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Published Online:https://doi.org/10.2217/nnm.11.144

Photodynamic therapy (PDT) employs the combination of nontoxic photosensitizers and visible light that is absorbed by the chromophore to produce long-lived triplet states that can carry out photochemistry in the presence of oxygen to kill cells. The closed carbon-cage structure found in fullerenes can act as a photosensitizer, especially when functionalized to impart water solubility. Although there are reports of the use of fullerenes to carry out light-mediated destruction of viruses, microorganisms and cancer cells in vitro, the use of fullerenes to mediate PDT of diseases such as cancer and infections in animal models is less well developed. It has recently been shown that fullerene PDT can be used to save the life of mice with wounds infected with pathogenic Gram-negative bacteria. Fullerene PDT has also been used to treat mouse models of various cancers including disseminated metastatic cancer in the peritoneal cavity. In vivo PDT with fullerenes represents a new application in nanomedicine.

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

  • Mroz P, Tegos GP, Gali H, Wharton T, Sarna T, Hamblin MR. Photodynamic therapy with fullerenes. Photochem. Photobiol. Sci.6(11),1139–1149 (2007).▪ First review of the use of fullerenes as photosensitizers in photodynamic therapy (PDT).
  • Hamblin MR, Mroz P. Advances in Photodynamic Therapy: Basic, Translational and Clinical. Artech House, Norwood, MA, USA (2008).▪ Most recent and comprehensive textbook covering all aspects of PDT from chemistry, physics and biology to many different clinical applications of PDT for diverse diseases.
  • Agostinis P, Berg K, Cengel KA et al. Photodynamic therapy of cancer: an update. CA Cancer J. Clin.61(4),250–281 (2011).▪▪ Recent, comprehensive review of mechanisms and clinical application of PDT for cancer.
  • Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat. Rev. Cancer3(5),380–387 (2003).
  • Dougherty TJ, Gomer CJ, Henderson BW et al. Photodynamic therapy. J. Natl Cancer Inst.90(12),889–905 (1998).
  • Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem. Photobiol.55(1),145–157 (1992).
  • Abels C. Targeting of the vascular system of solid tumours by photodynamic therapy (PDT). Photochem. Photobiol. Sci.3(8),765–771 (2004).
  • Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer6(7),535–545 (2006).▪ Discusses the particular ability of PDT of cancer to activate the immune system in addition to destroying the tumor and therefore potentially changing a local treatment into a systemic therapy.
  • Hancock RE, Bell A. Antibiotic uptake into Gram-negative bacteria. Eur. J. Clin. Microbiol. Infect. Dis.7(6),713–720 (1988).
  • 10  Detty MR, Gibson SL, Wagner SJ. Current clinical and preclinical photosensitizers for use in photodynamic therapy. J. Med. Chem.47(16),3897–3915 (2004).
  • 11  Szeimies RM, Karrer S, Abels C et al. 9-Acetoxy-2,7,12,17-tetrakis-(beta-methoxyethyl)-porphycene (ATMPn), a novel photosensitizer for photodynamic therapy. uptake kinetics and intracellular localization. J. Photochem. Photobiol. B.34(1),67–72 (1996).
  • 12  Rosenthal I. Phthalocyanines as photodynamic sensitizers. Photochem. Photobiol.53(6),859–870 (1991).
  • 13  Agostinis P, Vantieghem A, Merlevede W, De Witte PA. Hypericin in cancer treatment: more light on the way. Int. J. Biochem. Cell Biol.34(3),221–241 (2002).
  • 14  Stockert JC, Juarranz A, Villanueva A, Canete M. Photodynamic damage to HeLa cell microtubules induced by thiazine dyes. Cancer Chemother. Pharmacol.39(1–2),167–169 (1996).
  • 15  Bottiroli G, Croce AC, Balzarini P et al. Enzyme-assisted cell photosensitization: a proposal for an efficient approach to tumor therapy and diagnosis. The rose bengal fluorogenic substrate. Photochem. Photobiol.66(3),374–383 (1997).
  • 16  Cataldo F, Da Ros T. Medicinal Chemistry and Pharmacological Potential of Fullerenes and Carbon Nanotubes. Springer Science+Business Media, NY, USA (2008).▪ Textbook covering a wide range of potential applications of fullerenes and carbon nanotubes in medicine, drug delivery and pharmaceutical science.
  • 17  Duncan LK, Jinschek JR, Vikesland PJ. C60 colloid formation in aqueous systems: effects of preparation method on size, structure, and surface charge. Environ. Sci. Technol.42(1),173–178 (2008).
  • 18  Hotze EM, Labille J, Alvarez P, Wiesner MR. Mechanisms of photochemistry and reactive oxygen production by fullerene suspensions in water. Environ. Sci. Technol.42(11),4175–4180 (2008).
  • 19  Culotta L, Koshland DE Jr. Buckyballs: wide open playing field for chemists. Science254(5039),1706–1709 (1991).▪ One of the first suggestions that fullerenes had an important future role to play in biomedicine and what was later to become known as the field of nanomedicine.
  • 20  Oberdorster G. Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. J. Intern. Med.267(1),89–105 (2010).
  • 21  Gharbi N, Pressac M, Hadchouel M, Szwarc H, Wilson SR, Moussa F. [60]fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity. Nano Lett.5(12),2578–2585 (2005).
  • 22  Kato S, Aoshima H, Saitoh Y, Miwa N. Biological safety of liposome-fullerene consisting of hydrogenated lecithin, glycine soja sterols, and fullerene-C60 upon photocytotoxicity and bacterial reverse mutagenicity. Toxicol. Ind. Health25(3),197–203 (2009).
  • 23  Kato S, Aoshima H, Saitoh Y, Miwa N. Fullerene-C60/liposome complex: defensive effects against UVA-induced damages in skin structure, nucleus and collagen type I/IV fibrils, and the permeability into human skin tissue. J. Photochem. Photobiol. B.98(1),99–105 (2009).
  • 24  Doi Y, Ikeda A, Akiyama M et al. Intracellular uptake and photodynamic activity of water-soluble [60]- and [70]fullerenes incorporated in liposomes. Chemistry14(29),8892–8897 (2008).
  • 25  Yan A, Von Dem Bussche A, Kane AB, Hurt RH. Tocopheryl polyethylene glycol succinate as a safe, antioxidant surfactant for processing carbon nanotubes and fullerenes. Carbon N Y45(13),2463–2470 (2007).
  • 26  Akiyama M, Ikeda A, Shintani T et al. Solubilisation of [60]fullerenes using block copolymers and evaluation of their photodynamic activities. Org. Biomol. Chem.6(6),1015–1019 (2008).
  • 27  Kojima C, Toi Y, Harada A, Kono K. Aqueous solubilization of fullerenes using poly(amidoamine) dendrimers bearing cyclodextrin and poly(ethylene glycol). Bioconjug. Chem.19(11),2280–2284 (2008).
  • 28  Pan B, Cui D, Xu P et al. Synthesis and characterization of polyamidoamine dendrimer-coated multi-walled carbon nanotubes and their application in gene delivery systems. Nanotechnology20(12),125101 (2009).
  • 29  Hooper JB, Bedrov D, Smith GD. Supramolecular self-organization in PEO-modified C60 fullerene/water solutions: influence of polymer molecular weight and nanoparticle concentration. Langmuir24(9),4550–4557 (2008).
  • 30  Nitta N, Seko A, Sonoda A et al. Is the use of fullerene in photodynamic therapy effective for atherosclerosis? Cardiovasc. Intervent. Radiol.31(2),359–366 (2008).
  • 31  Liu J, Ohta S, Sonoda A et al. Preparation of PEG-conjugated fullerene containing Gd3+ ions for photodynamic therapy. J. Control. Release117(1),104–110 (2007).▪▪ Important study of PDT of a tumor in vivo with a fullerene derivatized to be both soluble and also to contain gadolinium ions that allow MRI and facilitate biodistribution studies.
  • 32  Tabata Y, Murakami Y, Ikada Y. Photodynamic effect of polyethylene glycol-modified fullerene on tumor. Jpn J. Cancer Res.88(11),1108–1116 (1997).▪ First report of the use of a functionalized fullerene to mediate PDT of a tumor in vivo.
  • 33  Filippone S, Heimann F, Rassat A. A highly water-soluble 2:1 beta-cyclodextrin-fullerene conjugate. Chem. Commun. (Camb.)14,1508–1509 (2002).
  • 34  Zhao B, He YY, Bilski PJ, Chignell CF. Pristine (C60) and hydroxylated [C60(OH)24] fullerene phototoxicity towards HaCaT keratinocytes: type I vs type II mechanisms. Chem. Res. Toxicol.21(5),1056–1063 (2008).
  • 35  Bansal T, Mustafa G, Khan ZI, Ahmad FJ, Khar RK, Talegaonkar S. Solid self-nanoemulsifying delivery systems as a platform technology for formulation of poorly soluble drugs. Crit. Rev. Ther. Drug Carrier Syst.25(1),63–116 (2008).
  • 36  Shakeel F, Faisal MS. Nanoemulsion: a promising tool for solubility and dissolution enhancement of celecoxib. Pharm. Dev. Technol.15(1),53–56 (2009).
  • 37  Bali V, Ali M, Ali J. Novel nanoemulsion for minimizing variations in bioavailability of ezetimibe. J. Drug Target18(7),506–519 (2010).
  • 38  Amani A, York P, Chrystyn H, Clark BJ. Factors affecting the stability of nanoemulsions – use of artificial neural networks. Pharm. Res.27(1),37–45 (2010).
  • 39  Boyd PD, Reed CA. Fullerene-porphyrin constructs. Acc. Chem. Res.38(4),235–242 (2005).
  • 40  El-Khouly ME, Araki Y, Ito O et al. Spectral, electrochemical, and photophysical studies of a magnesium porphyrin-fullerene dyad. Phys. Chem. Chem. Phys.7(17),3163–3171 (2005).
  • 41  Imahori H. Porphyrin-fullerene linked systems as artificial photosynthetic mimics. Org. Biomol. Chem.2(10),1425–1433 (2004).
  • 42  Schuster DI, Cheng P, Jarowski PD et al. Design, synthesis, and photophysical studies of a porphyrin-fullerene dyad with parachute topology; charge recombination in the marcus inverted region. J. Am. Chem. Soc.126(23),7257–7270 (2004).
  • 43  Vail SA, Schuster DI, Guldi DM et al. Energy and electron transfer in beta-alkynyl-linked porphyrin-[60]fullerene dyads. J. Phys. Chem. B.110(29),14155–14166 (2006).
  • 44  Gebhart SC, Lin WC, Mahadevan-Jansen A. In vitro determination of normal and neoplastic human brain tissue optical properties using inverse adding-doubling. Phys. Med. Biol.51(8),2011–2027 (2006).
  • 45  Tuchin VV, Wang RK, Yeh AT. Optical clearing of tissues and cells. J. Biomed. Opt.13(2),021101 (2008).
  • 46  Hirshburg J, Choi B, Nelson JS, Yeh AT. Correlation between collagen solubility and skin optical clearing using sugars. Lasers Surg. Med.39(2),140–144 (2007).
  • 47  Jiang J, Boese M, Turner P, Wang RK. Penetration kinetics of dimethyl sulphoxide and glycerol in dynamic optical clearing of porcine skin tissue in vitro studied by Fourier transform infrared spectroscopic imaging. J. Biomed. Opt.13(2),021105 (2008).
  • 48  Kogan A, Garti N. Microemulsions as transdermal drug delivery vehicles. Adv. Colloid Interface Sci.123–126,369–385 (2006).
  • 49  Goeppert-Mayer M. Über elementarakte mit zwei Quantensprüngen. Ann. Phys.9,273–295 (1931).
  • 50  Bhawalkar JD, Kumar ND, Zhao CF, Prasad PN. Two-photon photodynamic therapy. J. Clin. Laser Med. Surg.15(5),201–204 (1997).
  • 51  Karotki A, Khurana M, Lepock JR, Wilson BC. Simultaneous two-photon excitation of photofrin in relation to photodynamic therapy. Photochem. Photobiol.82(2),443–452 (2006).
  • 52  Samkoe KS, Clancy AA, Karotki A, Wilson BC, Cramb DT. Complete blood vessel occlusion in the chick chorioallantoic membrane using two-photon excitation photodynamic therapy: implications for treatment of wet age-related macular degeneration. J. Biomed. Opt.12(3),034025 (2007).
  • 53  Samkoe KS, Cramb DT. Application of an ex ovo chicken chorioallantoic membrane model for two-photon excitation photodynamic therapy of age-related macular degeneration. J. Biomed. Opt.8(3),410–417 (2003).
  • 54  Arbogast JW, Darmanyan AP, Foote CS et al. Photophysical properties of C60. J. Phys. Chem. A. Mol. Spectrosc. Kinet. Environ. Gen. Theory95(1),11–12 (1991).
  • 55  Foote CS. Photophysical and photochemical properties of fullerenes Top. Curr. Chem.169,347–363 (1994).
  • 56  Yamakoshi Y, Umezawa N, Ryu A et al. Active oxygen species generated from photoexcited fullerene (C60) as potential medicines: O2-* versus 1O2. J. Am. Chem. Soc.125(42),12803–12809 (2003).▪▪ Provides convincing evidence that fullerenes operate via a type I photochemical mechanism producing superoxide especially in aqueous biological environments.
  • 57  Koeppe R, Sariciftci NS. Photoinduced charge and energy transfer involving fullerene derivatives. Photochem. Photobiol. Sci.5(12),1122–1131 (2006).
  • 58  Guldi DM, Prato M. Excited-state properties of C(60) fullerene derivatives. Acc. Chem. Res.33(10),695–703 (2000).
  • 59  Arbogast JW, Foote CS, Kao M. Electron-transfer to triplet C-60. J. Am. Chem. Soc.114(6),2277–2279 (1992).
  • 60  Lens M, Medenica L, Citernesi U. Antioxidative capacity of C(60) (buckminsterfullerene) and newly synthesized fulleropyrrolidine derivatives encapsulated in liposomes. Biotechnol. Appl. Biochem.51(Pt 3),135–140 (2008).
  • 61  Spohn P, Hirsch C, Hasler F, Bruinink A, Krug HF, Wick P. C60 fullerene: a powerful antioxidant or a damaging agent? The importance of an in-depth material characterization prior to toxicity assays. Environ. Pollut.157(4),1134–1139 (2009).
  • 62  Cai X, Jia H, Liu Z et al. Polyhydroxylated fullerene derivative C(60)(OH)(24) prevents mitochondrial dysfunction and oxidative damage in an MPP+-induced cellular model of Parkinson’s disease. J. Neurosci. Res.86(16),3622–3634 (2008).
  • 63  Dugan LL, Gabrielsen JK, Yu SP, Lin TS, Choi DW. Buckminsterfullerenol free radical scavengers reduce excitotoxic and apoptotic death of cultured cortical neurons. Neurobiol. Neurosci.3(2),129–135 (1996).
  • 64  Andrievsky GV, Bruskov VI, Tykhomyrov AA, Gudkov SV. Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostuctures in vitro and in vivo. Free Radic. Biol. Med.47(6),786–793 (2009).▪ Provides a possible explanation of the seeming paradox that on the one hand fullerenes can generate cytotoxic reactive oxygen species on illumination, and on the other hand, that fullerenes can quench reactive oxygen species and act as powerful antioxidants.
  • 65  Weiss DR, Raschke TM, Levitt M. How hydrophobic buckminsterfullerene affects surrounding water structure. J. Phys. Chem. B.112(10),2981–2990 (2008).
  • 66  Tokuyama H, Yamago S, Nakamura E. Photoinduced biochemical activity of fullerene carboxylic acid. J. Am. Chem. Soc.115,7918–7919 (1993).
  • 67  Burlaka AP, Sidorik YP, Prylutska SV et al. Catalytic system of the reactive oxygen species on the C60 fullerene basis. Exp. Oncol.26(4),326–327 (2004).
  • 68  Rancan F, Rosan S, Boehm F et al. Cytotoxicity and photocytotoxicity of a dendritic C(60) mono-adduct and a malonic acid C(60) tris-adduct on Jurkat cells. J. Photochem. Photobiol. B.67(3),157–162 (2002).
  • 69  Yang XL, Fan CH, Zhu HS. Photo-induced cytotoxicity of malonic acid [C(60)]fullerene derivatives and its mechanism. Toxicol. In Vitro16(1),41–46 (2002).
  • 70  Mroz P, Pawlak A, Satti M et al. Functionalized fullerenes mediate photodynamic killing of cancer cells: type I versus type II photochemical mechanism. Free Radic. Biol. Med.43(5),711–719 (2007).▪ Shows that functionalized fullerenes are efficient mediators of PDT killing of cancer cells via a type I photochemical mechanism.
  • 71  Chiang LY, Padmawar PA, Rogers-Haley JE et al. Synthesis and characterization of highly photoresponsive fullerenyl dyads with a close chromophore antenna-C(60) contact and effective photodynamic potential. J. Mater. Chem.20(25),5280–5293 (2010).
  • 72  Kasermann F, Kempf C. Photodynamic inactivation of enveloped viruses by buckminsterfullerene. Antiviral Res.34(1),65–70 (1997).
  • 73  Hirayama J, Abe H, Kamo N et al. Photoinactivation of vesicular stomatitis virus with fullerene conjugated with methoxy polyethylene glycol amine. Biol. Pharm. Bull.22(10),1106–1109 (1999).
  • 74  Lin CP, Lynch MC, Kochevar IE. Reactive oxidizing species produced near the plasma membrane induce apoptosis in bovine aorta endothelial cells. Exp. Cell Res.259(2),351–359 (2000).
  • 75  Lee I, Mackeyev Y, Cho M et al. Photochemical and antimicrobial properties of novel C60 derivatives in aqueous systems. Environ. Sci. Technol.43(17),6604–6610 (2009).
  • 76  Tegos GP, Demidova TN, Arcila-Lopez D et al. Cationic fullerenes are effective and selective antimicrobial photosensitizers. Chem. Biol.12(10),1127–1135 (2005).▪ First demonstration that photoactivated cationic functionalized fullerenes are highly active, selective, broad-spectrum antimicrobials.
  • 77  Spesia MB, Milanesio ME, Durantini EN. Synthesis, properties and photodynamic inactivation of Escherichia coli by novel cationic fullerene C60 derivatives. Eur. J. Med. Chem.43(4),853–861 (2008).
  • 78  Huang L, Terakawa M, Zhiyentayev T et al. Innovative cationic fullerenes as broad-spectrum light-activated antimicrobials. Nanomedicine6(3),442–452 (2009).
  • 79  Mizuno K, Zhiyentayev T, Huang L et al. Antimicrobial photodynamic therapy with functionalized fullerenes: quantitative structure-activity relationships. J. Nanomedic. Nanotechnol.2(2),100109–100117 (2011).
  • 80  Isobe H, Tomita N, Nakamura E. One-step multiple addition of amine to [60]fullerene. synthesis of tetra(amino)fullerene epoxide under photochemical aerobic conditions. Org. Lett.2(23),3663–3665. (2000).
  • 81  Ikeda A, Doi Y, Nishiguchi K et al. Induction of cell death by photodynamic therapy with water-soluble lipid-membrane-incorporated [60]fullerene. Org. Biomol. Chem.5(8),1158–1160 (2007).
  • 82  Ikeda A, Matsumoto M, Akiyama M, Kikuchi J, Ogawa T, Takeya T. Direct and short-time uptake of [70]fullerene into the cell membrane using an exchange reaction from a [70]fullerene-gamma-cyclodextrin complex and the resulting photodynamic activity. Chem. Commun. (Camb.)12,1547–1549 (2009).
  • 83  Ikeda A, Nagano M, Akiyama M et al. Photodynamic activity of C70 caged within surface-cross-linked liposomes. Chem. Asian J.4(1),199–205 (2009).
  • 84  Scrivens JMT, K.E. Creek, L Pirisi. Synthesis of C-14-labeled C-60, its suspension in water, and its uptake by human keratinocytes. J. Am. Chem. Soc.116,4517–4518. (1994).
  • 85  Foley S, Crowley C, Smaihi M et al. Cellular localisation of a water-soluble fullerene derivative. Biochem. Biophys. Res. Commun.294(1),116–119 (2002).
  • 86  Porter AE, Gass M, Muller K, Skepper JN, Midgley P, Welland M. Visualizing the uptake of C60 to the cytoplasm and nucleus of human monocyte-derived macrophage cells using energy-filtered transmission electron microscopy and electron tomography. Environ. Sci. Technol.41(8),3012–3017 (2007).
  • 87  Levi N, Hantgan RR, Lively MO, Carroll DL, Prasad GL. C60-Fullerenes: detection of intracellular photoluminescence and lack of cytotoxic effects. J. Nanobiotechnol.4,14–25 (2006).
  • 88  Tabata Y, Murakami Y, Ikada Y. Photodynamic effect of polyethylene glycol-modified fullerene on tumor. Jpn J. Cancer Res.88(11),1108–1116 (1997).
  • 89  Chi Y, Canteenwala T, Chen HC, Chen BJ, Canteenwala M, Chiang LY. Hexa(sulfobutyl)fullerene-induced photodynamic effect on tumors in vivo and toxicity study in rats. Proc. Electrochem. Soc.99,234–249 (1999).
  • 90  Otake E, Sakuma S, Torii K et al. Effect and mechanism of a new photodynamic therapy with glycoconjugated fullerene. Photochem. Photobiol.86(6),1356–1363 (2010).
  • 91  Mroz P, Xia Y, Asanuma D et al. Intraperitoneal photodynamic therapy mediated by a fullerene in a mouse model of abdominal dissemination of colon adenocarcinoma. Nanomedicine doi:10.1016/j.nano.2011.04.007 (2011) (Epub ahead of print).▪ Shows that a photoactivated, functionalized fullerene was able to produce tumor response and increased survival in a new and challenging mouse model of disseminated metastatic cancer.
  • 92  Lu Z, Dai T, Huang L et al. Photodynamic therapy with a cationic functionalized fullerene rescues mice from fatal wound infections. Nanomedicine (Lond.)5(10),1525–1533 (2010).▪▪ First study to show that PTD with a functionalized fullerene is able to save the life of mice at risk of dying from a highly aggressive and invasive bacterial infection.
  • 93  Chen HH, Yu C, Ueng TH et al. Acute and subacute toxicity study of water-soluble polyalkylsulfonated C60 in rats. Toxicol. Pathol.26(1),143–151 (1998).