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

• 批准号: 8269562
• 负责人: Nancy Joan Boudreau
• 金额: $ 26.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269562
• 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

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：乳腺癌是女性最常见的癌症和第二大死亡原因。新辅助化疗在手术前越来越多地用于“收缩”肿瘤，并实现了乳房保守的方法。但是，长期生存仍然很差，部分原因是将细胞毒性药物递送到肿瘤组织的因素。肿瘤血管异常，改变了跨内皮的渗透性和增加的间质液压（IFP），共同限制大分子细胞毒性药物的递送。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有效地通过克服高IFP并促进对流驱动对对流的大分子分子吸收到组织中，从而有效地增加化学治疗剂的组织积累。为此，我们发现了一种新型的内源性途径，该途径调节了血管渗透性，该途径在肿瘤血管中保持起作用。转化生长因子β1（TGF？1）限制了正常的血管渗透性，抑制在血管细胞中表达的I型TGF ??受体ALK5，但增强了正常和肿瘤血管中的血管渗透性（Sounni等人的手稿提交）。因此，我们建议使用ALK5抑制剂与大分子化学治疗剂结合使用，以改善乳腺肿瘤灌注和常规化学治疗剂的积累。矛盾的是，尽管通过阻断血管内皮生长因子（VEGF）的“归一化”来实现肿瘤灌注的增加和细胞毒性剂的渗透率的增加，并且可以通过降低血管渗透率来降低这些作用，但这些作用在很大程度上限制在早期阶段肿瘤中，这些作用却很大。随着肿瘤的进展，肿瘤血管成熟并成为VEGF阻塞的难治性。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保持起作用，并进一步预测，ALK5阻断将改善早期和晚期肿瘤的细胞毒性药物渗透。我们将比较Doxil在用ALK5抑制剂治疗的乳腺肿瘤小鼠中的积累，而不是接受抗VEGF抗体治疗的小鼠（DC101），并评估MMTV-PYMT小鼠的早期和晚期tamors中的血管通透性和doxil的积累。此外，虽然先前的研究已使用MR成像数据来弥补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，大分子分子对比培养基（MMCM）的MR成像与Doxil积累相关，从而可以使用大多数驱动力的含量来改善毒药的comptoxic，从而可以将其与Cytox comptox相关。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担，肿瘤潜伏期（终止点）以及肺转移的频率，并进一步证明MR基于Image cormeral corpareication corpareicati corpareicati corpareication corporeication corperication corpericati corpareication，我们将通过监测乳腺腺癌的组织病理学特征以及肺部的频率，并进一步证明MR对药物累积的预测均具有较适应性的预测。我们还将检查用ALK5抑制剂加Doxil与Doxil作为单一疗法治疗的小鼠原始植入的人类乳腺肿瘤细胞的反应，以证明Doxil在人类肿瘤细胞杀伤中的疗效增强。这些研究将共同​​确定1）在存在和不存在不同肿瘤阶段的ALK5抑制剂的情况下改善细胞毒性药物积累的有效性，2）MRI对肿瘤微血管通透性的积累和细胞毒性药物的积累的预测，以及3）增强了肿瘤反应，并增强了肿瘤的毒性，并降低了从化学疗法药物积累的细胞毒性。因此，通过利用新的预测性MRI相关性并利用一种调节血管通透性的新型内源性途径，该途径在乳腺癌中保持功能，化学治疗剂的递送以及早期和晚期乳腺癌的随后反应将得到从极大的改善。