Drug delivery technologies and immunological aspects of photodynamic therapy

Photodynamic therapy (PDT) has developed substantially since the mid-1970s when Tom Dougherty and coworkers started to utilize the photosensitizer (PS) mixture hematoporphyrin derivative (HpD) and generated enthusiasm for PDT, in particular for cancer therapy. HpD and later the somewhat purified version Photofrin have been and still are very much in use in PDT. Despite some success with HpD/Photofrin this drug has its limitations, e.g. poor absorption of light in the optimal therapeutic wavelength window (600–800 nm), relatively low specificity for tumor tissue and a long circulating half-life resulting in skin photosensitivity for several weeks and an acute, in some cases severe, response in the irradiated normal tissue surrounding the target lesion. It was therefore a major breakthrough when it was clinically shown in the early 1990s that the heme synthesis precursor 5-aminolevulinic acid (5-ALA) could be utilized to induce accumulation of protoporphyrin IX (PpIX) at a level sufficient for good therapeutic outcome. 5-ALA-induced PpIX, as well as 5-ALA-ester-induced PpIX, shows better specificity for cancerous and precancerous lesions and no skin photosensitivity, and has been very successful in treating non-melanoma skin cancers and for fluorescence-guided cancer detection. However, 5-ALA-based PDT is limited by the poor absorption of light in the 600–800 nm wavelength range and 5-ALA PDT alone is only recommended for lesions with thickness of less than 2 mm. In the last 20 years, and in parallel with the development of 5-ALA PDT, several hundred photosensitisers have been developed with improved spectral properties and various physico-chemical properties. Many of these have been clinically evaluated, but only very few have received market approval. Although to a lesser extent than with HpD/Photofrin, we still have to face the skin photosensitivity and specificity challenges (limited selectivity relative to normal surrounding tissue) utilizing chemically synthesized photosensitisers. It appears unlikely that these limitations can be solved by modifications of the physico-chemical properties of the sensitiser. One exception may be to use photosensitisers that are rapidly excreted and to irradiate the target lesion during or immediately after drug administration. This principle has been successfully used for treatment of age-related macular degeneration (AMD), but it still remains to be seen if this strategy is useful in cancer treatment. Another alternative is to utilize the technologies that have recently been developed for targeted delivery of drugs. Progress in basic research at the molecular level and novel strategies for optimized delivery and activation of drugs that can be utilized in PDT are encouraging and give us the hope that PDT in the future will become, to a larger extent, part of routine clinical practice. One part of this themed issue will therefore cover this topic.

In their Perspective articles Boyle and co-workers have highlighted the methods and advantages of conjugating PSs to antibodies (DOI: 10.1039/B915307C), peptides and proteins (DOI: 10.1039/C0PP00366B) for photodynamic therapy. The use of such biological agents significantly increases the targeting capability of the photosensitisers towards cancerous tissue.

The targeting capability in PDT also can be enhanced through the use of nanoparticles as a vehicle for photosensitiser delivery. Since each nanoparticle has multiple biological targeting and photosensitiser molecules a multi-valency binding effect can significantly enhance cancer cell binding. Examples of the state-of-the-art in this special issue include: the combined use of CdTe quantum dots with folic acid (Morosini et al., DOI: 10.1039/C0PP00380H); methylene blue-functionalised polyacrylamide nanoparticles using a F3 peptide for targeting (Qin et al., DOI: 10.1039/C1PP05022B); and a phthalocyanine/HER2 antibody-functionalised gold nanoparticle for the targeted treatment of breast cancer cells (Stuchinskaya et al., DOI: 10.1039/C1PP05014A). These three studies show that the use of multi-functionalised nanoparticles have considerable potential in future PDT treatments of cancer. A further area where nanoparticle delivery of photosensitiser agents may have considerable impact is within anti-microbial PDT. The potential of nanoparticles for antibacterial PDT has been highlighted by Perni et al. (DOI: 10.1039/C0PP00360C) in their Perspective article.

Two other attractive approaches for enhancing specificity in PDT are to utilize protease-sensitive prodrugs and photochemical internalization. Modulations of protease expression in many neoplastic and invasive diseases may be used for activation of the photosensitizing property of PDT drugs only in the target tissue. Photosensitisers may be tagged to peptides or macromolecules to make them optically silent until they encounter their target protease. This field has been reviewed with a focus on imaging and therapeutic purposes in the Perspective article by Gabriel et al. (DOI: 10.1039/C0PP00341G). Photochemical internalization (PCI) is a technology for cytosolic release of drugs and particles that are taken up into cells by endocytosis, but unable to escape the endocytic compartments. Jin et al. (DOI: 10.1039/C0PP00350F) have evaluated PCI for cytosolic delivery of LDL nanoparticle cargo. The authors found that PCI may be a useful method for cytosolic release and thereby activation of cargo-loaded LDL, although dependent on the drug and loading method used.

The therapeutic effect of PDT on solid tissues is due to damage to the parenchymal cells, the vasculature and the engagement of the inflammatory response. Both the innate and the acquired immune systems have been shown to be activated by PDT and there are indications for their impact on both local control as well as a systemic effect through anti-tumor immunity. In the second part of this issue, Firczuk et al. (DOI: 10.1039/C0PP00308E) explain how inflammatory response is elicited by PDT, and how it facilitates the immune recognition of the treated tumor and contributes to the anti-tumor effect of PDT. From the aspect of damage-associated molecular patterns (DAMPs), Garg et al. (DOI: 10.1039/C0PP00294A) also describe the proximal events that contribute to initiation of PDT-induced inflammation and the mechanisms that precipitate development of ensuing systemic immunity. It is proposed that increased secretion or surface exposure of DAMPs increases the immunogenicity of dying tumor cells by promoting their uptake by professional antigen-presenting cells, their activation and subsequent presentation of tumor-associated antigens (TAA) to naïve T cells. Brackett and Gollnick (DOI: 10.1039/C0PP00354A) further expand on the latter events and describe the role of adaptive immunity in controlling the growth of PDT-treated tumors. Preise et al. (DOI: 10.1039/C0PP00315H) show that PDT with drugs that primarily target the vascular cells can also lead to development of systemic immune response. Activation of anti-tumor immunity via stimulation of CD8⁺ T cells against TAA by PDT alone or in combination with other immunostimulatory agents is particularly attractive and is described in detail by St. Denis et al. (DOI: 10.1039/C0PP00326C). On the other hand, as described by Mroz and Hamblin (DOI: 10.1039/C0PP00345J), under certain still poorly defined conditions PDT can suppress immune reactions (as seen by dampened delayed-type hypersensitivity responses) and this aspect has potential to be exploited for treating a variety of autoimmune disorders. Elucidation of the molecular mechanisms participating in activation of dendritic cells and in the triggering of specific T cell-dependent immune responses led to development of a number of therapeutic strategies that might be explored to further expand the use of PDT. One of these includes generation of cancer vaccines based on administration of killed tumor cells or tumor lysates generated by PDT described here by Korbelik (DOI: 10.1039/C0PP00343C). Clinical reports in this issue include contributions by Daayana et al. (DOI: 10.1039/C0PP00344A) and Wang et al. (DOI: 10.1039/C0PP00373E) describing recent clinical observations that confirm the potential usefulness of PDT in designing effective immunotherapeutic approaches in cancer patients. A clinical study by Li et al. (DOI: 10.1039/C0PP00306A) describes impressive results obtained in treating late-stage breast cancer patients by using laser immunotherapy. They used innovative protocols somewhat different from PDT to generate localized thermal effects by laser irradiation of tumors followed by action of immunoadjuvant.

The understanding of both the impact of the immune system in various treatment regimens and how manipulation of immune responses can influence therapeutic outcome is rapidly evolving. Thus, a comprehensive overview of the immunological aspects of PDT is highly warranted and is the basis for establishing the second part of this themed issue.

We consider that the two topics presented in this themed issue are the most important fields for developing PDT into the mainstream of treatment of diseases such as cancer, rheumatoid arthritis and some infectious diseases.

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