Surface-Modified Carbon Dots for Cancer Therapy: Integrating Diagnostic and Therapeutic Applications

Abstract

Carbon dots (CDs) have become versatile nanomaterials that have found practical applications in cancer therapy due to their small size, tunable photoluminescence, and high biocompatibility. Modified CDs have shown remarkable potential in targeted drug delivery systems, enhancing solubility and specificity in tumor sites while minimizing systemic toxicity. Gene therapy applications take advantage of the ability of CDs to condense and protect genetic material from degradation, thereby facilitating efficient cellular uptake. Furthermore, metal-doped CDs can function as fluorophores and enhance imaging capabilities for tumor detection through fluorescence and MRI. Besides, in phototherapy applications, when combining photodynamic (PDT) and photothermal therapy (PTT), CDs exhibit synergistic effects wherein therapeutic efficacy is increased by the generation of reactive oxygen species (ROS) and heat. This review summarizes recent developments in surface-modified and doped CDs for in vitro and in vivo applications, particularly in drug delivery, gene therapy, multimodal imaging, photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT), sonodynamic therapy (SDT) and gas therapy, for cancer therapies. Advances in modalities of surface modification that include ligand binding and metal doping have significantly improved CDs' biocompatibility and targeting precision. However, limitations such as low drug-loading capacity, complex synthesis processes, and the challenges created by hypoxic tumor environments need to be opened for further research. Future directions will focus on enhancing drug-loading efficiency, establishing long-term biocompatibility, and optimizing multifunctional nanocomposite designs for integrated cancer therapies.

Keywords: cancer therapy; carbon dots; chemodynamic therapy; nanocarrier system; photodynamic therapy; photothermal therapy; sonodynamic therapy.

Figure 1

PEG-RLS/Fe@CDs: (A) schematic mechanism of cancer nanotheranostic platform for gene delivery, PTT and bioimaging applications. Reproduced from Luo T, Nie Y, Lu J, et al. Iron doped carbon dots based nanohybrids as a tetramodal imaging agent for gene delivery promotion and photothermal-chemodynamic cancer synergistic theranostics. Mater Des. 208. © 2021 The Authors. Published by Elsevier Ltd. Creative Commons CC-BY-NC-ND license. (B) In vivo photo-enhanced therapeutic effect of PEG-RLS/Fe@CDs under 660 nm (0.5 W/cm² for 5 min) in 4T1 breast cancer, tumor growth inhibition after different treatments, tumor tissues after treatment. HP-CDs/DNA: (C) Zeta potential of free DNA, HP-CDs and HP-CDs/DNA complex, identification of transfection efficiency of HP-CDs, fluorescent images of gene expression obtained by a confocal laser scanning microscope in HEK-293T cells transfected with DNA/HP-CDs complexes, (D) Schematic synthesis and biomedical applications of HP-CDs. Reproduced from Zhang M, Zhao X, Fang Z, et al. Fabrication of HA/PEI-functionalized carbon dots for tumor targeting, intracellular imaging and gene delivery. RSC Adv. 2017;7:3369–3375. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

Figure 2

AS1411-Gd-CDs: (A) Schema of preparation of AS1411-Gd-CDs and FL/MR-guided PTT of tumor, (B) In vitro MR imaging properties, T1-weighted MR images of 4 T1 and NIH-3T3 cells treated with Gd-CDs. The red circles indicated the tumor cells, (C) In vivo fluorescence and PR imaging tests of 4 T1 tumor-bearing mice model pre- and post-injection of Gd-CDs and AS1411-Gd-CDs at various time intervals. The red circles represent the tumor area. Mn-CDs-NH: (D) MRI images of tumor -bearing mice treated with Gadovist or Mn-CDs-NH, (E) Metastatic investigation of lungs with MRI imaging. PEG-RLS/Fe@CDs: (F) In vitro tetramodal imaging in 4T1 cells by confocal fluorescence imaging, T1-weighted magnetic resonance (MR) images with different concentrations of PEG-RLS/Fe@CDs, (G) Real-time in vivo fluorescence images under 660 nm light irradiation (0.5 W/cm²). The white circles show the position of the tumor. (A,C,D) Reproducced from Jiao M, Wang Y, Wang W, et al. Gadolinium doped red-emissive carbon dots as targeted theranostic agents for fluorescence and MR imaging guided cancer phototherapy. Chem Eng J. 2022;440. © 2022 The Author(s). Published by Elsevier B.V. Creative Commons CC-BY-NC license. (E,F,G) Reproduced from Tiron A, Stan CS, Luta G, et al. Manganese-doped n-hydroxyphthalimide-derived carbon dots—theranostics applications in experimental breast cancer models. Pharmaceutics. 2021;13. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.

Figure 3

CQDs@Pt: (A) Schematic illustration of synthesis of CQDs@Pt, (B) TEM images and corresponding size distribution histograms and (C) FT-IR spectra of CQDs@Pt, (D) Cell viability of CQDs@Pt in HeLa cells after treatment, (E) Singlet oxygen of CQDs@PtPor, (F) confocal fluorescence microscopy images of HeLa cells under 405 nm excitation after treatment with CQDs, PtPor and CQDs@PtPor. And (G) PL Spectra of CQDs@Pt. Reproduced from Wu F, Yue L, Su H, et al. Carbon Dots @ platinum porphyrin composite as theranostic nanoagent for efficient photodynamic cancer therapy. Nanoscale Res Lett. 13. © The Author(s). 2019, corrected publication January 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License.

Figure 4

Fc-CDs: (A) Schematic representation of Fc-CD application for enhanced tumor accumulation, imaging-guided, PTT and CDT. (B) In vitro studies in 4T1 cells line (highlighted by red square) and tumor growth inhibition after PTT/CDT at different time points (highlighted by black square). (C) Photothermal studies: hemolysis rate, PA images, and FL images of major organs after injection of Fc-CDs. (D) PA images and FL signal of tumor bearing mice after injection of Fc‐CD NPs at different time points. The strongest PA signal was observed 4 hours post-injection of Fc‐CD NPs (indicated by Orange highlighting), (E) FL images of major organs: H (heart), Li (liver), S (spleen), Lu (lung), K (kidneys) and T (tumors) gathered from mice at different time points post-injection. Tumor areas are marked by red circles. The strongest FL signal was detected 4 hours after injection (indicated by orange highlighting). Reproduced from Sun S, Chen Q, Li Y, et al. Tumor-specific and photothermal-augmented chemodynamic therapy by ferrocene-carbon dot-crosslinked nanoparticles. SmartMat. 2022;3:311–322. © 2022 The Authors. SmartMat published by Tianjin University and John Wiley & Sons Australia, Ltd. Creative Commons CC BY license.

Figure 5

P-n-CDs: (A) Mechanism of p-n-CDs for sonodynamic therapy Reproduced from Geng B, Hu J, Li Y, et al. Near-infrared phosphorescent carbon dots for sonodynamic precision tumor therapy. Nat Commun. 2022;13.Copyright © 2022, The Author(s). Creative Commons CC BY license. (B) In vitro and In vivo studies on p-n-CDs: cell viability of 143B cells and tumor growth curves of mice after treatment, (C) Ex vivo NIR imaging of tumors with p-n-CDs. Cu-CDs: (D) In vivo antiglioma effects of Cu-CDs: bioluminescent imaging of the brain in orthotopic U87-luc xenograft nude mice, (E) Histological analysis of mouse gliomas after Cu-CDs application, (F) Quantification of bioluminescence intensity within the brains of nude mice after SDT. (D,E,F) Reproduced from Cheng M, Liu Y, You Q, et al. Metal-doping strategy for carbon-based sonosensitizer in sonodynamic therapy of glioblastoma. Adv. Sci. © 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH. Creative Commons CC BY license. C-dots MBs: (G) In vitro studies of C-dots MBs: Cytotoxicity effect in TRAMP cells. (H) In vivo studies: lifetime of C-dots MBs detected by US imaging and distribution of C-dots MBs in tumor tissue detected by US imaging; (I) In vivo studies of C-dots MBs in mice.