Intratibial osteosarcoma growth and pulmonary metastasis inhibition by HIPPO signaling pathway-induced photodynamic therapy

Schematic illustration of the function and molecular mechanism of PDT with TPBC-PEG micelles in suppressing primary osteosarcoma growth and pulmonary metastasis. (a) pH-responsive TPBC-PEG micelles with photosensitizer absorbing 735-nm visible light were constructed. (b & c) PDT of TPBC-PEG micelles inhibited the growth of primary osteosarcoma and pulmonary metastasis by activating the HIPPO signaling pathway. (b) After intravenous injection into osteosarcoma xenograft mouse models, TPBC-PEG micelles passively targeted and accumulated in osteosarcoma lesions by the enhanced permeability and retention (EPR) effect, and then the photosensitizer TPBC was released into osteosarcoma lesions through an acidic pH response. (c) After PDT at primary osteosarcoma lesions, the expressions of MST1 and LATS1 were downregulated, and nuclear translocation of YAP/TAZ was inhibited, which in turn inactivated TEAD-mediated transcription of the downstream target genes AMOTL2, CTGF, CYR61 and ANKRD1. Finally, this led to the decrease of viability, arrest of cell cycle, inhibition of colony proliferation, migration, and invasion abilities, as well as increase of apoptosis in osteosarcoma cells, thus inhibiting the growth, development and pulmonary metastasis of osteosarcoma to achieve a comprehensive anti-osteosarcoma efficacy. [Display omitted] •Photodynamic therapy of TPBC-PEG micelles inhibits primary osteosarcoma growth and pulmonary metastasis.•TPBC-PEG nanoplatform activates HIPPO pathway for intratibial osteosarcoma therapy.•Photodynamic therapy of TPBC-PEG micelles had no significant toxicity in the heart, liver, spleen, or kidney. Cancer is a global leading cause of death, with nearly 10 million people dying from cancer in 2020. Photodynamic therapy (PDT) has emerged as a promising cancer treatment modality; however, the potential molecular mechanisms remain obscure. Herein, we designed a near-infrared (NIR) light-activated nanoplatform (TPBC-PEG) to explore the therapeutic effects and mechanisms of PDT by using a model of intratibial primary and pulmonary metastasis osteosarcoma. Under laser irradiation, TPBC-PEG photosensitizer dose-dependently inhibited proliferative and metastatic capabilities while promoting apoptosis of osteosarcoma cells in vitro, and also effectively suppressed carcinogenesis and pulmonary metastasis in osteosarcoma xenograft mouse model. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis after high-throug