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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...

HAL fluorescence cystoscopy is a new, sensitive, promising diagnostic procedure that showed improved detection of bladder tumors, in particular CIS. The procedure is well tolerated and can easily be implemented in current clinical practice.

The purpose of this review is to compile preclinical and clinical results on phthalocyanines (Pcs) as photosensitizers (PS) for Photodynamic Therapy (PDT) and contrast agents for fluorescence imaging. Indeed, Pcs are excellent candidates in these fields due to their strong absorbance in the NIR region and high chemical and photo-stability. In particular, this is mostly relevant for their in vivo activation in deeper tissular regions. However, most Pcs present two major limitations, i.e., a strong tendency to aggregate and a low water-solubility. In order to overcome these issues, both chemical tuning and pharmaceutical formulation combined with tumor targeting strategies were applied. These aspects will be developed in this review for the most extensively studied Pcs during the last 25 years, i.e., aluminium-, zinc- and silicon-based Pcs.

Fluorescence photodetection (PD) and photodynamic therapy (PDT) are techniques currently under clinical assessment for both visualization and local destruction of malignant tumours and premalignant lesions. One drawback of these methods found with some photosensitizers is a more or less long-term cutaneous photosensitivity (Wagnières et al, 1998;Dougherty et al, 1990). A more recent strategy for administering photosensitizers involves the application of 5-aminolaevulinic acid (ALA) in order to stimulate the formation of protoporphyrin IX (PpIX) in situ. The exogenous ALA bypasses the negative feedback control from haem to ALA synthase that catalyses the condensation of glycine and succinyl-coenzyme A (CoA). Given in excess, exogenous ALA thus can result in a temporary accumulation of PpIX, in particular, in cells with higher metabolic turnover. Since PPIX has fairly good photosensitizing properties (Cox et al, 1982;Kennedy et al, 1990) proposed ALA as a possible photodynamic agent. Following this pioneering work, this treatment modality has been widely studied for various cancers (Kennedy et al, 1992;Peng et al, 1992;Svanberg et al, 1994).As well as for the PDT of malignant or premalignant lesions, ALA-induced PpIX is now being used for the detection of such lesions. This technique has been shown to work, among other applications, in urology, where easy instillation in the bladder, combined with the fact that this organ is readily accessible endoscopically, makes it an ideal object. Alongside classical techniques such as cytology or white light examination, fluorescence PD by ALA-induced PpIX provides some advantages (Leveckis et al, 1994;Kriegmair et al, 1996;Jichlinski et al, 1997). This inspection modality allows an exact mapping which pinpoints, with a high level of sensitivity and specificity, the locations of carcinoma in situ (CIS) as well as early stages of cancer-like dysplasias, which are normally difficult to recognize under white light examination.However, when using topically instilled ALA for the PDT of CIS and precancerous lesions, this modality appears to be limited by the amount of ALA that enter the target cells or by the tissue penetration and the distribution of the resulting PpIX in the targeted tissue. Almost all of these possible disadvantages accompanying the use of ALA can be ascribed to the physical-chemical properties of the molecule itself. Applied under physiological conditions, ALA is a zwitterion (Novo et al, 1996). Because the lipid bilayer of biological membranes is relatively impermeable to charged molecules, the cellular uptake of ALA is shallow. Consequently, in order to increase the transport across cellular membranes, fairly high drug doses and increased administration times have to be used. This deficiency results in a low penetration depth (Warloe et al, 1992;Loh et al, 1993;Peng et al, 1995) and an ALA-induced PpIX distribution, which is not optimized for the PDT of the deep layers of nodular lesions in the urothelium (Iinuma et al, 1995;Chang et al, 1996) after topical A...

The introduction of lipophilic derivatives of the naturally occurring heme precursor 5-aminolevulinic acid (5-ALA) into photomedicine has led to a true revival of this research area. 5-ALA-mediated photodynamic therapy (PDT) and fluorescence photodetection (FD) of neoplastic disease is probably one of the most selective cancer treatments currently known in oncology. To date, this method has been assessed experimentally for the treatment of various medical indications. However, the limited local bioavailability of 5-ALA has widely prevented its use in daily clinical practice. Although researchers were already aware of this drawback early during the development of 5-ALA-mediated PDT, only recently have well-established concepts in pharmaceutical science been adapted to investigate ways to overcome this drawback. Recently, two derivatives of 5-ALA, methylaminolevulinate (MAL) and hexylaminolevulinate (HAL), gained marketing authorization from the regulatory offices in Europe and Australia. MAL is marketed under the trade name Metvix for the treatment of actinic keratosis and difficult-to-treat basal cell carcinoma. HAL has recently been launched under the trade name Hexvix to improve the detection of superficial bladder cancer in Europe. This review will first present the fundamental concepts underlying the use of 5-ALA derivatives in PDT and FD from a chemical, biochemical and pharmaceutical point of view. Experimental evidences from preclinical data on the improvements and limits observed with 5-ALA derivatives will then be introduced. The state-of-the-art from clinical studies with 5-ALA esters will be discussed, with special emphasis placed on the process that led to the development of MAL in dermatology and to HAL in urology. Finally, we will discuss promising medical fields in which use of 5-ALA derivatives might potentially lead to further use of this methodology in photomedicine.

Degenerative diseases such as cancer usually involve more than one pathological process. Therefore, attempts to combat such diseases with monotherapeutic approaches may not always do so efficiently. For this reason, the use of combination therapy with modalities that target different disease pathways represents an alternative strategy. Photodynamic therapy (PDT) has already been established as an alternative therapy for the treatment of various types of malignant disorders, including oesophageal, lung and bladder cancer as well as other degenerative diseases. This technique involves the administration of a tumor localizing photosensitizer followed by its activation with light of a specific wavelength. In the presence of tissue oxygen, the photoactive sensitizer triggers a series of photochemical and photobiological processes that may lead to direct cancer cell damage, tumor microvascular occlusion and host immune response. Due to these multiple actions, PDT has increasingly gained recognition as a potential adjuvant for conventional cancer treatments. Several preclinical studies and some clinical trials suggest that the use of PDT in combination with established treatments or with newly-developed modalities may be of benefit as compared to the individual modalities. In this review, we briefly introduce the reader to the main photobiological aspects of PDT, and then discuss the use of PDT in combination with other pharmacological approaches for the treatment of cancer.