Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Department of Experimental Therapeutics, Immunopharmacology and Targeted Therapy Laboratory, M.D. Anderson Cancer Center, Houston, USA.
J Control Release. 2014 Apr 28;180:1-9. doi: 10.1016/j.jconrel.2014.02.003. Epub 2014 Feb 13.
Vascular targeting for cancer is increasingly recognized as a therapeutic strategy although the lack of objective responses and the development of resistance are major limitations for clinically-available drugs. Endothelial targeted toxins exert increased toxicity compared to antiangiogenic drugs and may therefore overcome these limitations. The specificity and toxicity of targeted toxins may be increased by utilization of a drug delivery system which provides selective release of the targeted toxins in the target cells. Photochemical internalization (PCI) is a non-invasive modality which causes translocation into the cytosol of agents that are trapped in endosomes. This study describes the first use of PCI in combination with a recombinant fusion toxin targeting tumor vasculature. Endothelial cells bearing VEGFR2 treated with VEGF121/rGel showed dramatic enhancement of toxicity after PCI utilizing the photosensitizer TPCS2a (Amphinex®). We compared the PCI of VEGF121/rGel to that of bleomycin which is currently under clinical evaluation. The VEGFR2 specificity of VEGF121/rGel was shown to be preserved by the PCI treatment. PCI of VEGF121/rGel was further shown to induce vascular collapse and edema in the invasive areas of CT26.CL25 colon carcinoma tumors as shown by CD31 IHC. Antitumor effects, as assessed by tumor growth delay were found for PCI of VEGF121/rGel and PCI of bleomycin with cure rates of 40% and 33% respectively. PCI of VEGF121/rGel was, however, better tolerated compared to PCI of bleomycin. Thus, PCI of vascular targeted toxins provides higher specificity and increased tolerability compared to PCI of bleomycin and may represent an interesting clinical future for the PCI technology.
血管靶向治疗作为一种治疗策略，越来越受到人们的关注，尽管目前临床上可用的药物缺乏客观反应和耐药性的发展是主要限制。与抗血管生成药物相比，内皮靶向毒素的毒性更大，因此可能克服这些限制。通过利用药物输送系统，靶向毒素的特异性和毒性可以得到提高，该系统可以选择性地在靶细胞中释放靶向毒素。光化学内化（PCI）是一种非侵入性的方法，它可以将被内体捕获的药物转移到细胞质中。本研究首次描述了将 PCI 与靶向肿瘤血管的重组融合毒素联合使用。用 VEGF121/rGel 处理的携带 VEGFR2 的内皮细胞在利用光敏剂 TPCS2a（Amphinex®）进行 PCI 后，毒性明显增强。我们比较了 VEGF121/rGel 与目前正在临床评估的博来霉素的 PCI。结果表明，VEGF121/rGel 的 PCI 保留了 VEGFR2 的特异性。进一步研究表明，VEGF121/rGel 的 PCI 可诱导 CT26.CL25 结肠癌肿瘤侵袭区的血管塌陷和水肿，这可通过 CD31 IHC 检测到。通过肿瘤生长延迟评估的抗肿瘤作用发现，VEGF121/rGel 的 PCI 和博来霉素的 PCI 的治疗效果分别为 40%和 33%。然而，与博来霉素的 PCI 相比，VEGF121/rGel 的 PCI 耐受性更好。因此，与博来霉素的 PCI 相比，血管靶向毒素的 PCI 提供了更高的特异性和更高的耐受性，可能为 PCI 技术的未来提供了一个有趣的前景。
