A versatile strategy for improving phototherapeutic efficacy on deep-sited tumor by tissue optical clearing technique

Phototherapies are almost entirely ineffective against deep-sited tumors, due to the poor tissue-penetration ability of light, including ultraviolet light, visible light and infrared light. Although tissue optical clearing (TOC) technique, based on refractive index matching between scatterers and media, has been used to improve in vivo optical imaging quality, it is the first time that TOC technique was employed to realize efficient phototherapeutic effect on deep-sited tumor in the present work. A hybrid TOC agent consisting of glycerol, polyethylene glycol 400 and butylbenisothiazolene (TGP), were optimized for achieving the synergistic antitumor efficacy of photothermal therapy (PTT) and chemotherapy on a simulated deep-sited tumor model (with the coverage of pigskin). Temperature-sensitive gold nanocages (PGNCs) was used to load doxorubicin (DOX@PGNCs) as a nano-platform model of PTT and chemotherapy, for a proof of concept to prove the TOC effect of TGP on the phototherapeutic efficacy against deep-sited tumor. As the pigskin was treated by TGP for 30 min, the ΔT of DOX@PGNCs increased to 12.1 °C under NIR irradiation, while it only increased to ca. 2.0 °C with the coverage of untreated-pigskin. Moreover, PTT-triggered release of DOX increased from 6.3% with the coverage of untreated pigskin up to 22.8% with the coverage of TGP-treated pigskin under three times of NIR irradiation, indicating enhanced photothermal conversion efficiency. Meanwhile, the TOC effect of TGP enhanced cellular uptakes of DOX@PGNCs and boosted delivery efficiency of DOX@PGNCs into the tumor by photothermal-induced hydrophilicity–hydrophobicity transition. Owing to the improvement on the tissue-penetration depth of NIR light, DOX@PGNCs accomplished a robustly synergistic antitumor efficacy of PTT-chemotherapy on a deep-sited H22 tumor model. It is promising to be developed as a versatile strategy for improving PTT efficacy on deep-sited tumors and showed great potential in the improvement of clinical application of various phototherapies. [Display omitted] •The TOC effect improves the efficacy of phototherapy on deep-sited tumor by enhanced tissue-penetration depth of NIR light.•The photothermal effect of DOX@PGNCs is enhanced by TOC effect, and shows favorable PTT-triggered pulsatile DOX release.•DOX@PGNCs show PTT-directed intratumoral delivery thanks to their temperature sensitive phase transition.•The hybrid TOC agent (TGP) has good bio-safety, and might be widely applied i