OXYGEN AND LIGHT DEPENDENCY OF PHOTODYNAMIC THERAPY

描述：(申请者摘要)提供的证据表明 光动力疗法(PDT)可以影响血管对大分子和 以一种允许增强肿瘤摄取的方式的大分子络合物 治疗药物在人肿瘤移植瘤或可移植小鼠中的应用 肿瘤。这可以显著增强肿瘤控制，如图所示 脂质体包裹的阿霉素。被称为“渗透性”的光动力疗法 (P)-PDT与传统的PDT的不同之处在于它本身没有或几乎没有 抗肿瘤作用。目前，该协议涉及两个节点之间的交互 光敏剂、阴离子焦脱镁叶绿酸衍生物(HPPH)和 阳离子染料维多利亚蓝(VBBO)。理解和利用 P-PDT降低大鼠血管屏障的机制 分子治疗药物可能提供一种新的治疗方法。 实体肿瘤的治疗。初步数据得出了这样的假设 P-PDT通过打开内皮间隙影响微血管系统，从而允许 大分子从血管系统中流出，进入间质肿瘤 太空。申请人进一步假设，这一机制将促进 携带化疗药物的脂质体和微球的外流 免疫调节细胞因子，从而增强细胞毒性或刺激 抗肿瘤免疫反应或增强病毒基因载体的转染性 效率。此应用程序的总体目标是进行一系列 将测试这些可能性的实验。在目标1中，申请人提议 通过探索其他治疗方案来优化治疗参数 光敏剂。这些实验不仅将改善治疗，而且 还提供了关于所涉及的机制的重要提示。在《目标2》中她 建议扩大这种治疗的应用范围，从交付 脂质体将化疗药物携带到微球中 细胞因子GM-CSF和表达β-半乳糖苷酶的病毒基因载体 (β-半乳糖)基因。目标3将通过以下方式重点研究大分子外流的机制 通过监测血管间隙的变化来确定产生的血管间隙的大小 通过功能磁共振实时检测血流灌注和通透性，并通过给药 一些生理性血管活性介质的抑制剂最终在目标4中 她建议通过激活Present来增加治疗性PDT成分 治疗用光剂量可导致光动力肿瘤的光敏剂 毁灭。她假设，这增加了光动力疗法后的细胞减少 最大限度的化疗药物摄取将有利于肿瘤控制。 类似地，PDT破坏的肿瘤细胞可能提供肿瘤抗原 前一次注射GM-CSF所产生的树突状细胞分化。

DESCRIPTION: (Applicant's Abstract) Evidence is provided that Photodynamic Therapy (PDT) can affect vascular permeability to macromolecules and macromolecular complexes in a way that allows enhanced tumor uptake of therapeutic agents in human tumor xenografts or in transplantable murine tumors. This can lead to significantly enhanced tumor control, as shown with liposome-encapsulated doxorubicin. The PDT protocol, termed "permeabilizing" (P)-PDT, differs from conventional PDT in that it by itself has no or minimal anti-tumor effects. At present, this protocol involves the interaction of two photosensitizers, an anionic pyropheophorbide derivative (HPPH) and the cationic dye Victoria Blue-BO (VBBO). Understanding and exploiting the mechanisms by which P-PDT lowers the vascular barrier encountered by large molecular therapeutic agents may provide an additional approach in the treatment of solid tumors. The preliminary data have led to the hypothesis that P-PDT affects the microvasculature by opening endothelial gaps that allow macromolecules to egress from the vasculature and enter the interstitial tumor space. The applicant further hypothesizes that this mechanism will facilitate the egress of liposomes and microspheres carrying chemotherapeutic drugs or immunomodulating cytokines, thus enhancing cytotoxicity or stimulating anti-tumor immune responses, or of viral gene vectors enhancing transfection efficiencies. The overall goal of this application is to conduct a series of experiments that will test these possibilities. In Aim 1 the applicant proposes to optimize treatment parameters by exploring additional treatment regimes and photosensitizers. These experiments will not only improve the treatment, but also provide important hints as to the mechanisms involved. In Aim 2 she proposes to expand the application of this treatment from the delivery of liposomally carried chemotherapeutic drugs to microspheres carrying the cytokine GM-CSF and a viral gene vector expressing the beta-galactosidase (beta-gal) gene. Aim 3 will focus on the mechanisms of macromolecular egress by determining the size of vascular gaps produced, by monitoring changes in perfusion and permeability in real time by functional MRI, and by administering a number of inhibitors to physiological vasoactive mediators Finally, in Aim 4 she proposes to add a therapeutic PDT component by activating the present photosensitizers with therapeutic light doses that cause photodynamic tumor destruction. She hypothesizes that this added cytoreduction by PDT after maximal chemotherapeutic drug uptake will be beneficial for tumor control. Similarly, PDT destroyed tumor cells may provide tumor antigen to differentiating dendritic cells generated by preceding delivery of GM-CSF.