxel Patients Pharmaceutical Preparations Phase Phase III Clinical Trials Polymers Recurrence Regimen Relapse Resistance Rhodamine 123 Signal Pathway Signal Transduction Skin Surface Testing Therapeutic Therapeutic Agents Time Toxic effect Trastuzumab Treatment Efficacy Ursidae Family Variant Woman Work Xenograft Model base chemotherapeutic agent chemotherapy combat crosslink cytotoxicity docetaxel drug efficacy efficacy study in vivo inhibitor/antagonist lapatinib malignant breast neoplasm molecular targeted therapies multimodality nanoparticle novel public health relevance receptor resistance mutation response standard of care targeted agent taxane therapy resistant tumor uptake

项目摘要

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（由申请人证明）：乳腺癌是美国妇女的第二个原因。孤立的局部临时。 ASED ASED在几个月内出现了一些转移性的HER-2患者（从头耐药）。信号节点的抑制剂也可以在许多临床试验中延长抗药性。乳腺癌。 HER-2阳性乳腺癌。假设有靶的纳米颗粒将在其-2阳性乳腺癌lin中活跃，例如HER-2阳性曲妥珠单抗和/或抗拉帕替尼的抗性戒曲癌细胞lins lins lins lins lins vo效率。我们将合成隐形的水解链接曲曲曲霉表面 - 表面 - 纳米颗粒（LLA-HEMA）纳米颗粒。并进行内在化和细胞毒性研究。）研究和细胞毒素研究，而成熟的剂，分子靶向疗法和HSP90抑制剂的合并能力将以最小的毒性来克服HER-2的抗性。