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And Nano-Based Transdermal Delivery Systems of Photosensitizing Drugs for the Treatment of Cutaneous Malignancies

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And Nano-Based Transdermal Delivery Systems of Photosensitizing Drugs for the Treatment of Cutaneous Malignancies pharmaceuticals Review Micro- and Nano-Based Transdermal Delivery Systems of Photosensitizing Drugs for the Treatment of Cutaneous Malignancies Isabella Portugal 1, Sona Jain 1 , Patrícia Severino 1 and Ronny Priefer 2,* 1 Programa de Pós-Graduação em Biotecnologia Industrial, Universidade Tiradentes, Aracaju 49032-490, Brazil; [email protected] (I.P.); [email protected] (S.J.); [email protected] (P.S.) 2 Massachusetts College of Pharmacy and Health Sciences, University, Boston, MA 02115, USA * Correspondence: [email protected] Abstract: Photodynamic therapy is one of the more unique cancer treatment options available in today’s arsenal against this devastating disease. It has historically been explored in cutaneous lesions due to the possibility of focal/specific effects and minimization of adverse events. Advances in drug delivery have mostly been based on biomaterials, such as liposomal and hybrid lipoidal vesicles, nanoemulsions, microneedling, and laser-assisted photosensitizer delivery systems. This review summarizes the most promising approaches to enhancing the photosensitizers’ transdermal delivery efficacy for the photodynamic treatment for cutaneous pre-cancerous lesions and skin cancers. Additionally, discussions on strategies and advantages in these approaches, as well as summarized challenges, perspectives, and translational potential for future applications, will be discussed. Citation: Portugal, I.; Jain, S.; Severino, P.; Priefer, R. Micro- and Keywords: photodynamic therapy; drug delivery; transdermal; cutaneous; cancer Nano-Based Transdermal Delivery Systems of Photosensitizing Drugs for the Treatment of Cutaneous Malignancies. Pharmaceuticals 2021, 1. Introduction 14, 772. https://doi.org/10.3390/ ph14080772 In past decades, clinical demands for the utilization of photosensitizers (PSs) have increased with the advent of photodynamic therapy (PDT). PDT is an alternative therapy Academic Editor: Maria whereby an initial activation of a PS at a specific wavelength (visible light or near-infrared Stefania Sinicropi (NIR) leads to the formation of reactive oxygen species (ROS), which in turn induces cell death. Notably, PDT has been primarily applied in cancer therapy. The advantages Received: 16 July 2021 of low light irradiation therapies have made it possible to widen the range of target Accepted: 3 August 2021 diseases [1]. For example, the antimicrobial properties of PDT (aPDT) have been applied Published: 6 August 2021 for the treatment of bacterial, fungal, parasitic, and viral infections [2]. PDT has also been explored for wound healing [3,4], immune-mediated cutaneous diseases [5], anesthetic Publisher’s Note: MDPI stays neutral purposes [6], and aesthetic applications [7]. with regard to jurisdictional claims in Historically, phototherapy can trace its roots to Ancient Egyptian, Chinese, and Indian published maps and institutional affil- civilizations. Light combined with photosensitizing natural formulations were used to iations. treat illnesses such as vitiligo, psoriasis, and skin cancer. In 1900, Raab and von Tappeiner described the phenomena of cell death induced by a combination of chemicals (acridine dye) and light on the protozoa paramecia (Figure1)[ 8]. Further investigations gave birth to the revolutionary Photodynamic Action. The first biomedical use of this innovation was reported Copyright: © 2021 by the authors. by Friedrich Meyer-Betz, in 1912, who self-injected hematoporphyrin, resulting in pain Licensee MDPI, Basel, Switzerland. and swelling on light-exposed areas [9]. Subsequently, in 1961, Lipson et al. demonstrated This article is an open access article that hematoporphyrin derivatives (HpD) accumulated in tumors and emitted fluorescence distributed under the terms and could be applied as a diagnostic tool [10]. conditions of the Creative Commons Further, Dougherty et al. introduced PDT in the 1970s by observing complete mam- Attribution (CC BY) license (https:// mary tumor remission in vivo using HpD combined with the red light [11]. A subsequent creativecommons.org/licenses/by/ clinical study using 25 patients showed complete response in 98 out of 113 skin tumors, 4.0/). Pharmaceuticals 2021, 14, 772. https://doi.org/10.3390/ph14080772 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 772 2 of 19 partial response in 13, and only two resistant tumors [12]. These findings led to the first approval of the PDT drug, Photofrin®, to treat bladder cancer in Canada in 1993 [13]. In 2001, Foscan® became the first second-generation PS agent commercially available for PDT, Pharmaceuticals 2021, 14, x FOR PEERespecially RE- in head-and-neck squamous cell carcinoma (HNSCC) treatment. Ultimately, VIEW in 2012, silicon phthalocyanine (Pc) 4 entered a phase I clinical trial as the first topical PDT agent (Figure1 ) [14]. Currently, PDT is employed to treat a wide range of diseases,2 of 23 such as leishmaniasis, psoriasis, neovascular macular degeneration, cardiology, urology, immunology, ophthalmology, dentistry, and dermatology [15]. Figure 1. The developmental timeline of photodynamic therapy through the centuries. Abbr.: hematoporphyrin (HP), Figure 1. The developmental timeline of photodynamic therapy through the centuries. Abbr.: hematoporphyrin (HP), photodynamic therapy (PDT), hematoporphyrin derivative (HpD), head-and-neck squamous carcinoma (HNSC), phthalo- photodynamic therapy (PDT), hematoporphyrin derivative (HpD), head-and-neck squamous carcinoma (HNSC), phthal- cyanine (Pc). ocyanine (Pc). The distinctiveness of PDT relies on its highly selective mechanism of action. Utilizing two independentlyFurther, Dougherty nontoxic et al. componentsintroduced PDT (i.e., in a the PS 1970s and light) by observing to produce complete cytotoxicity mam- withinmary tumor a tumor. remission There in is vivo a high using level HpD of tumor combined selectivity with the to red PS duelight to [11] increased. A subsequent tumor vasculatureclinical study surface using area,25 patients higher showed membrane complete permeability response of in cancer 98 out cells, of 113 and skin decreased tumors, lymphaticpartial response drainage in 13, [16 and]. An only ideal two PS resist remainsant tumors inert until [12]. aThese light findings source is led focused to the onto first theapproval intended of the area PDT to “activate”drug, Photofrin the PS,® , boostingto treat bladder its selectivity cancer overin Canada surrounding in 1993 healthy[13]. In tissues.2001, Foscan Ultimately,® became a thirdthe first intrinsic second component-generation for PS PDT, agent molecular commercially oxygen, available present for in tissue’sPDT, especially extracellular in head and-and intracellular-neck squamous spaces, servescell carcinoma as the substrate (HNSC forC) treatment ROS formation.. Ulti- Themately, generation in 2012, of silicon singlet phthalocyanine oxygen and superoxide (Pc) 4 entered anions a phase results I inclinical tumor trial cytotoxicity as the first as bothtopical can PDT directly agent react (Figure with 1 and) [14] damage. Currently, biomolecules PDT is suchemployed as lipids, to treat proteins, a wide and range nucleic of acidsdiseases, [17]. such as leishmaniasis, psoriasis, neovascular macular degeneration, cardiology, urology,Several immunology, studies have ophthalmology, demonstrated dentistry, PDT as a and viable dermatology treatment [15] option. against early- stageThe esophageal distinctive dysplasia,ness of PDT lung, relies HNSC, on its anal,highly bladder, selective peritoneal mechanism ovarian, of action. and Utiliz- non- melanomaing two independently skin cancers nontoxic (NMSC) components [18]. Despite (i.e., the a PS encouraging and light) clinicalto produce results cytotoxicity of PDT, somewithin PSs a tumor. themselves There have is a beenhigh reportedlevel of totumor have selectivity prolonged to skin PS phototoxicity,due to increased low tumor lesion selectivity,vasculature hydrophobic surface area, nature, higher aggregation membrane proneness,permeability poor of bioavailability,cancer cells, and high-dose decreased re- quirements, adverse side effects, off-targeting, and development of drug resistance [19–21]. lymphatic drainage [16]. An ideal PS remains inert until a light source is focused onto the The use of drug delivery systems (DDS) to overcome these shortcomings has been exam- intended area to “activate” the PS, boosting its selectivity over surrounding healthy tis- ined. In this context, PSs can be ideally delivered to therapeutic action sites while reducing sues. Ultimately, a third intrinsic component for PDT, molecular oxygen, present in tis- adverse side effects [21]. Among DDS, the transdermal route stands out for dermatological sue’s extracellular and intracellular spaces, serves as the substrate for ROS formation. The applications. However, the inherent protective epidermic layer, the high molecular weight generation of singlet oxygen and superoxide anions results in tumor cytotoxicity as both of some PSs (>500 Daltons), and extremes of polarity remain a challenge for crossing the can directly react with and damage biomolecules such as lipids, proteins, and nucleic ac- skin barrier [22]. ids [17]. Several innovative transdermal delivery systems (tDDS) have recently become avail- Several studies have demonstrated PDT as a viable treatment option against early- able to study photobiology, improve drug penetration, enhance site-specific delivery, and stage esophageal dysplasia, lung, HNSC, anal, bladder,
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