Recent advances in innovative strategies for enhanced cancer photodynamic therapy

Abstract

Photodynamic therapy (PDT), a non-invasive therapeutic modality, has received increasing attention owing to its high selectivity and limited side effects. Although significant clinical research progress has been made in PDT, the breadth and depth of its clinical application have not been fully realized due to the limitations such as inadequate light penetration depth, non-targeting photosensitizers (PSs), and tumor hypoxia. Consequently, numerous investigations put their emphasis on innovative strategies to overcome the aforementioned limitations and enhance the therapeutic effect of PDT. Herein, up-to-date advances in these innovative methods for PDT are summarized by introducing the design of PS systems, their working mechanisms and application examples. In addition, current challenges of these innovative strategies for clinical application, and future perspectives on further improvement of PDT are also discussed.

Keywords: light source; photodynamic therapy; photosensitizers; tumor hypoxia.

Scheme 1

Mechanism of photodynamic reaction: PSs in S₀ can transform into S₁ by absorbing light. The S₁ can change to T₁ through ISC. The direct energy transfer from T₁ to ³O₂ or electron transfer between T₁ and cellular substrates can produce ROS to induce cell death. Abbreviations: S₀: ground state; S₁: excited singlet state; T₁: triplet state.

Figure 1

Schematic illustration of the innovative strategies for overcoming limitations (such as inadequate light penetration depth, non-targeting PSs, and tumor hypoxia) and enhancing the therapeutic effect of PDT. Abbreviations: PDT: photodynamic therapy.

Figure 2

(A) Schematic diagram of UCNPs-GQD with mitochondria-targeting potency for high-efficient cells apoptosis upon laser irradiation. Reproduced with permission from Ref. , Copyright © 2017, Elsevier. (B) Schematic illustration of IPA/LDH nanohybrids as two-photon PSs for ¹O₂ generation under 808 nm NIR laser. Reproduced with permission from Ref. , Copyright © 2018, Nature Publishing Group. Abbreviations: UCNPs: upconversion nanoparticles; GQD: graphene quantum dot; IPA: isophthalic acid; LDH: layered double hydroxides; PSs: photosensitizers; ¹O₂: singlet oxygen; NIR: near-infrared.

Figure 3

(A) Schematic representation of R-AIE-Au for fluorescence and CT imaging-guided X-ray-induced PDT. Reproduced with permission from Ref. , Copyright © 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Schematic illustration of X-ray activated NaCeF₄:Gd,Tb ScNPs for fluorescence/CT/MR imaging-guided PDT of cancer. Reproduced with permission from Ref. , Copyright © 2019, American Chemical Society. (C) Construction process of Hb-CPNs@liposome. (D) Working model of the luminescing and O₂-supplying PDT system for cancer treatment. Reproduced with permission from Ref. , Copyright © 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Abbreviations: PDT: photodynamic therapy; CT: computed tomography; MR: magnetic resonance; Hb: hemoglobin.

Figure 4

(A) Synthetic schematic of IR780-sMnO₂-PCM nanoparticles. (B) Immunofluorescence staining of HIF-1α under different conditions. Reproduced with permission from Ref. , Copyright © 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (C) Schematic illustrations of the preparation of Exo-PMA/Au-BSA@Ce6 nanovehicles for targeted PDT. (D) Tumor growth of mice after different treatments for 18 days. (E) Tumor volumes curves, (F) survival rates, and (G) body weight of mice after different treatments: (1) PBS; (2) PBS+laser; (3) free Ce6; (4) free Ce6+laser; (5) PMA/Au-BSA@Ce6; (6) PMA/Au-BSA@Ce6+laser; (7) Exo-PMA/Au-BSA@Ce6; (8) Exo-PMA/Au-BSA@Ce6+laser. Reproduced with permission from Ref. , Copyright © 2019, Elsevier. Abbreviations: PCM: phase change materials; Exo: exosomes; PMA: amphiphilic polymer; Ce6: chlorin e6; PDT: photodynamic therapy.

Figure 5

(A) Schematic illustration of the preparation of CM@M-MON@Ce6 for PDT. Reproduced with permission from Ref. , Copyright © 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Chemical structures of amino acids modified PpIX and schematic illustration of plasma membrane-targeted PDT. (C) Tumor targeted delivery of Ac-K(PpIX)-En for PDT-induced plasma membrane rupture. Reproduced with permission from Ref. , Copyright © 2019, Elsevier. Abbreviations: CM: cell membrane; Ce6: chlorin e6; PDT: photodynamic therapy; PpIX: protoporphyrin IX.

Figure 6

(A) Schematic illustration of PS system based on Hb and ICG co-loaded RBCs for tumor-boosted PDT. Reproduced with permission from Ref. , Copyright © 2016, Nature Publishing Group. (B) Schematic of PFCs internalized Oxy-PDT agent for tumor inhibition. Reproduced with permission from Ref. , Copyright © 2015, Nature Publishing Group. (C) Schematic of the synthetic procedure of CuTz-1-O₂@F127 for enhanced PDT. Reproduced with permission from Ref. , Copyright © 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Abbreviations: Hb: hemoglobin; ICG: indocyanine green; RBCs: artificial red blood cells; PDT: photodynamic therapy; PFCs: perfluorocarbons.

Figure 7

(A) Schematic illustration of the fabrication of HSA-MnO₂-Ce6&Pt nanoparticles. (B) Tumor volume curves of mice on day 14 after various treatments, and (C) corresponding photographs of tumors collected from mice at the end of treatment. (D) H&E staining assay of tumor slices from different groups of mice collected 24 h after 661 nm light irradiation. Reproduced with permission from Ref. , Copyright © 2016, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Abbreviations: Ce6: chlorin e6; H&E: hematoxylin and eosin.

Figure 8

(A) Schematic illustration of PCCN-mediated water splitting enhanced PDT. Reproduced with permission from Ref. , Copyright © 2016, American Chemical Society. (B) Scheme diagram of the two-photon excited Fe-C₃N₄@Ru@HOP (FCRH) nanocomposite for efficient PDT against hypoxic tumor. (C) Fluorescence imaging and micro-CT transillumination fluorescent combination imaging (top right) of FCRH in vivo, and its ex vivo fluorescence imaging in heart, liver, spleen, lung, kidney and tumor (bottom right). (D) HIF-α, TUNEL, CD31 and H&E staining assays of tumors after various treatments. Reproduced with permission from Ref. , Copyright © 2018, Elsevier. Abbreviations: PDT: photodynamic therapy; CT: computed tomography; H&E: hematoxylin and eosin.

Figure 9

(A) Schematic illustration of S/HSA/ICG as an O₂ generation system for photosynthesis-boosted PDT. (B) PA images of tumors taken at different time points after intravenous injection of PBS and S/HSA/ICG. Reproduced with permission from Ref. , Copyright © 2020, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Abbreviations: ICG: indocyanine green; PDT: photodynamic therapy; PA: photoacoustic.

Figure 10

(A) Chemical structures of Ru1 and Ru2. (B) Tumor volume curves of mice after various treatments, and (C) corresponding tumor weights after 14 days of treatment. (D) H&E staining of tumor slices from different groups. Reproduced with permission from Ref. , Copyright © 2018, Royal Society of Chemistry. (E) Structure of Ti-TBP and schematic diagram of type I and type II PDT under light irradiation. Reproduced with permission from Ref. , Copyright © 2019, American Chemical Society. Abbreviations: H&E: hematoxylin and eosin.

Figure 11

(A) Schematic diagram of mitochondrial respiratory inhibition enhanced PDT against tumor cells. (B) In vivo PA images of tumors after various treatments for 0.5, 3, 6, and 12 h. (C) Corresponding tumor volume changes of mice during the 21 days evaluation period with various treatments, and (D) corresponding tumor images at 21st-day post-treatment. Reproduced with permission from Ref. , Copyright © 2020, American Chemical Society. Abbreviations: PDT: photodynamic therapy; PA: photoacoustic.