Dual-modal Imaging Guided Targeting Drug Delivery Nanocarriers For Theranostics Of Tumor

Photothermal therapy(PTT)is an emerging medical technology which strongly absorbs near-infrared(NIR)light and converts it into cytotoxic heat to destroy hyperthermia sensitive tumor cells with minimal effects on the surrounding normal cells,providing an alternative way for cancer treatment.However,the development of treatment protocols that resulted in a complete response to PTT was usually hampered by uneven heat distribution and heat resistance of tumor cells.Here,an NIR fluorescence and photoacoustic dual-modal imaging-guided active targeted thermal sensitive liposomes(TSLs)based on the photothermal therapy agent Indocyanine green(ICG)and antiangiogenic agent Rapamycin(RAPA)was developed to realize enhanced therapeutic and diagnostic functions.Firstly,the mass ratios of ICG/RAPA/lipids in the FA-ICG/RAPA-TSLs were determined based on the encapsulation efficiency and loading efficiency.Then,FA-ICG/RAPA-TSLs were characterized: the transmission electron microscopy images of FA-ICG/RAPA-TSLs revealed their spherical shapes;what’s more,during 4 weeks storage,the aqueously dissolved TSLs remained around 140-160 nm in size without obvious aggregation,demonstrating their excellent aqueous stability;besides,the photostabiliy of ICG was significantly enhanced when incorporated into the TSLs.The FA-ICG/RAPA-TSLs aqueous solutions performed an obvious higher temperature elevation in response to continuous 808 nm laser irradiation,demonstrating their excellent hyperthermia-generating effect.In addition,the in vitro drug release studies exhibited the satisfactory result of drug released from the TSLs under hyperthermia conditions induced by NIR stimulation.The in vitro cellular studies confirmed that the FA-ICG/RAPA-TSLs plus NIR laser exhibited efficient drug accumulation and cytotoxicity in tumor cells and epithelial cells,demonstrating NIR-induced hyperthermia could dramatically enhance the uptake of the two agents into HeLa cells and HUVECs,thus performing the excellent antitumor effect of FA-ICG/RAPA-TSLs.After 24 h intravenous injection of FA-ICG/RAPA-TSLs,the margins of tumor and normal tissue were accurately identified via the in vivo NIR fluorescence and photoacoustic dual-modal imaging.The in vivo thermal imaging results demonstrated that FA-ICG/RAPA-TSLs were accumulated specifically in tumor tissue and efficiently converted NIR light to local hyperthermia.In addition,FA-ICG/RAPA-TSLs combined with NIR irradiation treated tumor-bearing nude mice inhibited tumor growth to a great extent and possessed much lower side effects to normal organs.In summary,all detailed evidence suggested that the theranostic TSLs which were capable of enhancing the therapeutic index might be a suitable drug delivery system for dual-modal imaging-guided therapeutic tools for diagnostics as well as the treatment of tumors.