Improved Drug Delivery to Tumors Using Novel Tissue Perfusion Approaches

使用新型组织灌注方法改善肿瘤药物输送

基本信息

批准号：
8077221
负责人：
Nancy Joan Boudreau
金额：
$ 24.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8077221
关键词：
Antibodies Asses Blood Vessels Breast Breast Adenocarcinoma Cause of Death Cells Characteristics Contrast Media Convection Cytotoxic agent DC101 Monoclonal Antibody Data Diagnostic Diagnostic Imaging Diagnostic Neoplasm Staging Disease Doxorubicin Hydrochloride Liposome Drug Delivery Systems Effectiveness Frequencies Goals Human Image Implant Intercellular Fluid Intravenous Magnetic Resonance Imaging Mammary Neoplasms Manuscripts Mediating Metastatic Neoplasm to the Lung Microvascular Permeability Molecular Monitor Mouse Mammary Tumor Virus Mus Neoadjuvant Therapy Neoplasms in Vascular Tissue Operative Surgical Procedures Organ Pathway interactions Penetration Perfusion Permeability Pharmaceutical Preparations Refractory Second Primary Cancers Staging TGF-beta type I receptor Therapeutic Therapeutic Agents Tissues Tumor Burden Tumor Tissue Tumor stage Vascular Endothelial Growth Factors Vascular Permeabilities Woman base cell killing chemotherapeutic agent chemotherapy cytotoxic cytotoxicity drug distribution hemodynamics human TGFB1 protein improved in vivo inhibitor/antagonist malignant breast neoplasm neoplastic cell novel pressure receptor response tumor uptake vascular bed

项目摘要

DESCRIPTION: Breast cancer is the most common cancer and second leading cause of death in women. Neoadjuvant chemotherapy is increasingly used to "shrink" tumors prior to surgery and enable breast conservative approaches; however, long-term survival remains poor, in part due to factors that limit delivery of cytotoxic drugs to tumor tissue. Abnormal tumor blood vessels and altered transendothelial permeability and increased interstitial fluid pressures (IFP), conspire to limit delivery of macromolecular cytotoxic drugs. Thus, approaches that aim to alter tumor vessel hemodynamics and vascular permeability would effectively increase tissue accumulation of chemotherapeutic agents by overcoming high IFP and promoting convection driven uptake of large macromolecular agents into tissues. To this end, we have discovered a novel, endogenous pathway regulating vascular permeability that remains functional in tumor vessels. Whereas transforming growth factor beta 1 (TGF?1) restricts normal vascular permeability, inhibition of the type I TGF??receptor Alk5 expressed in vascular cells, enhances vascular permeability in normal as well as tumor vasculature (Sounni et al. manuscript submitted). Thus, we propose to administer an Alk5 inhibitor, in combination with macromolecular chemotherapeutic agents to improve breast tumor perfusion and accumulation of conventional chemotherapeutic agents. Paradoxically, while increases in tumor perfusion and improved penetration of cytotoxic agents have also been achieved by 'normalization' of tumor vasculature by blocking vascular endothelial growth factor (VEGF) to reduce vascular permeability, these effects are transient and largely limited to immature vessels more frequently associated with early stage tumors. As tumors progress, tumor vessels mature and become refractory to VEGF blockade. Importantly, we have also observed that TGFb1-mediated vascular stabilization remains functional in more mature tumor vessels, and further predict that Alk5 blockade will improve cytotoxic drug penetration in both early as well as late stage tumors. We will compare accumulation of Doxil in mammary tumor-bearing mice treated with Alk5 inhibitor as opposed to those treated with anti-VEGF antibody (DC101), and assess vascular permeability and accumulation of Doxil in both early and late stage tumors in MMTV-PymT mice. Moreover, while previous studies have used MR imaging data to asses breast cancer responses after cytotoxic drug administration, we will demonstrate that MR imaging of macromolecular contrast media (MMCM) in the presence or absence of Alk5 blockade correlates with Doxil accumulation and thus can be used to predict macromolecular drug distribution and to identify tumors most likely to benefit from cytotoxics combined with agents that improve vascular permeability. In addition, we will assess the anti-tumor impact of improved Doxil accumulation following Alk5 blockade by monitoring histopathologic characteristics of mammary adenocarcinomas, as well as tumor burden, tumor latency (to endpoint), and frequency of pulmonary metastasis, and further demonstrate that MR imaging based predictions of drug accumulation also correlates with therapeutic responses. We will also examine responses of orthotopically implanted human breast tumor cells in mice treated with Alk5 inhibitor plus Doxil versus Doxil as monotherapy, to demonstrate enhanced efficacy of Doxil in human tumor cell killing. Together these studies will establish the effectiveness of 1) improved cytotoxic drug accumulations in the presence and absence of ALK5 inhibitors at different tumor stages, 2) MRI predictions of tumor microvascular permeability and cytotoxic drug accumulation, and 3) enhanced tumor responses and reduced cytotoxicity from improved chemotherapeutic drug accumulation in tumors. Thus, by utilizing new predictive MRI correlations and exploiting a novel endogenous pathway regulating vascular permeability that remains functional in breast cancer, the delivery of chemotherapeutic agents and subsequent response of both early and late stage breast tumors will be radically improved.

描述：乳腺癌是最常见的癌症，也是女性死亡的第二大原因。新辅助化疗越来越多地用于在手术前“缩小”肿瘤并实现乳房保守治疗；然而，长期生存率仍然很差，部分原因是限制细胞毒性药物向肿瘤组织输送的因素。肿瘤血管异常、跨内皮细胞通透性改变以及间质液压力（IFP）增加，共同限制了大分子细胞毒性药物的输送。因此，旨在改变肿瘤血管血流动力学和血管通透性的方法将通过克服高IFP并促进对流驱动的大分子药物吸收到组织中，有效地增加化疗药物的组织积累。为此，我们发现了一种新的内源性调节血管通透性的途径，该途径在肿瘤血管中仍然发挥作用。转化生长因子 β 1 (TGF?1) 限制正常血管通透性，而抑制血管细胞中表达的 I 型 TGFβ 受体 Alk5，则增强正常和肿瘤脉管系统的血管通透性（Sounni 等人提交的手稿）。因此，我们建议联合使用Alk5抑制剂和大分子化疗药物来改善乳腺肿瘤的灌注和常规化疗药物的积累。矛盾的是，虽然通过阻断血管内皮生长因子（VEGF）以降低血管通透性来实现肿瘤脉管系统的“正常化”，从而增加了肿瘤灌注并改善了细胞毒性药物的渗透性，但这些影响是短暂的，并且主要局限于更常见的未成熟血管。与早期肿瘤有关。随着肿瘤的进展，肿瘤血管成熟并对 VEGF 阻断产生耐药性。重要的是，我们还观察到 TGFb1 介导的血管稳定在更成熟的肿瘤血管中仍然发挥作用，并进一步预测 Alk5 阻断将改善早期和晚期肿瘤中的细胞毒性药物渗透。我们将比较用 Alk5 抑制剂治疗的乳腺肿瘤小鼠与用抗 VEGF 抗体 (DC101) 治疗的小鼠中 Doxil 的积累，并评估 MMTV-PymT 小鼠早期和晚期肿瘤中的血管通透性和 Doxil 的积累。此外，虽然之前的研究已经使用 MR 成像数据来评估细胞毒性药物给药后的乳腺癌反应，但我们将证明，在存在或不存在 Alk5 阻断的情况下，大分子造影剂 (MMCM) 的 MR 成像与 Doxil 积累相关，因此可以使用预测大分子药物分布并确定最有可能受益于细胞毒素与改善血管通透性药物的肿瘤。此外，我们将通过监测乳腺腺癌的组织病理学特征以及肿瘤负荷、肿瘤潜伏期（至终点）和肺转移频率来评估 Alk5 阻断后 Doxil 积累改善的抗肿瘤影响，并进一步证明 MR基于成像的药物蓄积预测也与治疗反应相关。我们还将检查用 Alk5 抑制剂加 Doxil 治疗的小鼠与 Doxil 作为单一疗法治疗的小鼠中原位植入的人类乳腺肿瘤细胞的反应，以证明 Doxil 在杀死人类肿瘤细胞方面的增强功效。这些研究将共同确定 1) 在不同肿瘤阶段存在和不存在 ALK5 抑制剂的情况下改善细胞毒性药物积累的有效性，2) 肿瘤微血管通透性和细胞毒性药物积累的 MRI 预测，以及 3) 增强肿瘤反应并降低细胞毒性改善肿瘤中化疗药物的积累。因此，通过利用新的预测性 MRI 相关性并开发在乳腺癌中保持功能的调节血管通透性的新内源性途径，化疗药物的输送以及早期和晚期乳腺肿瘤的后续反应将得到根本性改善。