Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative particularly in early-stage tumors. It can prolong survival in inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment.

Photodynamic therapy (PDT) uses non-toxic photosensitizers and harmless visible light in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumour microvasculature and stimulate the host immune system. In contrast to surgery, radiotherapy and chemotherapy that are mostly immunosuppressive, PDT causes acute inflammation, expression of heat-shock proteins, invasion and infiltration of the tumour by leukocytes, and might increase the presentation of tumour-derived antigens to T cells.The principle of photodynamic therapy (PDT) was first proposed over 100 years ago 1 . A recent review in Nature Reviews Cancer by Rakesh Jain and colleagues described some of the historical milestones in the development of PDT as a cancer treatment2. Many of the photosensitizers (PSs) that have been studied since PDT was first proposed are based on a porphyrin-like nucleus 3 . PSs function as catalysts when they absorb visible light and then convert molecular oxygen to a range of highly reactive oxygen species (ROS). The ROS that are produced during PDT have been shown to destroy tumours by multifactorial mechanisms4 , 5 (FIG. 1). PDT has a direct affect on cancer cells, producing cell death by necrosis and/or apoptosis 6 . PDT also has an affect on the tumour vasculature, whereby illumination and ROS production causes the shutdown of vessels and subsequently deprives the tumour of oxygen and nutrients 7,8 . Finally, PDT also has a significant effect on the immune system 9-11 , which can be either immunostimulatory or immunosuppressive.Most of the commonly used cancer therapies are immunosuppressive. Chemotherapy and ionizing radiation delivered at doses sufficient to destroy tumours are known to be toxic to the bone marrow, which is the source of all cells of the immune system, and neutropaenia and other forms of myelosuppression are often the dose-limiting toxicity of these therapies. However, it should be noted that low doses of either ionizing radiation12 , 13 or chemotherapy14 can have immunostimulatory effects, including the induction of heat-shock © 2006 Nature Publishing Group Correspondence to M.R.H. Hamblin@helix.mgh.harvard.edu. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Cancer. Author manuscript; available in PMC 2010 September 6. Published in final edited form as:Nat Rev Cancer. 2006 July ; 6(7): 535-545. doi:10.1038/nrc1894. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript proteins 15 . Less well known is the fact that major surgery can also have an immunosuppressive effect that leads to a significant diminution of lymphocyte and natural killer (NK) cell function 16 . The ideal cancer therapy would not only destroy the primary tumour, but at the same time trigger the immune system to recognize, track down and destroy any remaining tumour cells, be they at or near the site of the primary tumour or distant microm...

Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT.

Fullerenes are a class of closed-cage nanomaterials made exclusively from carbon atoms. A great deal of attention has been focused on developing medical uses of these unique molecules especially when they are derivatized with functional groups to make them soluble and therefore able to interact with biological systems. Due to their extended π-conjugation they absorb visible light, have a high triplet yield and can generate reactive oxygen species upon illumination, suggesting a possible role of fullerenes in photodynamic therapy. Depending on the functional groups introduced into the molecule, fullerenes can effectively photoinactivate either or both pathogenic microbial cells and malignant cancer cells. The mechanism appears to involve superoxide anion as well as singlet oxygen, and under the right conditions fullerenes may have advantages over clinically applied photosensitizers for mediating photodynamic therapy of certain diseases.

Photodynamic therapy (PDT) is a rapidly developing cancer treatment that utilizes the combination of nontoxic dyes and harmless visible light to destroy tumors by generating reactive oxygen species. PDT produces tumor-cell destruction in the context of acute inflammation that acts as a 'danger signal' to the innate immune system. Activation of the innate immune system increases the priming of tumor-specific T lymphocytes that have the ability to recognize and destroy distant tumor cells and, in addition, lead to the development of an immune memory that can combat recurrence of the cancer at a later point in time. PDT may be also successfully combined with immunomodulating strategies that are capable of overcoming or bypassing the escape mechanisms employed by the progressing tumor to evade immune attack. This article will cover the role of the immune response in PDT anti-tumor effectiveness. It will highlight the milestones in the development of PDT-mediated anti-tumor immunity and emphasize the combination strategies that may improve this therapy. Keywordsanti-tumor immunity; cancer vaccines; cytotoxic T-lymphocytes; damage-associated molecular patterns; dendritic cells; photodynamic therapy; Toll-like receptor agonists; tumor-associated antigens Since Richard Nixon's declaration to make the 'conquest of cancer a national crusade', our understanding of the development and propagation of cancer has considerably improved. As a result of major investments in cancer research and cancer prevention, treatment and survival has significantly improved over the last 40 years [1]. Consequently, the increasing knowledge created by basic scientific research becomes gradually translated into more (and sometimes more effective) treatment options [2]. Despite the increasing emergence of drugs produced by biotechnological techniques, in 2008 half a million individuals diagnosed with cancer died from their disease in the USA [1].© 2011 Expert Reviews Ltd † Author for correspondence: Tel.: +1 617 726 6182, Fax: +1 617 726 8566, hamblin@helix.mgh.harvard.edu. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NIH Public Access Author ManuscriptExpert Rev Clin Immunol. Author manuscript; available in PMC 2011 November 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptSome of these drugs directed against tumor-associated factors such as ligands, receptors and transduction signaling factors are expensive, intrinsically cannot be used in a broad population of cancer patients and often fail to demonstrate their superiority over conventional chemotherapeutic drugs [3][4][5][6]. Furthermore, treating tumors with such 'onetarget' drugs poses other problems to physicians. Some tumors remain persist...

Photodynamic therapy (PDT) employs the combination of nontoxic photosensitizers (PS) and harmless visible light to generate reactive oxygen species (ROS) and kill cells. Most clinically studied PS are based on the tetrapyrrole structure of porphyrins, chlorines, and related molecules, but new nontetrapyrrole PS are being sought. Fullerenes are soccer-ball shaped molecules composed of 60 or 70 carbon atoms and have attracted interest in connection with the search for biomedical applications of nanotechnology. Fullerenes are biologically inert unless derivatized with functional groups, whereupon they become soluble and can act as PS. We have compared the photodynamic activity of six functionalized fullerenes with 1, 2, or 3 hydrophilic or 1, 2, or 3 cationic groups. The octanol-water partition coefficients were determined and the relative contributions of Type I photochemistry (photogeneration of superoxide in the presence of NADH) and Type II photochemistry (photogeneration of singlet oxygen) were studied by measurement of oxygen consumption, 1270-nm luminescence and EPR spin trapping of the superoxide product. We studied three mouse cancer cell lines: (J774, LLC, and CT26) incubated for 24 h with fullerenes and illuminated with white light. The order of effectiveness as PS was inversely proportional to the degree of substitution of the fullerene nucleus for both the neutral and the cationic series. The monopyrrolidinium fullerene was the most active PS against all cell lines and induced apoptosis 4-6 h after illumination. It produced diffuse intracellular fluorescence when dichlorodihydrofluorescein was added as an ROS probe, suggesting a Type I mechanism for phototoxicity. We conclude that certain functionalized fullerenes have potential as novel PDT agents and phototoxicity may be mediated both by superoxide and by singlet oxygen.

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We previously showed that covalent conjugates between poly-L-lysine and chlorin(e6) were efficient photosensitizers (PS) of both gram-positive and gram-negative bacteria. The polycationic molecular constructs increased binding and penetration of the PS into impermeable gram-negative cells. We have now prepared a novel set of second-generation polycationic conjugates between chlorin(e6) and three molecular forms of polyethyleneimine (PEI): a small linear, a small cross-linked, and a large cross-linked molecule. The conjugates were characterized by high-pressure liquid chromatography and tested for their ability to kill a panel of pathogenic microorganisms, the gram-positive Staphylococcus aureus and Streptococcus pyogenes, the gramnegative Escherichia coli and Pseudomonas aeruginosa, and the yeast Candida albicans, after exposure to low levels of red light. The large cross-linked molecule efficiently killed all organisms, while the linear conjugate killed gram-positive bacteria and C. albicans. The small cross-linked conjugate was the least efficient antimicrobial PS and its remarkably low activity could not be explained by reduced photochemical quantum yield or reduced cellular uptake. In contrast to polylysine conjugates, the PEI conjugates were resistant to degradation by proteases such as trypsin that hydrolyze lysine-lysine peptide bonds, The advantage of protease stability combined with the ready availability of PEI suggests these molecules may be superior to polylysine-PS conjugates for photodynamic therapy of localized infections.Photodynamic therapy (PDT) employs a nontoxic dye termed a photosensitizer (PS) and low-intensity visible light, which in the presence of oxygen produce cytotoxic species (4-6). PDT has the advantage of dual selectivity in that the PS can be targeted to its destination cell or tissue, and in addition the illumination can be spatially directed to the lesion. PDT was originally discovered over 100 years ago by its effect on microorganisms (35) but since then has been principally developed as a treatment for cancer (11) and age-related macular degeneration (3).Because of the well-known increase in multiantibiotic resistance among pathogenic microbes of all classes, PDT has attracted attention as a possible treatment for localized infections (9, 14, 46). It is known that gram-negative bacteria are resistant to PDT with many commonly used PS that will readily lead to phototoxicity for gram-positive species (29) and that PS bearing a cationic charge (33) or the use of agents that increase the permeability of the outer membrane will increase the efficacy of killing of gram-negative organisms (29).In 1997 our laboratory formed the hypothesis that by covalently conjugating a suitable PS such as chlorin(e6) (ce6) to a poly-L-lysine (pL) chain, a bacterially targeted PS delivery vehicle could be constructed that would efficiently inactivate both gram-positive and gram-negative species (42). Because the resulting polycationic entity is a macromolecule, it is taken up by mammalian cells by th...