Endogenous NO-releasing Carbon Nanodots for Tumor-specific Gas Therapy. (December 2021)

• Record Type: Journal Article
• Authors: Liu, Xue; Liu, Yulin; Thakor, Avnesh S.; Kevadiya, Bhavesh D.; Cheng, Jiamin; Chen, Manling; Li, Yang; Xu, Qian; Wu, Qiuhua; Wu, Yang; Zhang, Guolin
• Is Part Of: Acta biomaterialia. Volume 136(2021)
• Page Start: 485
• Page End: 494
• Publication Date: 2021-12
• Subjects: nanomedicine -- tumor microenvironment -- density functional theory -- Sakaguchi reaction -- guanidinium groups -- fluorescence imaging; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2021.09.051
• Languages: English
• ISSNs: 1742-7061

Abstract

Abstract: Carbon nanodots based on L-arginine (L-Arg) were developed for enhanced nitric oxide (NO) gas therapy for cancer. The L-Arg-based carbon nanodots (Arg-dots) produced high levels of NO in the tumor environment rich in endogenous H2 O2 . In vitro cell experiments revealed that the Arg-dots could kill tumor cells (including human breast cancer cell line MCF-7, female gastric cancer cell line BGC-823, male lung cancer cell line A549, and female leukemic cell line K562) but did not affect the activity of normal cells (human normal lung epithelial cell line BEAS-2B). The Arg-dots produced twice the amount of NO for an equivalent amount of L-Arg. Theoretical calculations showed that the carbonization structure of the Arg-dots promoted significantly more electrons toward the guanidinium groups of L-Arg and boosted the adsorption of H2 O2 molecules. In vitro and in vivo investigations confirmed that the Arg-dots reduced the multidrug resistance (MDR) effect of the tumor cells (MCF-7/ADR cells) and produced a combined antitumor efficacy with traditional chemotherapeutic drugs (adriamycin [ADR]). The fluorescence property (quantum yield, 6.88%) allows the Arg-dots to be used as a suitable fluorescent probe for fluorescence imaging of tumor cells. The ultra-small size of the Arg-dots (diameter: ca. 2.5 nm) enables them not only to penetrate deep tumors and provide enhanced antitumor activity but also to be removed through kidney filtration and have a renal clearance property. Statement of significance: Nitric oxide (NO), which serves as a biological messenger, can be used in gas therapy for cancer. The development of a safe and efficient NO cancer therapy is, however, challenging because of 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 these limitations through a single approach has been seldom achieved. In the present work, carbon nanodots (Arg-dots) from L-arginine were used for gas therapy of cancer. The Arg-dots produced NO in the H2 O2 -rich tumor environment. Theoretical calculations were consistent with the mechanism of enhanced NO release amount. The Arg-dots also reduced the multidrug resistance effect in cancer chemotherapy. In vivo and in vitro toxicity assessments confirmed that the Arg-dots have excellent biosafety. Graphical Abstract: Image, graphical abstract