Photodynamic and Photothermal Therapies: Synergy Opportunities for Nanomedicine

Abstract

Tumoricidal photodynamic (PDT) and photothermal (PTT) therapies harness light to eliminate cancer cells with spatiotemporal precision by either generating reactive oxygen species or increasing temperature. Great strides have been made in understanding biological effects of PDT and PTT at the cellular, vascular and tumor microenvironmental levels, as well as translating both modalities in the clinic. Emerging evidence suggests that PDT and PTT may synergize due to their different mechanisms of action, and their nonoverlapping toxicity profiles make such combination potentially efficacious. Moreover, PDT/PTT combinations have gained momentum in recent years due to the development of multimodal nanoplatforms that simultaneously incorporate photodynamically- and photothermally active agents. In this review, we discuss how combining PDT and PTT can address the limitations of each modality alone and enhance treatment safety and efficacy. We provide an overview of recent literature featuring dual PDT/PTT nanoparticles and analyze the strengths and limitations of various nanoparticle design strategies. We also detail how treatment sequence and dose may affect cellular states, tumor pathophysiology and drug delivery, ultimately shaping the treatment response. Lastly, we analyze common experimental design pitfalls that complicate preclinical assessment of PDT/PTT combinations and propose rational guidelines to elucidate the mechanisms underlying PDT/PTT interactions.

Keywords: PDT; PTT; cancer; combination therapies; drug delivery; multimodal nanoparticles; photodynamic therapy; photomedicine; photothermal therapy; theranostics.

Figure 1

Simplified Jablonski diagram illustrating the photophysical and photochemical basis of PDT and PTT. S₀ – ground state, S₁ – excited singlet state, T₁ – excited triplet state, ISC – intersystem crossing.

Figure 2

Use of nanoparticles for dual PDT/PTT treatment. A. Nanoparticles passively accumulate in tumors due to the EPR effect, where they can be activated with light to produce ROS or heat. B. Common delivery vehicles include liposomes, micelles, nanoemulsions, lipoproteins and lipoprotein mimetics, protein-based nanoparticles, polymeric nanoparticles, metal, silica, black-phosphorus and carbon-based nanomaterials. C. Left panel: PDT/PTT-active nanoparticles can be designed with a single monomer that can act as a PTT agent within an intact nanostructure and a PS upon dissociation. Right panel: Hybrid PDT/PTT-active nanoparticles can incorporate two or more photoactive agents, one of which acts as a PS, while another enhances heat generation.

Figure 3

Porphysome nanovesicles as a dual PDT/PTT agent. A. Schematic representation of the structure and function of porphysomes and the porphyrin-lipid (pyro-lipid) building blocks. Intact porphysomes in the extracellular space remain fluorescently and photodynamically quenched and have the capacity to generate heat upon 671 nm laser irradiation (lower panel, right). When are dissociated upon cellular uptake, the ROS generation is unquenched, resulting in PDT activity (lower panel, left). Adapted with permission under a Creative Commons Attribution 4.0 International (CC BY 4.0) License from ref (169). Copyright 2021 Keegan Guidolin et al., published by De Gruyter. B. Porphysome-enabled PTT in an orthotopic prostate tumor model. In vivo MR-thermometry demonstrates a significant temperature increase in animals injected with porphysomes upon laser irradiation. Left panel: MRI images of orthotopic prostate tumors from axial and sagital directions. Right panel: MR-thermometry map. C. Quantification of temperature increase in a prostate tumor during the laser irradiation process (mean ± SD, n = 5). Adapted with permission from ref (174). Copyright 2016 Wiley Periodicals, Inc. D. Relative tumor volume change in animals bearing subcutaneous A549 lung tumors treated with porphysome-PDT (red), Photofrin-PDT (dark blue), porphysomes-only (magenta) and Photofrin-only (light blue) up to 30 days post PDT (mean ± SD, n = 5). Adapted with permission under a Creative Commons Attribution 4.0 International (CC BY 4.0) License from ref (169). Copyright 2021 Keegan Guidolin et al., published by De Gruyter.

Figure 4

Human serum albumin-ICG (HSA-ICG) nanoparticles as a single-agent PDT/PDT nanoplatform. A. Time-dependent heat (left) and singlet oxygen generation (right) during NIR laser irradiation. B.Ex vivo fluorescence biodistribution of free ICG and HSA-ICG nanoparticles 24 h post IV injection. C. Tumor growth curves and D. survival rates of mice bearing orthotopic 4T1 tumors after different treatments. PDT only: HSA-ICG NPs-interval laser; PDT + PTT: HAS-ICG NPs-laser. (n = 5, **p < 0.01). Adapted with permission from ref (175). Copyright 2014 American Chemical Society.

Figure 5

Schematic representation of discretely integrated nanoconstructs for PDT, PTT and cisplatin (Pt) chemotherapy. A. Discretely integrated nanoconstructs (DIN) containing ICG, cisplatin and polymeric spacer (PES) balance the desired photophysical properties, including singlet oxygen quantum yield (Φ_Δ) and aggregation-induced quenching. B. Singlet oxygen quantum yield of Pt-ICG/PES (ICG concentration 5.0 μg/mL) under 808 nm laser irradiation (1 W/cm², 5 min). The PES/ICG molar ratio was tuned by changing the feeding ratio of sulfonates in p(MEO2MA-co-OEGMA)-b-pSS (PES) and ICG. C. Absorption and emission spectra (λ_ex: 780 nm) of Pt-ICG/PES. D. Heat generation by Pt-ICG/PES (5 μg/mL of ICG) under 808 nm laser irradiation at 1 W/cm² for 5 min. E. Experimental design and timeline of Pt-ICG/PES-enabled PDT/PTT/chemotherapy treatment. Tumor growth curves of primary F. and distant G. 4T1 tumors in the immunocompetent BALB/c mice treated with systemically administered Pt + ICG, Pt-PES, Mg-ICG/PES and Pt-ICG/PES, with or without 808 nm laser treatment (1 W/cm², 10 min), mean ± SEM, n = 6. Adapted with permission from ref (184). Copyright 2022 Wiley-VCH GmbH.

Figure 6

Schematic representation of an upconversion nanoparticle (UCNP)-based antigen-capturing nanoplatform (UCNP/ICG/RB-mal) for PDT/PTT treatment of metastatic breast cancer. A. UCNP/ICG/RB-mal synthesis. B.In vitro viability of 4T1 tumor cells incubated with different nanoparticles, followed by irradiation with an 805 nm laser (5 min, 0.75 W/cm²). Nanoparticles integrating both photothermal (UCNP/ICG) and photodynamic (RB) components produced the greatest decrease in cell viability (*p < 0.05 vs UCNP/ICG/RB-mal group). C. Extracellular release of HMGB1 after different treatments (***p < 0.001 vs PBS + laser group). Data are expressed as means ± SD (n = 4). D. Experimental workflow investigating the abscopal effects UCNP/ICG/RB-mal based phototherapy combined with CTLA-4 immune checkpoint blockade. E. Growth curves of primary tumors of mice after various treatments demonstrate superior tumor growth control upon treatment with UCNP/ICG/RB-mal and light (***p < 0.001 vs PBS + laser group.) F. Growth curves of distant nodules in mice that received different treatments (mean ± SD, n = 5). Adapted with permission under a Creative Commons Attribution 4.0 International (CC BY 4.0) License from ref (201). Copyright 2019 Meng Wang et al., published by WILEY-VCH Verlag GmbH& Co. KGaA, Weinheim.

Figure 7

A. Schematic representation of a multifunctional core–satellite nanoconstructs (CSNCs) formulated by assembling CuS nanoparticles on the surface of [⁸⁹Zr]-labeled hollow mesoporous silica nanoshells containing porphyrin molecules and its use for multimodal cancer imaging and phototherapy. B. Transmission electron microscopy images of CSNCs at different magnifications. C. Representative positron emission tomography (PET), fluorescence (FL), Cerenkov luminescence (CL) and Cerenkov radiation energy transfer (CRET) images of radiolabeled CSNCs. D. Time-dependent tumor growth curves after various treatments (CSNC - core–satellite nanoconstruct, L980–980 nm laser irradiation for PTT, L630–630 nm laser for PDT, n = 5. Adapted with permission from ref (202). Copyright 2017 WILEY-VCH Verlag GmbH& Co. KGaA, Weinheim.