Exploitation of Long-Lived Triplet IL Excited States for Metal-Organic Photodynamic Therapy: Verification in a Metastatic Melanoma Model

Richard Lincoln, Lars Kohler, Susan Monro, Huimin Yin, Mat Stephenson, Ruifa Zong, Abdellatif Chouai, Christopher Dorsey, Robie Hennigar, Randolph P. Thummel, and Sherri A. McFarland

     Cisplatin, arguably the most successful anticancer drug to date, remains one of the most widely used chemotherapeutic strategies despite its dose-limiting systemic toxicity and debilitating, long- term side effects. Photodynamic therapy (PDT), a method for destroying unwanted cells and tissue, represents a powerful alternative for treating cancer, alone or in combination with other therapies such as chemo- and immunotherapies, radiation, and surgery. Briefly, PDT overcomes the limi- tations that plague traditional chemotherapeutics by employing a relatively nontoxic prodrug that becomes toxic only when activated by light. Traditionally, PDT is mediated by singlet oxygen (¹∆_g), which is produced via excited state energy transfer from a photosensitizer (PS) to ground state molecular oxygen (³Σ⁻_g ) in what is known as a primary Type II photoprocess. Other photo- processes can occur, and certainly do, but the general consensus in the field is that singlet oxygen (¹O₂) plays a dominant role and is a potent cytotoxic agent in sufficiently oxygenated tissue. Light- activated production of ¹O₂ ensures that tissue damage is localized only to the region of irradiation. This degree of spatial selectivity, which can be fine-tuned by judicious choice of the PS, exciting wavelength, and power/energy density, offers all of the advantages of highly targeted therapy (without the cost) with the breadth and scope of classical chemotherapy (without the side-effects).

     Despite the enormous potential that PDT presents for cancer therapy, in the 40 years since its first use in oncology, it has become neither widely known nor generally accepted as a powerful alternative to existing mainstream approaches except in a few highly specialized areas of medicine such as dermatological oncology and opthamology. Plaetzer et al. have provided very convincing reasons for the absence of PDT in mainstream cancer treatment modalities, which include (i) the sheer number of variables that must be optimized (PS, drug dose, light source, light dose, drug- to-light interval, dosimetry, and protocol) for each particular clinical application, (ii) the paucity of detailed protocols available to clinicians for existing PDT agents and tumor types, and (iii) the fact that large, controlled, comparative randomized clinical trials have either not been carried out or could not prove significant advantage over existing therapies for advanced cancers that are refractory to other treatments. At some level, each one of these reasons can be linked to the pervasive PS-based approach to drug discovery for PDT, whereby researchers continue to chase the proverbial ideal PDT agent with no foresight regarding the specific application or clinical setting in which PDT will be delivered. In order to exploit the full potential that PDT has to offer, researchers must recognize that there is no single ideal PS for all PDT applications and, thus, shift from a PS-centered approach to a tumor-centered approach, which will require working closely with clinicians, cancer biologists, and medical biophysicists. Equal attention must be paid to (i) the PS and proper dosimetry of the PS, light fluence, and oxygen supply in the tumour, (ii) the specific tumour type, application, and clinical setting, and (iii) the development of complete treatment packages that include the PS, light source, and detailed protocol.

     To date the PS-based approach has focused mainly on PDT agents that absorb red light, with significant effort toward developing improved agents that can be activated in the PDT window (700–900 nm), a range that maximizes tissue penetration while maintaining sufficient energy for ¹O₂ production. These qualities have long been touted as must-have properties of the ideal PS although more recently, the ideal PS must exhibit an oxygen-independent mechanism of action for PDT for treating hypoxic tissue. When researchers move toward a tumour-centered approach, the ideal PS properties and many others will be defined by the tumour type and clinical application. For example, a superficial tumour that is well oxygenated does not demand a NIR PDT agent that functions in hypoxia for the same reason that a deep tumour isolated from the primary vasculature will not benefit from a blue PDT agent with unity production of ¹O₂. Herein, we outline the first steps toward implementing this tumour-centered approach in our own laboratories, whereby we provide proof-of-principle that blue/green-absorbing PDT agents with extremely long excited state lifetimes of 3IL character yield the largest reported photocytotoxicity indices (PIs) in a standard HL60 cancer cell line. Furthermore, these agents are capable of destroying melanocytes with metastatic potential, enabling PDT in pigmented melanoma cell lines that have traditionally proven less responsive to PDT.

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