Ai Fujin, Sun Tianying, Xu Zoufeng, Wang Zhigang, Kong Wei, To Man Wai, Wang Feng, Zhu Guangyu
Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong SAR.
Department of Physics and Materials Science, City University of Hong Kong, Kowloon Tong, Hong Kong SAR.
Dalton Trans. 2016 Aug 16;45(33):13052-60. doi: 10.1039/c6dt01404f.
Platinum-based antineoplastic drugs are among the first-line chemotherapeutic agents against a variety of solid tumors, but toxic side-effects and drug resistance issues limit their clinical optimization. Novel strategies and platforms to conquer cisplatin resistance are highly desired. Herein, we assembled a multimodal nanoplatform utilizing 808 nm-excited and biocompatible core-shell-shell upconversion nanoparticles (UCNPs) [NaGdF4:Yb/Nd@NaGdF4:Yb/Er@NaGdF4] that were covalently loaded with not only photosensitizers (PSs), but also Pt(iv) prodrugs, which were rose bengal (RB) and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2NH2)2], respectively. The UCNPs had the capability to convert near infrared (NIR) light to visible light, which was further utilized by RB to generate singlet oxygen. At the same time, the nanoplatform delivered the Pt(iv) prodrug into cancer cells. Thus, this upconversion nanoplatform was able to carry out combined and simultaneous photodynamic therapy (PDT) and Pt chemotherapy. The nanoplatform was well characterized and the energy transfer efficiency was confirmed. Compared with free cisplatin or UCNPs loaded with RB only, our nanoplatform showed significantly improved cytotoxicity upon 808 nm irradiation in both cisplatin-sensitive and -resistant human ovarian cancer cells. A mechanistic study showed that the nanoparticles efficiently delivered the Pt(iv) prodrug into cancer cells, resulting in Pt-DNA damage, and that the nanoplatform generated cellular singlet oxygen to kill cancer cells. We, therefore, provide a comprehensive strategy to use UCNPs for combined Pt chemotherapy and PDT against cisplatin resistance, and our nanoplatform can also be used as a theranostic tool due to its NIR bioimaging capacity.
铂类抗肿瘤药物是治疗多种实体瘤的一线化疗药物,但毒性副作用和耐药性问题限制了它们的临床应用优化。人们迫切需要征服顺铂耐药性的新策略和平台。在此,我们组装了一种多模态纳米平台,该平台利用808nm激发且具有生物相容性的核壳壳型上转换纳米颗粒(UCNPs)[NaGdF4:Yb/Nd@NaGdF4:Yb/Er@NaGdF4],其不仅共价负载了光敏剂(PSs),还负载了Pt(iv)前药,分别为孟加拉玫瑰红(RB)和c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2NH2)2]。UCNPs能够将近红外(NIR)光转换为可见光,RB进一步利用该可见光产生活性单线态氧。同时,该纳米平台将Pt(iv)前药递送至癌细胞中。因此,这种上转换纳米平台能够同时进行联合光动力疗法(PDT)和铂化疗。对该纳米平台进行了充分表征并确认了能量转移效率。与游离顺铂或仅负载RB的UCNPs相比,我们的纳米平台在808nm照射下对顺铂敏感和耐药的人卵巢癌细胞均显示出显著提高的细胞毒性。机理研究表明,纳米颗粒能有效地将Pt(iv)前药递送至癌细胞中,导致Pt-DNA损伤,并且该纳米平台产生活性单线态氧以杀死癌细胞。因此,我们提供了一种综合策略,利用UCNPs进行联合铂化疗和PDT以对抗顺铂耐药性,并且我们的纳米平台因其近红外生物成像能力还可作为一种诊疗工具。
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