Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China,
Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Int J Nanomedicine. 2018 Dec 10;13:8411-8427. doi: 10.2147/IJN.S184728. eCollection 2018.
Local photothermal therapy (PTT) provides an easily applicable, noninvasive adjunctive therapy for colorectal cancer (CRC), especially when multidrug resistance (MDR) occurs. However, using PTT alone does not result in complete tumor ablation in many cases, thus resulting in tumor recurrence and metastasis.
In this study, we aim to develop a personalized local therapeutic platform combining PTT with long-acting chemotherapy for the treatment of MDR CRC. The platform consists of polyethylene glycol (PEG)-coated gold nanorods (PEG-GNRs) and D-alpha-tocopheryl PEG 1000 succinate (TPGS)-coated paclitaxel (PTX) nanocrystals (TPGS-PTX NC), followed by the incorporation into an in situ hydrogel (gel) system (GNRs-TPGS-PTX NC-gel) before injection. After administration, PEG-GNRs can exert quick and efficient local photothermal response under near-infrared laser irradiation to shrink tumor; TPGS-PTX NC then provides a long-acting chemotherapy due to the sustained release of PTX along with the P-glycoprotein inhibitor TPGS to reverse the drug resistance.
The cytotoxicity studies showed that the IC of GNRs-TPGS-PTX NC-gel with laser irradiation decreased to ~178-folds compared with PTX alone in drug-resistant SW620 AD300 cells. In the in vivo efficacy test, after laser irradiation, the GNRs-TPGS-PTX NC-gel showed similar tumor volume inhibition compared with GNRs-gel at the beginning. However, after 14 days, the tumor volume of the mice treated with GNRs-gel quickly increased, while that of the mice treated with GNRs-TPGS-PTX NC-gel remained controllable due to the long-term chemotherapeutic effect of TPGS-PTX NC. The mice treated with GNRs-TPGS-PTX NC-gel also showed no weight loss and obvious organ damages and lesions during the treatment, indicating a low systemic side effect profile and a good biocompatibility.
Overall, the nano-complex may serve as a promising local therapeutic patch against MDR CRC with one-time dosing to achieve a long-term tumor control. The doses of PEG-GNRs and TPGS-PTX NC can be easily adjusted before use according to patient-specific characteristics potentially making it a personalized therapeutic platform.
局部光热疗法（PTT）为结直肠癌（CRC）提供了一种易于应用的非侵入性辅助治疗方法，特别是在出现多药耐药（MDR）时。然而，在许多情况下，单独使用 PTT 并不能完全消融肿瘤，从而导致肿瘤复发和转移。
在这项研究中，我们旨在开发一种将 PTT 与长效化疗相结合的个性化局部治疗平台，用于治疗 MDR CRC。该平台由聚乙二醇（PEG）包覆的金纳米棒（PEG-GNRs）和 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）包覆的紫杉醇（PTX）纳米晶体（TPGS-PTX NC）组成，然后将其掺入原位水凝胶（凝胶）系统（GNRs-TPGS-PTX NC-gel）中，再进行注射。给药后，PEG-GNRs 在近红外激光照射下能迅速有效地发挥局部光热反应，缩小肿瘤；TPGS-PTX NC 则通过持续释放紫杉醇和 P-糖蛋白抑制剂 TPGS 提供长效化疗，逆转耐药性。
细胞毒性研究表明，与单独使用紫杉醇相比，激光照射下 GNRs-TPGS-PTX NC-gel 的 IC 降低了约 178 倍。在体内疗效试验中，激光照射后，GNRs-TPGS-PTX NC-gel 与 GNRs-gel 相比，最初的肿瘤体积抑制效果相似。然而，14 天后，GNRs-gel 治疗组的肿瘤体积迅速增加，而 GNRs-TPGS-PTX NC-gel 治疗组的肿瘤体积仍可控制，这是由于 TPGS-PTX NC 的长期化疗作用。GNRs-TPGS-PTX NC-gel 治疗组的小鼠在治疗过程中体重没有减轻，也没有明显的器官损伤和病变，表明其全身副作用较小，生物相容性较好。
总的来说，该纳米复合物可能成为一种有前途的局部治疗贴剂，用于治疗 MDR CRC，只需一次性给药即可实现长期肿瘤控制。在使用前，可以根据患者的具体特征轻松调整 PEG-GNRs 和 TPGS-PTX NC 的剂量，使其成为一种个性化的治疗平台。
