Thermosensitive nanocomposite gel for intra-tumoral two-photon photodynamic therapy.

We propose here a new approach to achieve intratumoral near-infrared (NIR) two-photon photodynamic therapy (PDT). We established a composite micellar thermosensitive hydrogel made of clinically approved methoxy poly(ethylene glycol)-polylactide copolymer (mPEG-PDLLA) and Pluronic (F127). The mPEG-PDLLA form micelles that can be loaded with two-photon absorption compound (T1) and photosensitizer (PS), The F127 micelles are liquid at room temperature and while forming an hydrogel at body temperature. This enables an in situ gelification upon injection providing long-term retentio within the tumor. The NIR light is thus upconverted into visible light by T1 and excited PS. The morphology, rheology properties and releasing profiles of hydrogel were fully characterized. The rheology properties and releasing mechanism was investigated. The composite hydrogel showed significant cytotoxicity to 4 T1 murine breast cancer cells upon NIR laser irradiation, while it showed non-significant cytotoxicity without. Time-dependent in vivo and ex vivo distribution results suggested that hydrogel administrated via intra-tumoral injection could prolong both PDT agents retention in tumor. We show here that the use of NIR radiation allows deep tissue penetration and inhibition of tumor growth of >50% even under 1 cm thick muscle tissue.