光动力学疗法联合肿瘤血管正常化治疗肿瘤的相关机制研究

Systemic cytostatic treatment is often unsatisfactory due to the barriers of the tumor vessel which are known to interfere with cytostatic drug delivery to tumors. Photodynamic therapy (PDT) at low drug-light conditions has been explored as a pathway to increase the effective permeability of tumor vessels to macromolecules and selectively enhance their delivery to solid tumors.However, the further clinical application of this vessel effect which induced by low-dose PDT has been limited by the abnormal tumor vascular system(abnormality of tumor blood flow,disapear of the hydrostatic and oncotic pressure gradients across the vessel wall). Recently,preclinical and clinical evidence shows that certain antiangiogenic agents can "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for drug deliver. Therefore, we hypothesize that the pre-treatment of antiangiogenic agents can "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen、cytostatic drug and photosentitizer deliver to tumor;the microenviroments of the tumor can be "normalized" by this pre-treatment as well. Based on these "normalization" ,the therapeutic window of the PDT-induced vascular changes which are favourable for increased cytostatic drug distribution and efficiency could be significantly extended. An anti-VEGFR1 murine nonoclona antibody (DC101) will be used to normalize the tumor vasculature, followed with low dose Visudyne mediated PDT and intravenous injection of Caelyx?(liposomal doxorubicin). The mechanism of antiangiogenesis combined with PDT for tumors will be verified and demonstrared by these studies in order to develop a new direction for tumor combination therapies.

肿瘤的血管屏障导致化疗药物难以进入肿瘤组织是传统化疗效果较差的原因之一。低剂量光动力疗法可以增加肿瘤血管渗透性，进而促进化疗药物在肿瘤组织里的吸收，但肿瘤异常的血管系统（血流动力学紊乱，血管内外压力梯度消失等）限制了该方法的进一步应用。最新研究发现，合理使用抗血管生成药物能导致肿瘤血管结构和功能正常化，提高药物及氧运输到肿瘤组织的效率。本课题首次提出：利用抗血管生成药物达成肿瘤血管正常化，促进化疗药物、光敏剂及氧向肿瘤组织输送，同时恢复血管内外正常压力梯度，在此基础上利用低剂量光动力疗法增加肿瘤血管渗透性，预期可大幅增加化疗药物在肿瘤组织里的吸收。这两种治疗方法内在机制存在紧密联系，联合应用可发挥协同效应。本课题拟采用抗血管生成药物DC101联合低剂量光动力学疗法增加肿瘤对多柔比星脂质体的吸收，通过对该联合治疗的相关机制研究，为肿瘤的联合治疗提供一种新的思路，具有重要的理论意义及临床价值。

低剂量光动力学疗法（L-PDT）可以增加肿瘤血管渗透性，进而促进化疗药物在肿瘤组织里的吸收。但是目前仅发现该方法可瞬时改变肿瘤血管渗透性，严重限制了其对于肿瘤治疗方面的应用，L-PDT对于肿瘤血管的持续性研究尚未得知。本课题首次提出L-PDT对肿瘤血管具有持续性影响，并进一步揭示了其影响机制，联合化疗治疗取得了满意效果。本研究通过对构建的肿瘤动物模型进行L-PDT，探索了L-PDT对肿瘤血管渗透性的长期影响及其机制。结果发现：（1）L-PDT后7天，小鼠肿瘤血管渗透性仍高于未经处理的肿瘤血管（2）L-PDT后SDF-1水平明显上调，巨噬细胞在肿瘤组织富集，向M1型分化，并与SDF-1的调节显著正相关（3）AMD3100抑制了巨噬细胞的富集、分化，削弱了L-PDT后肿瘤血管的渗透性（4）L-PDT联合楷莱(多柔比星脂质体)抗肿瘤治疗，显著缩小了肿瘤体积。以上结果提示：L-PDT通过上调SDF-1/CXCR4通路，促进肿瘤相关巨噬细胞的富集及分化，持续性增强肿瘤血管的渗透性，联合化学药物治疗取得良好效果，为肿瘤治疗提供了新的思路及途径，具有重要的理论意义和临床价值。