Versatile Peptide-Based Nanosystems for Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) has become an important therapeutic strategy because it is highly controllable, effective, and does not cause drug resistance. Moreover, precise delivery of photosensitizers to tumor lesions can greatly reduce the amount of drug administered and optimize therapeutic outcomes. As alternatives to protein antibodies, peptides have been applied as useful targeting ligands for targeted biomedical imaging, drug delivery and PDT. In addition, other functionalities of peptides such as stimuli responsiveness, self-assembly, and therapeutic activity can be integrated with photosensitizers to yield versatile peptide-based nanosystems for PDT. In this article, we start with a brief introduction to PDT and peptide-based nanosystems, followed by more detailed descriptions about the structure, property, and architecture of peptides as background information. Finally, the most recent advances in peptide-based nanosystems for PDT are emphasized and summarized according to the functionalities of peptide in the system to reveal the design and development principle in different therapeutic circumstances. We hope this review could provide useful insights and valuable reference for the development of peptide-based nanosystems for PDT.

Keywords: peptide; photodynamic therapy; self-assembly; stimuli-responsive; targeting.

Figure 1

(A) Components and mechanism of photodynamic therapy. (B) Jablonski diagram illustrating the processes of fluorescence and phosphorescence decay and photothermal and photodynamic effects [12]. (hν, one-photon absorption; 2hν, two-photon absorption; S₀, ground state; S₁, singlet state; T₁, triplet state.) Reproduced with permission from Ref. [11]. Copyright © 2024, Springer Nature Limited, Cham, Germany. Reproduced with permission from Ref. [12]. Copyright 2012, Wiley Periodicals, Inc, Hoboken, NJ, USA.

Figure 2

Versatile peptide-based nanosystems for PDT: from property and functionality to applications.

Figure 3

Schematic illustration of tyrosinase-induced tripeptide assemblies and their intrinsic apoptotic effects on cisplatin-resistant melanoma cells. Reproduced with permission from Ref. [49]. Copyright 2022, American Chemical Society, New York, NY, USA.

Figure 4

Demonstration of the nucleus-targeting Pt^IV NPs. (i) Chemical structure of the polymeric chain containing the PtIV complex, the AIE unit, and terminal cancerous tissue/nucleus-targeting peptide R8K (P1). (ii) Within an aqueous environment, the polymer can self-assemble into nanoparticles (NPsT). Reproduced with permission from Ref. [52]. Copyright 2022, Wiley-VCH GmbH, Hoboken, NJ, USA.

Figure 5

Schematic illustration of (A) PCPK with PM-targeting ability endowed by cellular farnesylation processes and (B) PCPK-SR without PM-targeting ability by inhibited cellular farnesylation processes and the in vitro validation of (C) PCPK and (D) PCPK-SR by fluorescence imaging costained with the commercialized membrane tracker CellMask green plasma membrane. Levels of (E) HMGB-1 and (F) ATP in the cell supernatant and in vivo cytokine detection of (G) IL-6 and (H) TNF-α in sera from mice after different treatments. (1: PBS, 2: PCPK-SR, 3: PCPK, 4: PCPK-SR + L, and 5: PCPK + L; L indicates 660 nm light irradiation (LED light, 30 mW cm⁻²). (I) In vivo detection of DC maturation (CD80⁺ CD86⁺) in response to different treatments by FACS and (J) quantitative analysis of mature DCs. Significance was calculated via one-way ANOVA with a Tukey posthoc test. * p < 0.05, ** p < 0.01, *** p < 0.001. NS represented no significant difference. Adapted with permission from Ref. [57]. Copyright 2019, American Chemical Society.

Figure 6

The antitumor mechanism of FAL-ICG-HAuNS plus FAL-Hb-loaded liposomes. (A) Schematic illustration of enhanced immunogenic cancer cell death and anticancer effects induced by ER-targeting photothermal/photodynamic therapy. (DC: dendritic cell; CHOP: C/EBP-homologous protein-10, an ER apoptotic protein). (B) Biodistribution of Hb-lipo, FAL-Hb-lipo, ICG-HAuNS, and FAL-ICG-HAuNS after intravenous injection. (C) Volume of tumors in groups with different treatments as indicated in the figure. (D) Survival rate of tumor-bearing mice receiving different treatments as indicated in the figure. Reproduced with permission from Ref. [64] under a Creative Commons Attribution 4.0 International License.

Figure 7

Schematic illustration of the preparation procedure of PDA-Dox-Pc-QRH NPs and the working mechanism for synergistic PDT/CDT anticancer treatment. Reproduced with permission from Ref. [71]. Copyright 2021, The Royal Society of Chemistry, London, UK.

Figure 8

(A) Schematic illustration of the designed structure and functionality of TAT + AzoNPs. (i) DA-protected NP allows for stable circulation. (ii) DA is detached from NP in acidic tumor tissue. (iii) Under light irradiation, Ce6 produces ROS and induces hypoxia in tumor. (iv) NP disintegrate and release TPZ under hypoxia. (v) TPZ is activated under hypoxia condition.(B) the proposed anticancer mechanism through stepwise−activatable hypoxia−triggered PDT. (i) pH 7.4 in blood vessel. (ii) pH 6.8 in tumor tissue. (iii) hypoxia condition gradually become severe as oxygen is consumed to produce ROS. (iv) toxic ROS induces cell death. (v) activated TPZ induces cell death under hypoxia in cytosol. Reproduced with permission from Ref. [59]. Copyright 2020, Elsevier Ltd., Amsterdam, The Netherlands.

Figure 9

(A) Proposed mechanism of the assembly and disassembly behaviors of the temperature and photooxidation-responsive nanosystems containing elastin-like polypeptides (ELPs). (B) Schematic of the formation of co-assembled NPs without (i) and with (ii) the EGFR-targeting nanobody 7D12. Upon light irradiation, photo-oxidation can rapidly disassemble the Met-containing ELP-based NPs into smaller nanoclusters. Conjugation of 7D12 nanobodies endows the co-assembled NPs with EGFR-targeting ability. Reproduced with permission from Ref. [84]. Copyright 2021, American Chemical Society. Reproduced with permission from Ref. [85]. Copyright 2023, Wiley-VCH GmbH.

Figure 10

(A) Schematic illustration of peptide AIEgen D2P1 and its enzyme-mediated intracellular reduction and condensation with 3CBT, which result in an enhanced fluorescence signal and tumor treatment efficacy. (B) Cell viability of MDA-MB-231 and HT29 cells treated with 3CBT and D1P1 in the presence of light irradiation. (C) The volumes of tumor from groups with different treatment as indicated in the figure.(The level of significance was defined at ** p < 0.01, *** p < 0.001). Reproduced with permission from Ref. [92]. Copyright 2021, Wiley-VCH GmbH.

Figure 11

Schematic illustration of the light-triggered NO generation and structural transformation of peptide-based NPs for enhanced intratumoral retention and sensitizing PDT. (A) Molecular structure of the TRFC peptide monomer. (B) Schematic illustration of the self-assembly and in situ light-triggered nanosphere−to−nanorod structural transformation of TRFC NPs. (C) Schematic illustration of the structural transformation required for enhanced intratumoral retention and the mechanism of NO gas-sensitized PDT treatment. Cell viability of (D) 4T1 cell and (E) MCF-7 cell treated with TRF, TKFC, and TRFC NPs in the presence/absence of light irradiation. (F) LIVE/DEAD fluorescence images of 4T1 cells treated with TRF, TKFC, and TRFC NPs in the presence (left)/absence (right) of light irradiation. The level of significance was defined at *** p < 0.001. Reproduced with permission from Ref. [112] under the CC BY-NC-ND license.