OXYGEN AND LIGHT DEPENDENCY OF PHOTODYNAMIC THERAPY

描述：（申请人的摘要）提供的证据表明， 光动力疗法（PDT）可以影响血管对大分子的渗透性， 大分子复合物的方式，允许增强肿瘤摄取 在人肿瘤异种移植物或可移植鼠中的治疗剂 肿瘤的这可以导致显著增强的肿瘤控制，如图所示。 脂质体包封的阿霉素。PDT方案，称为“透化” （P）-PDT与常规PDT的不同之处在于，其本身不具有或具有最小的 抗肿瘤作用。目前，该协议涉及两个 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-BO（VBBO）。理解和利用 P-PDT降低血管屏障的机制， 分子治疗剂可以提供另外的方法， 治疗实体瘤。初步的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， 大分子从脉管系统中排出并进入间质性肿瘤 空间申请人进一步假设，该机制将促进 携带化疗药物的脂质体和微球的排出，或 免疫调节细胞因子，从而增强细胞毒性或刺激 抗肿瘤免疫应答，或增强转染的病毒基因载体 效率。本申请的总体目标是进行一系列 这些实验将测试这些可能性。在目标1中，申请人提出 通过探索其他治疗方案优化治疗参数， 光敏剂这些实验不仅会改善治疗， 也提供了有关机制的重要线索。在Aim 2中， 建议扩大这种治疗的应用， 将脂质体携带的化疗药物转移至携带化疗药物的微球。 细胞因子GM-CSF和表达β-半乳糖苷酶的病毒基因载体 （β-gal）基因。目标3将集中在大分子的出口机制， 通过监测血管间隙的变化来确定血管间隙的大小， 通过功能性MRI真实的观察灌注和渗透性， 一些生理性血管活性介质的抑制剂最后，在目标4中， 她建议通过激活目前的细胞， 具有引起光动力肿瘤的治疗光剂量的光敏剂 杀伤性她推测，这增加了PDT的细胞减少后， 最大的化疗药物摄取将有利于肿瘤控制。 类似地，PDT破坏的肿瘤细胞可以提供肿瘤抗原， 分化通过预先递送GM-CSF产生的树突状细胞。

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.