Lin Tzu-Yin, Li Yuanpei, Liu Qiangqiang, Chen Jui-Lin, Zhang Hongyong, Lac Diana, Zhang Hua, Ferrara Katherine W, Wachsmann-Hogiu Sebastian, Li Tianhong, Airhart Susan, deVere White Ralph, Lam Kit S, Pan Chong-Xian
Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, USA.
Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
Biomaterials. 2016 Oct;104:339-51. doi: 10.1016/j.biomaterials.2016.07.026. Epub 2016 Jul 22.
The overall prognosis of bladder cancer has not been improved over the last 30 years and therefore, there is a great medical need to develop novel diagnosis and therapy approaches for bladder cancer. We developed a multifunctional nanoporphyrin platform that was coated with a bladder cancer-specific ligand named PLZ4. PLZ4-nanoporphyrin (PNP) integrates photodynamic diagnosis, image-guided photodynamic therapy, photothermal therapy and targeted chemotherapy in a single procedure. PNPs are spherical, relatively small (around 23 nm), and have the ability to preferably emit fluorescence/heat/reactive oxygen species upon illumination with near infrared light. Doxorubicin (DOX) loaded PNPs possess slower drug release and dramatically longer systemic circulation time compared to free DOX. The fluorescence signal of PNPs efficiently and selectively increased in bladder cancer cells but not normal urothelial cells in vitro and in an orthotopic patient derived bladder cancer xenograft (PDX) models, indicating their great potential for photodynamic diagnosis. Photodynamic therapy with PNPs was significantly more potent than 5-aminolevulinic acid, and eliminated orthotopic PDX bladder cancers after intravesical treatment. Image-guided photodynamic and photothermal therapies synergized with targeted chemotherapy of DOX and significantly prolonged overall survival of mice carrying PDXs. In conclusion, this uniquely engineered targeting PNP selectively targeted tumor cells for photodynamic diagnosis, and served as effective triple-modality (photodynamic/photothermal/chemo) therapeutic agents against bladder cancers. This platform can be easily adapted to individualized medicine in a clinical setting and has tremendous potential to improve the management of bladder cancer in the clinic.
在过去30年里，膀胱癌的总体预后并未得到改善，因此，迫切需要开发新的膀胱癌诊断和治疗方法。我们开发了一种多功能纳米卟啉平台，该平台涂覆有一种名为PLZ4的膀胱癌特异性配体。PLZ4-纳米卟啉（PNP）在单个程序中整合了光动力诊断、图像引导光动力治疗、光热治疗和靶向化疗。PNP呈球形，相对较小（约23纳米），在用近红外光照射时能够优先发射荧光/热量/活性氧。与游离阿霉素相比，负载阿霉素的PNP具有更慢的药物释放速度和显著更长的全身循环时间。在体外和原位患者来源的膀胱癌异种移植（PDX）模型中，PNP的荧光信号在膀胱癌细胞中有效且选择性地增加，而在正常尿路上皮细胞中则没有，这表明它们在光动力诊断方面具有巨大潜力。用PNP进行的光动力治疗比5-氨基酮戊酸显著更有效，并且在膀胱内治疗后消除了原位PDX膀胱癌。图像引导的光动力和光热疗法与阿霉素的靶向化疗协同作用，显著延长了携带PDX的小鼠的总生存期。总之，这种独特设计的靶向PNP选择性地靶向肿瘤细胞进行光动力诊断，并作为针对膀胱癌的有效的三联疗法（光动力/光热/化疗）药物。该平台可以很容易地应用于临床环境中的个性化医疗，并且在改善临床膀胱癌管理方面具有巨大潜力。
