Graphene-Based Nanomaterials in Photodynamic Therapy: Synthesis Strategies, Functional Roles, and Clinical Translation for Tumor Treatment

Abstract

Photodynamic therapy (PDT) is an effective approach for inducing tumor cell death through reactive oxygen species (ROS) generated by light-activated photosensitizers (PSs). Despite its selectivity in tumor treatment, PDT still faces significant challenges in targeting deep-seated tumors due to limitations in tissue penetration and precise localization. Graphene-based nanomaterials, such as graphene oxide (GO), reduced graphene oxide (rGO), graphene quantum dots (GQDs), and graphene nanosheets (GNS), offer innovative solutions by enhancing light penetration, boosting PS activity, and improving tumor-targeting precision. This review highlights how graphene-based nanomaterials address these challenges through functionalization strategies, including receptor-mediated tumor targeting, size-dependent penetration, optical synergy, and hypoxia modulation. Additionally, it explores the synthesis and production challenges associated with these materials. Focusing on four key graphene derivatives-GO, rGO, GQDs, and GNS-this article examines how reaction conditions, catalyst types, and precursor purity influence their structural properties and functional performance in PDT. To facilitate the translation from laboratory research to clinical application, strategies for scaling up production are discussed, emphasizing the need to simplify synthesis processes and improve efficiency for broader biomedical use. This review provides valuable insights into advancing graphene-based nanomaterials for clinical PDT applications, bridging the gap between nanomaterial design and therapeutic precision.

Keywords: functionalization strategies; graphene-based nanomaterials; photodynamic therapy; targeting; tumor therapy.

Graphical abstract

Figure 1

(a–c) graphene bonding properties and (d) scanning electron microscope (SEM) image of single-layer graphene. Reprinted from Tiwari SK, Sahoo S, Wang N, Huczko A. Graphene research and their outputs: status and prospect. J Sci. 2020;5:10–29.

Figure 2

Photographs describing preparation process of GO by Tour’s method: (A) before addition of potassium permanganate; (B) after oxidation; (C) after pouring on ice; (D) after addition of H₂O2. Reprinted from Jiříčková A, Jankovský O, Sofer Z, Sedmidubský D. Synthesis and Applications of Graphene Oxide. Materials. 2022;15(3):920. Under Creative Common CC BY license.

Figure 3

Structure of graphene oxide obtained by different synthesis methods. Reproduced from Khan ZU, Kausar A, Ullah H, Badshah A, Khan WU. A review of graphene oxide, graphene buckypaper, and polymer/graphene composites: properties and fabrication techniques. J Plast Film Sheeting. 2016;32(4):336–379. doi:10.1177/8756087915614612. Sage is the original publisher of this figure.

Figure 4

The route of rGO synthesis by chemical reduction method. Reproduced from Alam N, Sharma N, Kumar L. Synthesis of Graphene Oxide (GO) by Modified Hummers Method and Its Thermal Reduction to Obtain Reduced Graphene Oxide (rGO) * Open Access. Graphene. 2017;6(01):1–18. Under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.

Figure 5

Two functionalization strategies for producing non-toxic graphene-based nanocomposites to enhance PDT efficacy.

Figure 6

Mechanism of PDT destruction of tumor. Reproduced from Correia JH, Rodrigues JA, Pimenta S, Dong T, Yang Z. Photodynamic Therapy Review: principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics. 2021;13(9):1332. Under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.

Figure 7

Schematic diagram of photochemical reactions of Type I and Type II involved in PDT under the action of PS. Reproduced from Li W-P, Yen C-J, Wu B-S, Wong T-W. Recent Advances in Photodynamic Therapy for Deep-Seated Tumors with the Aid of Nanomedicine. Biomedicines. 2021;9(1):69. Under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.

Figure 8

Schemes of the experimental design in photothermally enhanced PDT. KB cells were incubated with free Ce6 (a) and GO-PEG-Ce6 (b) for 20 min in the dark and then irradiated by the 660 nm laser (50 mW/cm², 5 min, 15 J/cm²) in control experiments. (c) To induce the photothermal effect, GO-PEG-Ce6 incubated cells were exposed to the 808 nm laser (0.3 W/cm², 20 min, 360 J/cm²) first before PDT. Reproduced from Li Y, Dong H, Li Y, Shi D. Graphene-based nanovehicles for photodynamic medical therapy. Int J Nanomed. 2015;10:2451–2459.

Figure 9

Synthesis of rGO/THPPEG/DOX and its combined effect on PTT/PDT/CT. Reprinted from Ma W, Yang H, Hu Y, Chen L. Fabrication of PEGylated porphyrin/reduced graphene oxide/doxorubicin nanoplatform for tumour combination therapy. Poly Int. 2021;70(9):1413–1420. © 2021 Society of Industrial Chemistry.

Figure 10

(a) Comparison of photostability for GQDs, PPIX, and CdTe, indicated by the absorbance ratio at 470 nm over time post-irradiation with a 500 W xenon lamp. (b) Bright-field image and (c) red-fluorescence image of a mouse following subcutaneous GQD injection. (d) Tumor volume measurements over time for three treatment groups (n = 5 per group), with significant differences (P < 0.05). PDT: GQD with irradiation, C1: GQD alone, C2: light irradiation alone. (e) Photographs of mice post various treatments, with the numbers indicating days after the initial treatment. Reproduced with permission from Ge J, Lan M, Zhou B, et al. A graphene quantum dot photodynamic therapy agent with high singlet oxygen generation. Nat Commun. 2014;5(1):4596..

Figure 11

Imaging analysis of in vitro PDT on HeLa cells with and without 532 nm laser using DCFDA fluorescent probe (L and C4 represent light and af-GQDs/UCNPs, respectively). Reprinted from Anjusha AJ, Thirunavukkarasu S, Resmi AN, Dhanapandian S, Krishnakumar N, Krishnakumar N. Multifunctional amino functionalized graphene quantum dots wrapped upconversion nanoparticles for photodynamic therapy and X-ray CT imaging. Inorg Chem Commun. 2023;149:110428. with permission from Elsevier.

Figure 12

GO/CisPt/Ce6@MH enhanced chemical-photodynamic synergistic therapy flow. Reproduced from Liu P, Xie X, Liu M, Hu S, Ding J, Zhou W. A smart MnO2-doped graphene oxide nanosheet for enhanced chemo-photodynamic combinatorial therapy via simultaneous oxygenation and glutathione depletion. Acta Pharmaceutica Sinica B. 2021;11(3):823–834. Under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.