Department of Radiation Oncology, Vanderbilt University, Nashville, Tennessee, USA.
Clin Cancer Res. 2010 Oct 15;16(20):4968-77. doi: 10.1158/1078-0432.CCR-10-0969. Epub 2010 Aug 27.
The purpose of this study was to achieve improved cancer-specific delivery and bioavailability of radiation-sensitizing chemotherapy using radiation-guided drug delivery.
Phage display technology was used to isolate a recombinant peptide (HVGGSSV) that binds to a radiation-inducible receptor in irradiated tumors. This peptide was used to target nab-paclitaxel to irradiated tumors, achieving tumor-specificity and enhanced bioavailability of paclitaxel.
Optical imaging studies showed that HVGGSSV-guided nab-paclitaxel selectively targeted irradiated tumors and showed 1.48 ± 1.66 photons/s/cm(2)/sr greater radiance compared with SGVSGHV-nab-paclitaxel, and 1.49 ± 1.36 photons/s/cm(2)/sr greater than nab-paclitaxel alone (P < 0.05). Biodistribution studies showed >5-fold increase in paclitaxel levels within irradiated tumors in HVGGSSV-nab-paclitaxel-treated groups as compared with either nab-paclitaxel or SGVSGHV-nab-paclitaxel at 72 hours. Both Lewis lung carcinoma and H460 lung carcinoma murine models showed significant tumor growth delay for HVGGSSV-nab-paclitaxel as compared with nab-paclitaxel, SGVSGHV-nab-paclitaxel,and saline controls. HVGGSSV-nab-paclitaxel treatment induced a significantly greater loss in vasculature in irradiated tumors compared with unirradiated tumors, nab-paclitaxel, SGVSGHV-nab-paclitaxel, and untreated controls.
HVGGSSV-nab-paclitaxel was found to bind specifically to the tax-interacting protein-1 (TIP-1) receptor expressed in irradiated tumors, enhance bioavailability of paclitaxel, and significantly increase tumor growth delay as compared with controls in mouse models of lung cancer. Here we show that targeting nab-paclitaxel to radiation-inducible TIP-1 results in increased tumor-specific drug delivery and enhanced biological efficacy in the treatment of cancer.
本研究旨在通过辐射引导的药物输送来提高癌症特异性和放射增敏化疗的生物利用度。
噬菌体展示技术用于分离与放射诱导的肿瘤受体结合的重组肽（HVGGSSV）。该肽用于将 nab-紫杉醇靶向至放射肿瘤，实现了紫杉醇的肿瘤特异性和生物利用度增强。
光学成像研究表明，HVGGSSV 引导的 nab-紫杉醇选择性地靶向放射肿瘤，与 SGVSGHV-nab-紫杉醇相比，放射光亮度提高了 1.48 ± 1.66 个光子/s/cm(2)/sr，与单独使用 nab-紫杉醇相比提高了 1.49 ± 1.36 个光子/s/cm(2)/sr（P < 0.05）。生物分布研究表明，与 nab-紫杉醇或 SGVSGHV-nab-紫杉醇相比，HVGGSSV-nab-紫杉醇治疗组的肿瘤中紫杉醇水平增加了 5 倍以上，在 72 小时时。Lewis 肺癌和 H460 肺癌小鼠模型均显示 HVGGSSV-nab-紫杉醇与 nab-紫杉醇、SGVSGHV-nab-紫杉醇和生理盐水对照组相比，肿瘤生长明显延迟。HVGGSSV-nab-紫杉醇治疗可显著降低照射肿瘤的血管数量，而未照射肿瘤、紫杉醇、SGVSGHV-nab-紫杉醇和未处理对照组的血管数量则无明显降低。
HVGGSSV-nab-紫杉醇被发现特异性结合于放射肿瘤中表达的 Tax 相互作用蛋白-1（TIP-1）受体，增强了紫杉醇的生物利用度，并与肺癌小鼠模型中的对照组相比，显著增加了肿瘤生长延迟。在这里，我们表明将 nab-紫杉醇靶向放射诱导的 TIP-1 可增加肿瘤特异性药物输送并提高癌症治疗的生物学疗效。
