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Photodynamic Therapy: Targeting Cancer Biomarkers for the Treatment of Cancers

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Photodynamic Therapy: Targeting Cancer Biomarkers for the Treatment of Cancers cancers Review Photodynamic Therapy: Targeting Cancer Biomarkers for the Treatment of Cancers Xinning Wang 1,* , Dong Luo 2 and James P. Basilion 1,2,* 1 Department of Biomedical Engineering, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-49, Cleveland, OH 44106, USA 2 Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA; [email protected] * Correspondence: [email protected] (X.W.); [email protected] (J.P.B.); Tel.: +216-844-4848 (X.W.); +216-983-3246 (J.P.B.); Fax: +216-844-4987 (X.W. & J.P.B.) Simple Summary: Photodynamic therapy (PDT) is a minimally invasive treatment option that can kill cancerous cells by subjecting them to light irradiation at a specific wavelength. The main problem related to most photosensitizers is the lack of tumor selectivity, which leads to undesired uptake in normal tissues resulting in side effects. Passive targeting and active targeting are the two strategies to improve uptake in tumor tissues. This review focused on active targeting and summarizes recent active targeting approaches in which highly potent photosensitizers are rendered tumor-specific by means of an appended targeting moiety that interacts with a protein unique to, or at least significantly more abundant on, tumor cell surfaces compared to normal cells. Abstract: Photodynamic therapy (PDT) is a well-documented therapy that has emerged as an effec- tive treatment modality of cancers. PDT utilizes harmless light to activate non- or minimally toxic photosensitizers to generate cytotoxic species for malignant cell eradication. Compared with con- ventional chemotherapy and radiotherapy, PDT is appealing by virtue of the minimal invasiveness, Citation: Wang, X.; Luo, D.; Basilion, J.P. Photodynamic Therapy: its safety, as well as its selectivity, and the fact that it can induce an immune response. Although Targeting Cancer Biomarkers for the local illumination of the cancer lesions renders intrinsic selectivity of PDT, most photosensitizers Treatment of Cancers. Cancers 2021, used in PDT do not display significant tumor tissue selectivity. There is a need for targeted delivery 13, 2992. https://doi.org/ of photosensitizers. The molecular identification of cancer antigens has opened new possibilities 10.3390/cancers13122992 for the development of effective targeted therapy for cancer patients. This review provides a brief overview of recent achievements of targeted delivery of photosensitizers to cancer cells by targeting Academic Editor: Michael Höpfner well-established cancer biomarkers. Overall, targeted PDT offers enhanced intracellular accumulation of the photosensitizer, leading to improved PDT efficacy and reduced toxicity to normal tissues. Received: 19 May 2021 Accepted: 14 June 2021 Keywords: photodynamic therapy; photosensitizer; targeted therapy; antibodies; ligands Published: 15 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Photodynamic therapy (PDT) is a novel minimally invasive treatment option that has been used to treat a wide variety of cancers and other diseases [1–4]. PDT includes a photosensitizer that is inactive in the dark. When irradiated with visible light, usually long wavelength red light, in the presence of oxygen, the photosensitizer will be activated to act as an energy transducer, transferring energy to molecular oxygen (Figure1). This Copyright: © 2021 by the authors. transfer results in the generation of a series of highly reactive oxygen species (ROS), such as Licensee MDPI, Basel, Switzerland. 1 This article is an open access article singlet oxygen ( O2)[5–7]. PDT destroys cancer tissues via three mechanisms: (1) During distributed under the terms and light irradiation, ROS species are generated, which will kill cancer cells directly; (2) PDT conditions of the Creative Commons will destroy a tumor through irreversible damage to the tumor vasculature; and (3) PDT Attribution (CC BY) license (https:// will stimulate the immune response directed against tumor cells [5–8] (Figure1). Based creativecommons.org/licenses/by/ on these mechanisms, PDT has several advantages for cancer treatment, including its 4.0/). minimal invasiveness, targeted toxicity of the defined tumor tissues using targeted visible Cancers 2021, 13, 2992. https://doi.org/10.3390/cancers13122992 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 20 Cancers 2021, 13, 2992 2 of 19 its minimal invasiveness, targeted toxicity of the defined tumor tissues using targeted vis- lightible irradiation,light irradiation, and the and ability the toability bypass to thebypass several the resistance several resistance mechanisms mechanisms displayed bydis- malignantplayed by cells malignant [9–11]. cells [9–11]. Tumor cell necrosis and Excited singlet state . apotosis Intersystem OH . - PS O2 1 crossing Excited H2O2 triplet state 1 O2 Inflammation Dendritic cell Absorption Fluorescence Intersystem crossing Light conversion Internal 3O Phosphorescence 2 PS0 Damage to Neutrophil Ground State neovasculature FigureFigure 1. 1.Modified Modified Jablonski Jablonski scheme scheme illustrating illustrating the the principles principles and and mechanisms mechanisms of of photodynamic photodynamic therapy. therapy. Reprinted Reprinted with with permissionpermission from from Ref. Ref. [8 [8].]. Copyright Copyright 2006 2006 Springer Springer Nature. Nature. VariousVarious photosensitizers photosensitizers have have been been reported. reported. Photofrin Photofrin (porfimer (porfimer sodium) sodium)(Figure (Figure2) 2) isis the the first first approvedapproved PDT agent agent for for the the treatment treatment of of cancer cancer and and is still is still widely widely used used to treat to treatlung, lung, esophageal, esophageal, bladder bladder cancers, cancers, and cervical and cervical cancer cancer [12–15]. [12 –The15]. limitations The limitations of Photo- of Photofrinfrin include include its lack its lackof purity, of purity, poor poor tissue tissue penetration penetration at the at theactivation activation light light (630 (630 nm) nm) and andprolonged prolonged skin skin phototoxicity phototoxicity [16]. [16 Theses]. Theses drawbacks drawbacks encouraged encouraged the thedevelopment development of sec- of second-generationond-generation PDT PDT agents, agents, including including macrocyc macrocycliclic compounds, compounds, such asas VerteporfinVerteporfin [ 17[17],], whichwhich is is a a 1:11:1 mixturemixture of regioisomers, Foscan Foscan (mTHPC) (mTHPC) [18], [18], silicon silicon phthalocyanine phthalocyanine 4 (Pc 4 (Pc4) [19], 4) [19 Tookad], Tookad [20], [20 Talaporfin], Talaporfin and and protopor protoporphyrinphyrin IX (PPIX) IX (PPIX) precursors, precursors, such such as 5-ami- as 5- aminolevulinicnolevulinic acid acid (5-ALA, (5-ALA, Levulan) Levulan) [21] [21 ](Figure (Figure 22).). ComparedCompared toto Photofrin,Photofrin, most most of of the the second-generationsecond-generation PSs PSs are are pure pure single single compounds compounds and and have have high high singlet singlet oxygen oxygen quantum quantum yieldsyields (Table (Table1). 1). Pc Pc 4 also 4 also has has a very a very high high quantum quantum yield yield for fluorescence, for fluorescence, enabling enabling it to also it to bealso utilized be utilized for theranostic for theranostic approaches, approaches, see below. see below. They are They excited are atexcited longer at wavelengths, longer wave- whichlengths, allows which deeper allows penetration deeper penetration of the light of into the the light tissue into and the cantissue be usedand can to treat be used deep- to seatedtreat deep-seated tumors, resulting tumors, in improvedresulting in treatment improved efficacy. treatment The efficacy. main drawbacks The main associated drawbacks withassociated second-generation with second-generation photosensitizers photosensi are poortizers water are solubility poor water and slow solubility body clearance and slow rate.body Although clearance 5-ALA rate. Although shows high 5-ALA tumor shows selectivity high totumor glioblastoma selectivity and to bladderglioblastoma cancers, and thebladder lack of cancers, selectivity the to lack desired of selectivity targets remains to desired a problem targets forremains most photosensitizers.a problem for most While pho- specifictosensitizers. delivery While of light specific to the delivery tumors of renderslight to the selectivity tumors renders to PDT selectivity treatment, to most PDT pho-treat- tosensitizersment, most arephotosensitizers non-selectively are distributed non-selectively in the distributed body and willin the cause body side and effects, will cause e.g., accumulationside effects, e.g., in skin, accumulation causing patients in skin, to causing shield themselvespatients to shield from brightthemselves light forfrom several bright days.light Thefor several development days. The of third-generation development of PSs third-generation aimed to improve PSs aimed the pharmacological to improve the characteristicspharmacological and characteristics tumor selectivity. and tumor PSs have selectivity. shown PSs improved have shown tumor improved accumulation tumor when incorporated into delivery systems, such as liposomes [22–25], micelles [26–28], gold accumulation when incorporated into delivery systems, such as liposomes [22–25], mi- nanoparticles [29–31], and silica-based nanoparticles [32]. Approaches of using nanopar- celles
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