nanomaterials Review Titanium Dioxide Nanoparticles: Prospects and Applications in Medicine Daniel Ziental 1 , Beata Czarczynska-Goslinska 2, Dariusz T. Mlynarczyk 3 , Arleta Glowacka-Sobotta 4, Beata Stanisz 5, Tomasz Goslinski 3,* and Lukasz Sobotta 1,* 1 Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland; [email protected] 2 Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland; [email protected] 3 Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland; [email protected] 4 Department and Clinic of Maxillofacial Orthopedics and Orthodontics, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland; [email protected] 5 Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland; [email protected] * Correspondence: [email protected] (T.G.); [email protected] (L.S.) Received: 4 January 2020; Accepted: 19 February 2020; Published: 23 February 2020 Abstract: Metallic and metal oxide nanoparticles (NPs), including titanium dioxide NPs, among polymeric NPs, liposomes, micelles, quantum dots, dendrimers, or fullerenes, are becoming more and more important due to their potential use in novel medical therapies. Titanium dioxide (titanium(IV) oxide, titania, TiO2) is an inorganic compound that owes its recent rise in scientific interest to photoactivity. After the illumination in aqueous media with UV light, TiO2 produces an array of reactive oxygen species (ROS). The capability to produce ROS and thus induce cell death has found application in the photodynamic therapy (PDT) for the treatment of a wide range of maladies, from psoriasis to cancer. Titanium dioxide NPs were studied as photosensitizing agents in the treatment of malignant tumors as well as in photodynamic inactivation of antibiotic-resistant bacteria. Both TiO2 NPs themselves, as well as their composites and combinations with other molecules or biomolecules, can be successfully used as photosensitizers in PDT. Moreover, various organic compounds can be grafted on TiO2 nanoparticles, leading to hybrid materials. These nanostructures can reveal increased light absorption, allowing their further use in targeted therapy in medicine. In order to improve efficient anticancer and antimicrobial therapies, many approaches utilizing titanium dioxide were tested. Results of selected studies presenting the scope of potential uses are discussed in this review. Keywords: composites; nanoparticles; photodynamic therapy; photosensitizer; titanium dioxide 1. Introduction The intensive development of photodynamic therapy (PDT) in recent years has involved the search for new photosensitizers and specific carriers for their delivery. Among many promising approaches to be noted for photodynamic research, those in which dyes and nanoparticles (NPs) were combined led to an increase in the selectivity of the photosensitizer (PS) and/or efficacy of the therapy. At the very beginning, it should be explained that NPs constitute a particular type of particles of the size between 1 and 100 nm (with the surrounding interfacial layer) [1]. The exact definition given in ISO technical specification 80004 states that NPs are "nano-objects with all three external dimensions in the nanoscale, whose longest and shortest axes do not differ significantly". It should be noted that in Nanomaterials 2020, 10, 387; doi:10.3390/nano10020387 www.mdpi.com/journal/nanomaterials Nanomaterials 2020, 10, 387 2 of 31 the broad sense, NPs also include polymeric NPs, liposomes (multilayer), lipid micelles (unilayer), quantum dots, dendrimers, fullerenes, cubosomes, niosomes, and metallic NPs. Particular attention should be paid to the last mentioned, but exceptional category containing metallic and metal oxide NPs, for example ZnO, Au, Fe2O3, TiO2. Several studies have indicated that the application of NPs in medicine can significantly improve the effectiveness of many existing therapies. Linking drugs with NPs can enhance their selective accumulation in diseased tissues as well as penetration abilities through cell membranes. Increasing the selectivity of drugs is a great challenge for modern medicine. This goal can be achieved by research focused on therapeutic systems with increased selectivity and reduced toxicity, accompanied by higher therapeutic efficiency [2,3]. In the current review, studies focusing on titanium dioxide (titanium(IV) oxide, titania, TiO2) nanoparticles, which belong to the category of metallic NPs are reviewed. Notably, the evaluation of current TiO2 functionalization methods accompanied by the biological and medical effects of these NPs were the driving force for this work. Mass production of TiO2 began in the early twentieth century as a non-toxic substitute for a white dye for paints. Nowadays, the annual production of TiO2 exceeds four million tons per year, and this molecule has found numerous applications in everyday products (FigureNanomaterials1)—as 2020 an excipient in the pharmaceutical industry, for sun cream production in the cosmetics2 of 32 industry, as a colorant in white plastics, and as a relatively cheap and nontoxic food pigment approved 44 given in ISO technical specification 80004 states that NPs are "nano-objects with all three external by the relevant European Union authorities for the safety of food additives [4]. Research on the possible 45 dimensions in the nanoscale, whose longest and shortest axes do not differ significantly". It should be noted applications of TiO NPs dates back to 1985 when one of the first works on the subject of photocatalytic 46 that in the broad2 sense, NPs also include polymeric NPs, liposomes (multilayer), lipid micelles disinfection was published [5]. Since that time, the use of TiO NPs in photodynamic therapy studies 47 (unilayer), quantum dots, dendrimers, fullerenes, cubosomes,2 niosomes, and metallic NPs. Particular has been constantly increasing. It concerns TiO NPs’ applications as photosensitizing agents in the 48 attention should be paid to the last mentioned,2 but exceptional category containing metallic and treatment of cancer as well as in photodynamic inactivation of antibiotic-resistant bacteria. Both TiO2 49 metal oxide NPs, for example ZnO, Au, Fe2O3, TiO2. Several studies have indicated that the 50 NPsapplication themselves, of NPs as in well medicine as their can composites, significantly combinations, improve the effectiveness or hybrids withof many other existing molecules, therapies. were 51 successfullyLinking drugs tested with as photosensitizersNPs can enhance in photodynamictheir selective therapy.accumulation Titanium(IV) in diseased oxide tissues NPs were as well applied as 52 interpenetration alia in the abilities synthesis through of bioconjugates cell membranes. with cell-specificIncreasing the monoclonal selectivity antibodies of drugs is for a great the treatment challenge of 53 malignantfor modern tumors medicine. or the This preparation goal can of be black achieved TiO2 NPsby research for antimicrobial focused on therapy therapeutic of antibiotic-resistant systems with 54 bacteriaincreased [6, 7selectivity]. and reduced toxicity, accompanied by higher therapeutic efficiency [2,3]. 55 56 Figure 1. Current applications and potential future use of TiO2. PDT, photodynamic therapy; PACT, Figure 1. Current applications and potential future use of TiO2. PDT, photodynamic therapy; PACT, 57 antimicrobialantimicrobial photodynamic photodynamic therapy;therapy; DSSC,DSSC, dye-sensitizeddye-sensitized solar cell. 58 2. Pharmacokinetics,In the current review, Biodistribution, studies focusing and Biological on titanium Fate dioxide of Titanium (titanium(IV) Dioxide oxide, titania, TiO2) 59 nanoparticles, which belong to the category of metallic NPs are reviewed. Notably, the evaluation of At present, relatively few publications have addressed issues related to TiO2 NPs’ 60 current TiO2 functionalization methods accompanied by the biological and medical effects of these pharmacokinetic characteristics. Also, some of the literature reports are contradictory or ambiguous. 61 NPs were the driving force for this work. Mass production of TiO2 began in the early twentieth 62 century as a non-toxic substitute for a white dye for paints. Nowadays, the annual production of TiO2 63 exceeds four million tons per year, and this molecule has found numerous applications in everyday 64 products (Figure 1)—as an excipient in the pharmaceutical industry, for sun cream production in the 65 cosmetics industry, as a colorant in white plastics, and as a relatively cheap and nontoxic food 66 pigment approved by the relevant European Union authorities for the safety of food additives [4]. 67 Research on the possible applications of TiO2 NPs dates back to 1985 when one of the first works on 68 the subject of photocatalytic disinfection was published [5]. Since that time, the use of TiO2 NPs in 69 photodynamic therapy studies has been constantly increasing. It concerns TiO2 NPs’ applications as 70 photosensitizing agents in the treatment of cancer as well as in photodynamic inactivation of 71 antibiotic-resistant bacteria. Both TiO2 NPs themselves, as well as their composites, combinations, or 72 hybrids with other molecules, were successfully tested as photosensitizers in photodynamic therapy. 73 Titanium(IV) oxide NPs were applied inter alia in the synthesis