Recent Emergence of Rhenium(I) Tricarbonyl Complexes As Photosensitisers for Cancer Therapy

molecules Review Recent Emergence of Rhenium(I) Tricarbonyl Complexes as Photosensitisers for Cancer Therapy Hui Shan Liew 1, Chun-Wai Mai 2,3 , Mohd Zulkefeli 3, Thiagarajan Madheswaran 3, Lik Voon Kiew 4, Nicolas Delsuc 5 and May Lee Low 3,* 1 School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; [email protected] 2 Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; [email protected] 3 School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; [email protected] (M.Z.); [email protected] (T.M.) 4 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; [email protected] 5 Laboratoire des Biomolécules, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, 75005 Paris, France; [email protected] * Correspondence: [email protected]; Tel.: +60-3-27317694 Academic Editor: Kogularamanan Suntharalingam Received: 8 July 2020; Accepted: 23 July 2020; Published: 12 September 2020 Abstract: Photodynamic therapy (PDT) is emerging as a significant complementary or alternative approach for cancer treatment. PDT drugs act as photosensitisers, which upon using appropriate wavelength light and in the presence of molecular oxygen, can lead to cell death. Herein, we reviewed the general characteristics of the different generation of photosensitisers. We also outlined the emergence of rhenium (Re) and more specifically, Re(I) tricarbonyl complexes as a new generation of metal-based photosensitisers for photodynamic therapy that are of great interest in multidisciplinary research. The photophysical properties and structures of Re(I) complexes discussed in this review are summarised to determine basic features and similarities among the structures that are important for their phototoxic activity and future investigations. We further examined the in vitro and in vivo efficacies of the Re(I) complexes that have been synthesised for anticancer purposes. We also discussed Re(I) complexes in conjunction with the advancement of two-photon PDT, drug combination study, nanomedicine, and photothermal therapy to overcome the limitation of such complexes, which generally absorb short wavelengths. Keywords: cancer; medicinal inorganic chemistry; metals in medicine; photodynamic therapy; photosensitisers; rhenium(I) tricarbonyl complexes 1. Introduction Cancer has caused approximately 10 million deaths around the world [1]. Despite the advancement in cancer diagnosis and therapy, it is still the second leading cause of death even in the United States [2]. Conventional cancer therapies include surgery, radiotherapy, and chemotherapy [3,4]. Surgery is the mainstay of treatment for most of the solid tumours. Unfortunately, not all tumours are resectable [5,6]. Cancer patients who can undergo radiotherapy would have better long-term survival, tumour cure, and local tumour regression. However, radiotherapy may induce metastatic spread, tissue complications, and high rates of loco-regional failure [7–10]. For patients who cannot receive surgery or radiotherapy, chemotherapy has been the mainstay of treatment. Cisplatin, gemcitabine, and doxorubicin are some of the commonly prescribed chemotherapies for most cancer patients. Molecules 2020, 25, 4176; doi:10.3390/molecules25184176 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 23 Cisplatin, gemcitabine, and doxorubicin are some of the commonly prescribed chemotherapies for Moleculesmost cancer2020, 25 ,patients. 4176 However, their poor cellular penetration and adverse side effects2 of 23may limit their therapeutic efficacy [11]. Although the recently emerging immunotherapy has promising However,therapeutic their efficacy poor cellular in selected penetration solid and tumours, adverse its side ef eficacyffects mayis often limit unpredictable their therapeutic due efficacy to the [11 variability]. Althoughin the host’s the recentlyimmune emerging system immunotherapyand the complicated has promising cancer-immune therapeutic crosstalk efficacy in [12,13]. selected The solid cancerous tumours,cells might its edevelopfficacy is resistance often unpredictable towards dueboth to chem the variabilityotherapy inand the immunotherapy host’s immune system when and its efficacy thedrops complicated to the sub-therapeutic cancer-immune zone. crosstalk Hence, [12 there,13]. is The an urgency cancerous to cells develop might more develop alternative resistance approaches towardsto prevent both and chemotherapy to overcome and immunotherapydrug resistance when [14] its. One efficacy of dropssuch toalternatives the sub-therapeutic would zone.be to utilise Hence,photodynamic there is an therapy urgency (PDT). to develop more alternative approaches to prevent and to overcome drug resistancePDT [is14 ].a treatment One of such modality alternatives that would uses beharmless to utilise visible photodynamic light to therapyactivate (PDT). non-toxic light-excitable moleculesPDT is (i.e., a treatment the photosensitisers), modality that uses for harmless the gene visibleration light of tocytotoxic activate non-toxicreactive light-excitableoxygen species (ROS, moleculestype I photoactivation) (i.e., the photosensitisers), and singlet for oxygen the generation (type ofII cytotoxicphotoactivation) reactive oxygen from speciesmolecular (ROS, oxygen type I (Figure photoactivation) and singlet oxygen (type II photoactivation) from molecular oxygen (Figure1)[ 15–21] 1) [15-21] within or at near vicinity to cancer cells, to cause cell death and tissue necrosis [22]. PDT within or at near vicinity to cancer cells, to cause cell death and tissue necrosis [22]. PDT was claimed towas be claimed relatively to selective be relatively and safe selective compared and to classical safe comp anticancerared to therapies classical due anticancer to the use therapies of harmless due to the therapeuticuse of harmless agents therapeutic during the agents process, during liberty the of activatingprocess, liberty only the of photosensitisersactivating only (PSs)the photosensitisers at the tumour(PSs) at region the tumour via selective region exposure via selective of the tumourexposure to light,of the and tumour increased to light, tendency and ofincreased the targeted tendency of photosensitisersthe targeted photosensitisers to accumulate at to the accumulate tumour site[ 21at ,23the]. PDTtumour can besite used [21,23]. repetitively PDT can without be used causing repetitively resistancewithout causing to tumour resistance or hypersensitivity to tumour to normal or hypersensiti tissue, as avity single to agent normal or in tissue, conjunction as a withsingle other agent or in anticancerconjunction therapies with other such asanticancer chemotherapy therapies and radiotherapysuch as chemotherapy [24–28]. and radiotherapy [24-28]. Figure 1. Schematic illustration of the mechanism of PDT which involves Type I and Type II mechanisms. Figure 1. Schematic illustration1 of the mechanism of PDT which involves Type I and Type II PS: photosensitiser; O2: oxygen; O2: singlet oxygen; ROS: reactive oxygen species. mechanisms. PS: photosensitiser; O2: oxygen; 1O2: singlet oxygen; ROS: reactive oxygen species. At present, a number of PSs have received approval from the FDA for the treatment of cancer (e.g., skin,At present, pancreatic a number and other of cancers—refer PSs have received to Table1 )[appr22]oval and non-cancer from the disordersFDA for (e.g.,the treatment verteporfin of cancer for(e.g., age-related skin, pancreatic macular degenerationand other cancers—refer treatment and 5-aminolevulinicto Table 1) [22] acid and for non-ca moderatencer to disorders severe (e.g., acneverteporfin vulgaris) for [29 age-related]. Despite themacular advantages, degeneration the extensive treatment clinical and use 5-aminolevulinic of PDT was limited acid by for the moderate inherentto severe weaknesses acne vulgaris) of common [29]. Despite photosensitisers, the advantag such ases, water the insolubility,extensive clinical aggregation use tendencyof PDT was in limited theby physiologicalthe inherent environment,weaknesses andof common requirement photosensitisers, of a rich oxygen environmentsuch as water for theinsolubility, production aggregation of singlettendency oxygen in the/ROS physiological [30–34]. In recent environment, years, Re(I) and complexes requirement have beenof a increasinglyrich oxygen explored environment as a for the new alternative choice of photosensitisers for PDT [19,35,36]. This review gives a brief account of the production of singlet oxygen/ROS [30-34]. In recent years, Re(I) complexes have been increasingly development of anticancer PDT and assesses the potential of Re(I) complexes as potent photosensitisers explored as a new alternative choice of photosensitisers for PDT [19,35,36]. This review gives a brief for PDT. account of the development of anticancer PDT and assesses the potential of Re(I) complexes as potent photosensitisers for PDT. Molecules 2020, 25, 4176 3 of 23 Table 1. Application of clinically approved photosensitisers for treatment of cancer. Photosensitisers Application References NPe6 (Talaporfin sodium) Non-small cell lung carcinoma [37] Motexafin lutetium Prostate cancer [38] Temoporfin Head, neck, prostate and pancreatic cancers [39–41] Obstructive oesophageal, lung, bladder and Porfimer sodium [28,42,43] cervical cancers 2-(1-Hexyloxyethyl)-2-devinyl Head,

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