Macrophage Targeted Photodynamic Therapy

描述（由申请人提供）： 光动力疗法（PDT）可以通过增强光动力疗法的递送来改进。 使用靶向大分子光敏剂（PS）治疗选定的病变 共轭最近，肿瘤相关巨噬细胞 （TAM）通过几种不同的机制帮助肿瘤生长和扩散 （旁分泌生长因子，血管生成增加和基质降解） 酶），并且已经提出它们是癌症治疗的有效靶标。 这项修订后的提案调查了一种新的方法，通过有针对性的 递送经修饰的白蛋白-二氢卟酚（e6）缀合物， 存在于TAM上的清道夫受体，以及肿瘤限制照明。 我们已经证明，这种方法可以非常具体的光破坏小鼠 巨噬细胞，并导致肿瘤生长的实质性抑制， 在巨噬细胞和非巨噬细胞肿瘤中的体内。这项提案将考验 假设巨噬细胞的选择性和定向 照明将杀死TAM而不伤害其它远处巨噬细胞 群体，并因此产生有益的肿瘤反应，包括生长 延迟，减少血管生成和转移，增加存活率， 肿瘤免疫的发展。缀合物与 巨噬细胞可能依赖于它们的细胞活化状态， 将研究基因表达阵列和定量 通过RT-PCR检测清道夫受体的表达。J774细胞具有高度侵袭性， 转移性皮下注射BALB/c小鼠肿瘤的生物分布和PDT反应 将这些缀合物与游离PS进行比较。免疫组织化学将 允许微血管密度、巨噬细胞含量和增殖指数 在来自治疗的肿瘤的冷冻切片中测定。一对的PDT反应 关于S.C.巨噬细胞含量和免疫原性不同的小鼠肿瘤（EMT-6 和RIF- 1）将通过定量比较靶向和 非靶向PDT在大致相等的有效剂量。光动力疗法的增强作用， 佐剂（OK 432），旨在增加TAM的肿瘤浸润程度 并提高它们的活化状态。提出了一 PDT反应是炎症性的，它将促进诱导特异性的炎症反应。 抗肿瘤免疫反应，这将是探讨通过再挑战治愈 具有相同和不相关细胞系的动物，以及效应子的测量 细胞功能（细胞毒性T淋巴细胞、自然杀伤细胞和巨噬细胞） 脾脏和引流淋巴结

DESCRIPTION (provided by applicant): Photodynamic therapy (PDT) may be improved by enhancing the delivery of photosensitizers (PS) to selected lesions using targeted macromolecular conjugates. Recently it has become accepted that tumor-associated macrophages (TAMs) assist the tumor to grow and spread by several distinct mechanisms (paracrine growth factors, increased angiogenesis, and matrix-degrading enzymes) and they have been proposed to be a valid target for cancer therapy. This revised proposal investigates a new approach to killing TAMs by targeted delivery of modified albumin-chlorin (e6) conjugates that are recognized by the scavenger receptors present on TAMs, together with tumor-confined illumination. We have shown that this approach allows very specific photodestruction of mouse macrophages in vitro and leads to substantial inhibition of tumor growth in vivo in both macrophage and non-macrophage tumors. This proposal will test the hypothesis that the combination of macrophage selectivity and directed illumination will kill TAMs without harming other distant macrophage populations, and hence produce beneficial tumor responses including growth delay, decreased angiogenesis and metastasis, increased survival, and development of tumor immunity. The interaction of the conjugates with macrophages is likely to depend on their cellular activation state and this will be investigated with gene expression arrays and quantitation of scavenger-receptor expression by RT-PCR. J774 cells form highly aggressive and metastatic s.c. tumors in BALB/c mice and the biodistribution and PDT response of these conjugates will be compared to free PS. Immunohistochemistry will allow microvessel density, macrophage content, and proliferative index to be determined in frozen sections from treated tumors. The PDT responses of a pair of s.c. mouse tumors differing in macrophage content and immunogenicity (EMT-6 and RIF- 1) will be determined with quantitative comparison of targeted and non-targeted PDT at roughly equal effective doses. The enhancement of PDT by an adjuvant (OK432) designed to increase the degree of tumor infiltration by TAMs and to increase their activation state will be explored. It is proposed that a PDT response which is inflammatory will encourage the induction of a specific anti-tumor immune response, which will be explored by rechallenging cured animals with the same and unrelated cell lines, and measurement of effector cell functions (cytotoxic T lymphocyte, natural killer cell and macrophage) from spleens and draining lymph nodes.