Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor

Abstract

Clinically, the conventional treatments of cancer are still often accompanied by tumor recurrence, metastasis and other poor prognosis. Nowadays, more attention has been paid to photodynamic therapy (PDT), which is regarded as an adjuvant antineoplastic strategy with superiorities in great spatiotemporal selectivity and minimal invasiveness. In addition to eliminating tumor cells via reactive oxygen species (ROS), more meaningfully, this phototherapy can trigger immunogenic cell death (ICD) that plays a vital role in photodynamic immunotherapy (PDIT). ICD-based PDIT holds some immunotherapeutic potential due to further enhanced antitumor efficacy by utilizing various combined therapies to increase ICD levels. To help the PDIT-related drugs improve pharmacokinetic properties, bioavailability and system toxicity, multifunctional nanocarriers can be reasonably designed for enhanced PDIT. In further consideration of severe hypoxia, low immunity and immune checkpoints in tumor microenvironment (TME), advanced nanotherapeutics-mediated PDIT has been extensively studied for boosting antitumor immunity by oxygen-augment, ICD-boosting, adjuvant stimulation and combined checkpoints blockade. Herein, this review will summarize different categories of nanocarriers consisting of their material type, targeting and stimuli-responsiveness. Moreover, we will focus on the latest progress of various strategies to enhance the antitumor immune effect for PDIT and elucidate their corresponding immune-activation mechanisms. Nevertheless, there are several thorny challenges in PDIT, including limited light penetration, tumor hypoxia, immune escape and the development of novel small-molecule compounds that replace immune checkpoint inhibitors (ICIs) for easy integration into nanosystems. It is hoped that these issues raised will be helpful to the preclinical study of nanotherapeutics-based PDIT, thus accelerating the transformation of PDIT to clinical practice.

Keywords: immunogenic cell death; nanotherapeutics; photodynamic therapy; tumor immunotherapy.

Scheme 1

Schematic illustration of various advanced nanotherapeutics for enhanced PDIT. Partial images were adapted with permission from copyright 2019, copyright 2019, copyright 2016, copyright 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; copyright 2018, copyright 2019, copyright 2017, copyright 2019, copyright 2016, copyright 2015, copyright 2020, copyright 2019 American Chemical Society; copyright 2019, copyright 2016 Springer Nature Limited; copyright 2021, copyright 2021 Wiley‐VCH GmbH; copyright 2019, copyright 2018 Ivyspring International Publisher; , copyright 2020 Springer Nature Switzerland AG; , copyright 2018 Elsevier Ltd.

Figure 1

(A) Schematic representation of iPS-MnO₂@Ce6-mediated antitumor photodynamic immunotherapy. (B) Confocal laser microscopy images of oxygen-sensing probe in iPS cells indicating the intracellular oxygen level incubated with nanoprobes for the certain time. (C) Mature DCs in tumor tissues and TDLN of staining with CD80 and CD86 for flow cytometry assay. (D) Images of H&E and Ki67 stained tumor slides from the mice after various treatments. Adapted with permission from , copyright 2020 Springer Nature Switzerland AG. (E) Schematic illustration of the mechanism of photodynamic tumor immunotherapy with MnO₂ nanoparticles. Adapted with permission from , copyright 2019 Ivyspring International Publisher. Abbreviations: iPSs: induced pluripotent stem cells; ICG: indocyanine green; H&E: hematoxylin and eosin; CTLs: cytotoxic T lymphocytes; TDLN: tumor draining lymph node.

Figure 2

(A) The scheme showing the formation of Ce6-CAT/PEGDA hydrogel for applying in enhanced PDIT. (B) The dissolved oxygen generation by various formulations. (C) Individual and (D) average tumor growth curves of 4T1 tumor-bearing mice from various formulations. (E) Images of H&E stained tumor slices from diverse groups of 4T1 tumor-bearing mice. Adapted with permission from , copyright 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (F) Schematic illustration of the mechanism of enhanced PDIT via utilizing PFCs. Adapted with permission from , copyright 2019 Elsevier Ltd. Abbreviations: CAT: catalase; PEGDA: PEG double acrylate; PFCs: perfluorocarbons; IDO: indoleamine 2,3-dioxygenase.

Figure 3

(A) Schematic illustration of PDT/chemotherapy combining with IDO inhibitor prodrugs to enhance antitumor efficacy. (B) Flow cytometric examination of CRT exposure. (C) Determination of HMGB1 release and (D) ATP secretion during antitumor PDIT. (E) Mature DCs ratio of tumor-bearing mice with different strategies. (F) Intratumoral infiltration ratio of CD8⁺ T cells and (G) Tregs in PDIT. Adapted with permission from , copyright 2021 American Chemical Society. Abbreviations: OXA: oxaliplatin; DOPA: dihydroxyphenylalanine; NTKPEG: NLG919-thioketal-PEG; Trp: tryptophan; Kyn: kynurenine; GSH: glutathione; OPCPN: oxaliplatin/phthalocyanine-based coordination polymer nanoparticle; CRT: calreticulin; HMGB1: high mobility group box 1; TAA: tumor-associated antigen.

Figure 4

(A) Schematic illustration of the preparation of Pp18-lipos and application in enhanced PDIT. (B) Flow cytometry analysis of the level of CRT exposure after different phototherapies. (C) Frequency of tumor-infiltrating mature DCs in tumor-bearing mice with different treatments. (D) Corresponding quantification of CD3⁺/CD8⁺ T cells of mice by various treatments. (E) Tumor growth curves by different phototherapies. Adapted with permission from , copyright 2020 Wiley-VCH GmbH. (F) Schematic illustration of the formulation of nanocarriers and the mechanism of enhanced ICD via ER-targeting PDT/PTT. Adapted with permission from , copyright 2019 Springer Nature Limited. Abbreviations: ER: endoplasmic reticulum; Pp18: purpurin 18; PEI: polyethylenimine; HAuNS: hollow gold nanospheres; Hb: hemoglobin; E80: egg phosphatidyl lipid-80; TA: thioctic acid.

Figure 5

(A) Schematic illustration of the preparation of PCN-ACF-CpG@HA and principle for enhanced tumor PDIT. (B) Frequency of DCs maturation in tumor-bearing mice receiving different treatments by flow cytometry. (C) The CD4 and CD8 immunohistochemical images of tumors by using various formulations. Adapted with permission from , copyright 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (D) Schematic illustration of the fabrication procedure and application of PLM-R837-ALG hydrogel during PDIT. Adapted with permission from , copyright 2021 Wiley-VCH GmbH. Abbreviations: ACF: acriflavine; H₂TCPP: tetrakis (4-carboxyphenyl) porphyrin; TAAs: tumor associated antigens; TLR: toll-like receptor; HIF-1: hypoxia inducible factor-1; HA: hyaluronic acid; ALG: alginate; PLM: persistent luminescence material.

Figure 6

(A) Schematic representation of triggered DOX release from TKHNP-C/D under 660 nm laser. (B) The working principle of antitumor immune responses in PDT combined with PD-1/PD-L1 blockade therapy. (C) Flow cytometric analysis of the intratumoral infiltration of CTLs by various treatments. Adapted with permission from , copyright 2019 Elsevier Ltd. (D) The preparation and MMP-2 response of IR780-M-APP NPs. (E) Schematic illustration of antitumor immune responses based on combination of PDT and ICB immunotherapy under 808 nm laser. Adapted with permission from , copyright 2020 Elsevier B.V. Abbreviations: TK-PPE: thioketal phosphoester; MMP-2: matrix metalloproteinase-2; APP: anti-PD-L1 peptide.

Figure 7

(A) Schematic illustration of preparation of POP micelleplexes loaded with PPa and siRNA and pH response in the acid surrounding. (B) Schematic drawing of POP/PD-L1 micelleplex-mediated tumor PDIT. (C) Western blot assay of PD-L1-KD in B16-F10 cells after receiving different POP micelleplexes loaded with 40, 80, 160 nM siRNA, respectively. (D) Proportion of tumor-infiltrating CD8⁺ T cells during PDIT. (E) Tumor growth inhibition curves by various strategies. (F) Images of TUNEL and H&E staining of the primary tumors. Adapted with permission from , copyright 2016 American Chemical Society. Abbreviations: siRNA: small interfering RNA; KD: knockdown; NF-κB: nuclear factor kappa B; PBS: phosphorus buffer saline; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick- end labeling.

Figure 8

(A) Schematic illustration showing the fabrication procedure of UCNP-Ce6-R837. (B) Mechanism of enhanced cancer PDIT by combining NIR-mediated PDT with CTLA4 checkpoint blockade therapy. (C&D) Frequency of tumor-infiltrating CD8⁺ CTLs (C) and Tregs (D) in the distant tumor. Adapted with permission from , copyright 2017 American Chemical Society. (E) Scheme of the co-delivery system loaded with CTLA4 antibodies and mechanism of antitumor immune responses induced by PDT in combination with CTLA4 blockade. Adapted with permission from , copyright 2020 Elsevier B.V. Abbreviations: UCNP: upconversion nanoparticle; TCR: T cell receptor; mDC: mature dendritic cell; ZnPc: zinc phthalocyanine.

Figure 9

(A) Schematic illustration of preparation of PpIX-NLG@Lipo and mechanism of enhanced PDIT. (B) Kyn/Trp ratios in plasma of 4T1 tumor-bearing mice by different formulations. (C) Frequency of CD8⁺ T cells infiltration in the distant tumors detected by flow cytometric analysis. (D) Primary and (E) distant tumor growth curves of mice after receiving different treatments during PDIT. Adapted with permission from , copyright 2019 Ivyspring International Publisher. (F) Schematic illustration of fabrication of HCNSP nanocarrier via host-guest interaction and working principle of combination antitumor immunotherapy by simultaneous ICD induction and IDO-1 inhibition. Adapted with permission from , copyright 2020 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. Abbreviations: PpIX: protoporphyrin IX; Kyn: kynurenine; Trp: tryptophan; HA: hyaluronic acid; CD: cyclodextrin; CRT: calreticulin.