Photodynamic Therapy for Atherosclerosis: Past, Present, and Future

Abstract

This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality through cardiovascular diseases such as myocardial infarction and stroke. Traditional therapeutic approaches have primarily focused on modulating risk factors such as hypertension and hyperlipidemia, with emerging evidence highlighting the pivotal role of inflammation. PDT, leveraging a photosensitizer, specific-wavelength light, and oxygen, offers targeted treatment by inducing cell death in diseased tissues while sparing healthy ones. This specificity, combined with advancements in nanoparticle technology for improved delivery, positions PDT as a promising alternative to traditional interventions. The review explores the mechanistic basis of PDT, its efficacy in preclinical studies, and the potential for enhancing plaque stability and reducing macrophage density within plaques. It also addresses the need for further research to optimize treatment parameters, mitigate adverse effects, and validate long-term outcomes. By detailing past developments, current progress, and future directions, this paper aims to highlight PDT's potential in revolutionizing atherosclerosis treatment, bridging the gap from experimental research to clinical application.

Keywords: atherosclerosis; nanoparticles; photodynamic therapy; plaque.

Figure 4

Innovative photosensitizers. (A) The fluorescence characteristics of PpIX in the plaque: (i) Excited by 405 nm light, the internal surface of the plaque exhibited a red fluorescence.; (ii) Fluorescence spectra were measured from plaques after ALA administration. Ref. [101], Copyright 2011, Elsevier. (B) A macrophage targetable near-infrared fluorescence emitting phototheranostic agent by conjugating dextran sulfate (DS) to chlorin e6 (Ce6): (i) chemical structure and synthetic procedure of DS-Ce6; (ii) in vivo imaging of the carotid atheroma at 48 h after the intravenous injection of DS-Ce6 or free Ce6, the result demonstrates the DS-Ce6 uptake in a carotid plaque. Ref. [103], Copyright 2021, BMC.

Figure 7

Other inorganic nanoparticles for PDT in atherosclerosis. (A) SR-A-targeted nanoplatform for sequential photothermal/photodynamic ablation of atherosclerosis (CS-CNCs@ Ce6/DS): (i) the key steps involved in the preparation of CS-CNCs@ Ce6/DS; (ii) high fluorescence signal was detected in nanoplatform; (iii,iv) CS-CNCs@ Ce6/DS nanoparticles have good irradiation toxicity in macrophages after irradiation (iv) compared with no laser irradiation (iii). Ref. [128], American Chemical Society. (B) A combination of MRI and chemiexcited PDT for atherosclerosis based on Fe³⁺: (i,ii) TEM images of nanoparticles (125.3 ± 6.4 nm); (iii) absorption spectra of FeNPs indicate Ce6 was encapsulated in FeNPs; (iv) fluorescence spectra of FeNPs indicate Ce6 was encapsulated in FeNPs; (v) T1-weighted MRI images of FeNPs at various concentrations; (vi) FeCNPs accumulate in aortae of high fat-diet ApoE^–/– mice. Ref. [131], Copyright 2022, Dove press.

Figure 1

The mechanism of atherosclerosis development. (i) The individual stages of atherosclerosis are fatty streak, intermediate lesion, fibrous plaque, rupture, and thrombosis. Ref. [19], Copyright 2024, MDPI. (ii) Atherosclerotic lesions develop at the site of vascular endothelium damage, leading to up-regulation of vascular adhesion molecules (e.g., VCAM1, ICAM) and expression of monocyte chemoattractants [monocyte chemoattractant protein-1 (e.g., MCP-1/CCL2)]. Together, these facilitate leukocyte migration and adhesion. Smooth muscle cells (vSMCs) proliferate and migrate to the lesion, undergoing a defifferentiation from contractile to synthetic SMCs. Recent studies investigating SMC plasticity during atherosclerosis suggest that SMC phenotypic switching can contribute multiple cell types within the lesion, including macrophage-like cells, foam-cell-like cells, myofibroblast-like cells, and mesenchymal stem cell-like cells. In response to proatherogenic stimuli within the vessel wall, macrophages transform into lipid-laden foam cells, which significantly contribute to lesion progression. T-cell activation and platelet adherence also occur. Plaque rupture occurs in advanced lesions as a result of fibrous cap thinning. Ref. [35], Copyright 2022, Portland Press.

Figure 2

The mechanism of PDT in atherosclerosis.

Figure 3

Innovative optical delivery system for intravascular PDT device. (i) Generic drawing of a stop-flow double balloon, multi-lumen nylon catheter; (ii) generic drawing of radial/cylindrical light diffuser for endovascular illumination; (iii) goniometer setup: rotating platform, mechanical arm with EM-CDD camera, neutral density filter and diffuse holder. Ref. [99], Copyright 2020, MDPI.

Figure 5

Liposome based nanoparticles for PDT in atherosclerosis. (A) a novel liposomal formulation of PVP-conjugated chlorin e6 (Photolon): (i) transmission electron micrographs of liposomal formulation of Photolon; (ii) fluorescence spectra indicating high encapsulation efficiency of Ce6 in nanoparticles. Ref. [117], Copyright 2019, MDPI. (B) CD68-modified Ce6-loaded liposomes for PDT in atherosclerosis: (i) schematic illustration of the preparation of CD68-Ce6-lip and their phototherapeutic mechanism at the atherosclerotic plaques; (ii) UV spectra of CD68-Ce6-lip demonstrates Ce6 was encapsulated in liposomal nanoparticles; (iii) TEM images and particle size distribution of Ce6-lip; (iv,v) the liposomes have good fluorescence stability and UV stability after 660 nm laser irradiation for 20 min. Ref. [118], Copyright 2023, Elsevier.

Figure 6

Upconversion nanoparticles for PDT in atherosclerosis. (A) Schematic diagram of UCNPs-Ce6-mediated PDT and the mechanism of autophagy. Ref. [123], Copyright 2017, Nature. (B) Core–shell–shell upconversion nanoparticles for NIR-Induced photodynamic therapy. Ref. [124], Copyright 2016, American Chemical Society. (C) Platelet membrane coated upconversion nanoparticles accumulate in atherosclerotic plaque: (i) schematic illustration showing the composition of PM-PAAO-UCNPs; (ii) TEM images of nanoparticles; (iii,iv) SPECT/CT and fluorescence images of PM-PAAO-UCNPsin model mouse illustrating nanoparticles accumulate in plaque. Ref. [125], Copyright 2021, Wiley-VCH GmbH.