Sujai Palasseri T, Joseph Manu M, Karunakaran Varsha, Saranya Giridharan, Adukkadan Ramya N, Shamjith Shanmughan, Thomas Reshmi, Nair Jyothi B, Swathi Rotti Srinivasamurthy, Maiti Kaustabh Kumar
Chemical Sciences and Technology Division (CSTD), CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695019, Kerala, India.
Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
ACS Appl Bio Mater. 2019 Jan 22;2(1):588-600. doi: 10.1021/acsabm.8b00746. Epub 2019 Jan 9.
Effective treatment of malignant melanoma requires an appropriate combination of therapeutic intervention with long-term prognosis as it often survives by monotherapies. Herein, we report a novel melanoma-targeted theranostic nanoenvelope (MTTNe: ISQ@BSA-AuNC@AuNR@DAC@DR5) which has been constructed by assembling a bovine serum albumin (BSA) stabilized gold nanocluster on a gold nanorod (BSA-AuNC@AuNR), a three-in-one theranostic modality, i.e., photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy, tethered with a surface-enhanced Raman scattering (SERS) detection technique. The resultant MTTNe was coloaded with the melanoma-specific FDA approved drug dacarbazine (DAC) and a newly synthesized near-infrared (NIR) absorbing squaraine molecule ISQ that served partly as a photosensitizer and multiplex Raman reporter. Finally, a nanoenvelope was anchored with anti-DR5 monoclonal antibodies as a targeting motif for highly expressed melanoma-specific death receptors in malignant cells. Significant phototherapies of MTTNe were initiated upon an 808 nm single laser trigger which showed a synergistic effect of photothermal hyperthermia as well as singlet oxygen (O) driven photodynamic effect in the presence of ISQ followed by on-demand thermoresponsive drug release in the intracellular milieu. Moreover, a multiplex SERS spectral pattern of ISQ (1345 cm) and DAC (1269 cm) has been utilized for monitoring precise drug release kinetics and target-specific recognition on melanoma cells by Raman imaging. Therapeutic performance of the nanoenvelope was evaluated by cytotoxicity studies in human melanoma cells (A375) and confirmed the apoptotic phenomenon by molecular-level monitoring of intracellular SERS fingerprints. Finally, to address the biocompatibility of MTTNe, subacute toxicity was conducted on BALB/c mice. Hence, the current studies mark a footstep of a facile strategy for the treatment of melanoma by synergistic multimodal photothermal/photodynamic/chemotherapy.
恶性黑色素瘤的有效治疗需要将治疗干预与长期预后进行适当结合，因为它通常通过单一疗法难以治愈。在此，我们报告了一种新型的黑色素瘤靶向诊疗纳米包膜（MTTNe：ISQ@BSA-AuNC@AuNR@DAC@DR5），它是通过在金纳米棒（BSA-AuNC@AuNR）上组装牛血清白蛋白（BSA）稳定的金纳米簇构建而成，这是一种三合一的诊疗模式，即光热疗法（PTT）、光动力疗法（PDT）和化疗，并与表面增强拉曼散射（SERS）检测技术相结合。所得的MTTNe共负载了黑色素瘤特异性的美国食品药品监督管理局（FDA）批准的药物达卡巴嗪（DAC）和新合成的近红外（NIR）吸收方酸菁分子ISQ，ISQ部分用作光敏剂和多重拉曼报告分子。最后，用抗DR5单克隆抗体作为靶向基序锚定纳米包膜，用于恶性细胞中高表达的黑色素瘤特异性死亡受体。在808 nm单激光触发下启动MTTNe的显著光热疗法，在ISQ存在的情况下，显示出光热高温以及单线态氧（O）驱动的光动力效应的协同作用，随后在细胞内环境中按需进行热响应药物释放。此外，ISQ（1345 cm）和DAC（1269 cm）的多重SERS光谱模式已用于通过拉曼成像监测黑色素瘤细胞上精确的药物释放动力学和靶标特异性识别。通过对人黑色素瘤细胞（A375）的细胞毒性研究评估了纳米包膜的治疗性能，并通过细胞内SERS指纹的分子水平监测证实了凋亡现象。最后，为了研究MTTNe的生物相容性，对BALB/c小鼠进行了亚急性毒性试验。因此，目前的研究标志着通过协同多模态光热/光动力/化疗治疗黑色素瘤的简便策略迈出了一步。
