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

Abstract

BackgroundPhotoactivity “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.MethodsHerein, 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).ResultsOnce 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.ConclusionIn 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.