Guiding Appropriate Timing of Laser Irradiation by Polymeric Micelles for Maximizing Chemo-Photodynamic Therapy

Abstract

Yun Zhu,1,2,* Fangying Yu,1,* Yanan Tan,1,3 Lijuan Wen,1,4 Yinghong Li,5 Hong Yuan,1 Fuqiang Hu1 1College of Pharmaceutical Science, Zhejiang University, Hangzhou, People’s Republic of China; 2Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 3Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 4National Engineering Research Center for Modernization of Traditional Chinese Medicine-Hakka Medical Resources Branch, College of Pharmacy, Gannan Medical University, Ganzhou, People’s Republic of China; 5Zhejiang Institute for Food and Drug Control, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fuqiang Hu Tel/ Fax [phone]Email [email protected]: Photoactivity “on-off” switchable nano-agents could shield phototoxicity until reaching target region, which immensely promoted photodynamic therapy. However, the masking ratio of nano-agents in vivo was dynamic and positively correlated with the phototoxicity induced by laser irradiation, in which case the timing of laser irradiation was unpredictable to maximize antitumor efficacy.Methods: Herein, low molecular weight chitosan and hydrophobic polymethylacrylamide derivatives were linked via GSH cleavable 3, 3ʹ-dithiodipropionic acid to construct polymeric micelles (Ce6-CSPD). The doxorubicin loading nano-agent (Ce6-CSPD/DOX) could quench both photoactivity and fluorescence of photosensitizer chlorin e6 (Ce6) and doxorubicin (DOX) under physiological condition by homo-fluorescence resonance energy transfer (homoFRET).Results: Once internalized by tumor cells, the photoactivity as well as fluorescence of Ce6 was recovered rapidly when motivated by intracellular high GSH. Specifically, the fluorescence intensity and photoactivity of Ce6 were proven to be positive linear correlated, upon which appropriate timing of laser irradiation could be determined by referring to the dynamic fluorescence intensity in vivo. In addition, the theranostic nano-agents also possessed the capacity of monitoring the DOX release process. Accordingly, under the guidance of fluorescence intensity, the experimental group subjected to laser irradiation at 18 h postadministration acquired the highest antitumor inhibition efficacy compared to that at four hours and 48 h, which held great potential for maximizing chemo-photodynamic therapy and avoiding nonspecific phototoxicity precisely to normal organs.Conclusion: In summary, we prepared homoFRET-based theranostic nano-agent (Ce6-CSPD/DOX) for monitoring PDT precisely and decreasing phototoxicity to normal organs before reaching target region. Under the guidance of dynamic fluorescence intensity, the appropriate laser irradiation timing could be monitored to maximize antitumor therapy efficacy, which offered opportunities for monitoring efficiency of chemo-photodynamic therapy in a timely and accurate manner.Keywords: theranostic, photodynamic therapy, tumor, micelle

Keywords

• theranostic
• photodynamic therapy
• tumor
• micelle