Endogenous NO-release Carbon Nanodots for Tumor-specific Gas Therapy.

Abstract Carbon nanodots based on L-arginine (L-Arg) were developed for enhanced nitric oxide (NO) gas therapy for cancers. The L-Arg carbon nanodots (Arg-dots) can produce high levels of NO in the tumor environment with rich endogenous H2O2. In vitro cell experiments reveal the Arg-dots can kill tumor cells (includinghuman breast cancer cell line MCF-7, female gastric cancer cell line BGC-823, male lung cancer cell line A549, andfemale leukemic cell line K562) but not affect the activity of normal noncancer cells (human normal lung epithelial cell lineBEAS-2B). The Arg-dots can produce twice NO as much as an equivalent amount of L-Arg. Theoretical calculations reveal that the carbonization structure of the Arg-dots promote significantly more electrons towards the guanidinium groups of L-Arg and boost the adsorption of H2O2 molecules. In vitro and in vivo investigations confirm the Arg-dots can reducethe multidrug resistance (MDR) effect of the tumor cells (MCF-7/ADR cells) and produce a combined antitumor efficacy with traditional chemotherapeutic drugs (adriamycin, ADR). The fluorescence property (quantum yields, 6.88%) allows the Arg-dots as a suitable fluorescent probe for fluorescence imaging of tumor cells. The ultra-small size of the Arg-dots (Diameter:ca. 2.5 nm) makes them not only penetrate the deep tumor and enhance the antitumor activity, but also pass through the kidney filtration and have a renal clearance property. Statement of Significance Nitric oxide (NO), serving as a biological messenger, can be applied in gas therapy for cancer. However, realizing safe and efficient NO cancer therapy is challenging owing to the low NO release amount and poor tumor specificity of most NO donors. Many efforts have been made to overcome these drawbacks, but solving both in one pot is seldom achieved. In this work, carbon nanodots (Arg-dots) from L-arginine were applied for cancer gas therapy.The Arg-dots produced nitric oxide (NO) in the H2O2-rich tumor environment.Theoretical calculations were consistent with the mechanism of enhanced NO release amount.The Arg-dots reduced the multidrug resistance effect in cancer chemotherapy.In vivo and in vitro toxicity assessments confirmed the Arg-dots excellent biosafety.