ABSTRACT
Chemo-photodynamic therapy shows great potential for cancer treatment. However, the rational integration of chemotherapeutic agents and photosensitizers to construct an intelligent nanoplatform with synergistic therapeutic effect is still a great challenge. In this work, curcumin-loaded reduction-responsive prodrug nanoparticles of new indocyanine green (Cur@IR820-ss-PEG) were developed for synergistic cancer chemo-photodynamic therapy. Cur@IR820-ss-PEG exhibit high drug loading content and special worm-like morphology, contributing to their efficient cellular uptake. Due to the presence of the disulfide bond between IR820 and PEG, Cur@IR820-ss-PEG display reduction responsive drug release behaviors. The efficient cellular uptake and reduction triggered drug release of Cur@IR820-ss-PEG lead to their enhanced in vitro cytotoxicity against 4T1cells as compared to the mixture of IR820 and curcumin (IR820/Cur) under laser irradiation. Besides, Cur@IR820-ss-PEG exhibit prolonged blood half-life time, better tumor accumulation and retention, enhanced tumor hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) suppression effect as compared to IR820/Cur. In vivo antitumor activity study, Cur@IR820-ss-PEG effectively inhibit the tumor angiogenesis, which potentiates the PDT efficacy and leads to the best in vivo antitumor effect of Cur@IR820-ss-PEG. This work provides a novel and relatively simple strategy for synergistic cancer chemo-photodynamic therapy.
ABSTRACT
New indocyanine green (IR820) is an indocyanine green analog which has attracted increasing attention in cancer phototherapy for the prominent absorbance at near-infrared region and improved stability. However, the lack of tumor targeting ability is still an obstacle that severely limits the application of IR820. Lactobionic acid (LA) is a ligand for the asialoglycoprotein receptors which are overexpressed on the membrane of hepatocellular carcinoma cells. In this work, three conjugates of LA and IR-820, namely LA-IR820, LA-SS-IR820, and LA-DEG-IR820, were developed for targeted photodynamic therapy of hepatocellular carcinoma (HCC). The in vitro photodynamic effect study shows that LA-IR820, LA-SS-IR820 and LA-DEG-IR820 exhibit similar singlet oxygen quantum yield as compared to free IR820. The cellular uptake study demonstrates that LA-IR820, LA-SS-IR820, and LA-DEG-IR820 exhibit enhanced cellular uptake amount as compared to free IR820 due to the ligand-receptor interactions between LA and asialoglycoprotein receptor overexpressed on the membrane of HepG2 cells. Among these three conjugates, LA-IR820 with hydrodynamic diameter of 154.6 ± 6.1 nm exhibits the highest cellular uptake amount. The cellular reactive oxygen species (ROS) generation study shows that LA-IR820, LA-SS-IR820 and LA-DEG-IR820 display enhanced cellular ROS level as compared to free IR820 and LA-IR820 exhibits the highest cellular ROS level upon 600 mW/cm2 660 nm laser irradiation. As a result, LA-IR820, LA-SS-IR820 and LA-DEG-IR820 exhibit enhanced photocytotoxicity against HepG2 cells as compared to free IR820 and LA-IR820 exhibits the highest photocytotoxicity. LA-IR820, LA-SS-IR820, and LA-DEG-IR820 show significant potential for the targeted photodynamic therapy of HCC.