Poudel Kishwor, Banstola Asmita, Gautam Milan, Soe Zar Chi, Pham Le Minh, Jeong Jee-Heon, Choi Han-Gon, Ku Sae Kwang, Yong Chul Soon, Tran Tuan Hiep, Kim Jong Oh
College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
Nanoscale. 2021 Jan 21;13(2):1231-1247. doi: 10.1039/d0nr07736d.
Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi2S3) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi2S3 and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi2S3 and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.
用于在肿瘤部位进行激光照射后释放治疗剂的靶向且对刺激敏感的纳米炸弹，作为个性化抗癌方案正受到广泛关注。在本研究中，通过将外层聚乙二醇（PEG）-S-S-甲氨蝶呤（MTX）与负载吲哚菁绿（ICG）的硫化铋（Bi2S3）纳米颗粒的内核融合，构建了用于化疗、光动力和光热疗法的氧化还原和光双响应、叶酸受体靶向的纳米urchin载体用于癌症治疗。MTX将载体引入叶酸受体，导致纳米颗粒特异性且越来越多地内化到癌细胞中。在癌细胞内部的还原环境中，MTX被裂解，导致突发释放，有效抑制肿瘤生长。同时，内核中Bi2S3和ICG的融合吸收近红外辐射（NIR）激光的能量以产热和活性氧，这进一步消融肿瘤并协同增强MTX的抗癌活性。这些结果表明成功制备了组合纳米urchin（NU），其显示出谷胱甘肽诱导的和激光响应的MTX和ICG释放，并通过Bi2S3和ICG产生热疗。通过靶向、氧化还原和NIR响应组合策略实现了纳米系统有效的体外细胞内化、细胞毒性和促凋亡行为。体内生物分布和光热成像也揭示了肿瘤选择性和滞留性以及热响应特性。最终，这项体内抗肿瘤研究表明这些纳米urchin能有效消融肿瘤而不影响重要器官。我们的研究结果表明，使用这些靶向氧化还原和激光响应的组合治疗载体可能是治疗表达叶酸受体肿瘤的一种有前途的策略。
