American Society for Photobiology

ASP Conference 2016: 21-26 May 2016
Tampa Marriott Waterside Hotel & Marina


Single Session



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2 - Current Trends in Photochemistry and Imaging

Florida 1   10:00 - 12:00

Chair(s): Alec Greer, Lisa Kelly
 
2-1   10:00  Phototherapy and Photoreporters " Efforts Towards Inorganic Therapeutics and Research Tools EG Glazer*, U Kentucky ; DK Heidary, U Kentucky; E Wachter, U Kentucky; Y Sun, U Kentucky

Abstract: The discovery and development of new therapeutic agents is slowed by complications from off-target effects and difficulties in correctly identifying mechanism of action, along with mechanisms for undesired toxicity. Many cytotoxic metal complexes interact with or damage DNA. While this provides for effective cell killing, the non-selective mechanism leads to general toxicity in terms of impacts on healthy tissues, and off-mechanism effects provide another danger. A promising approach is to develop compounds capable of targeting and damaging key biological molecules of particular importance in a specific disease, such as specific nucleic acid structures, sequences, or proteins. Agents that can be induced to form covalent bonds to their targets using light as an external trigger will be discussed, as such systems would permanently damage or inactivate essential biological molecules in a spatially limited treatment area. We are developing a research platform to aid in the advancement of a family of coordination complexes that can form covalent bonds only upon irradiation with visible to near-IR light. These compounds can be designed to target different nucleic acids or proteins within the cell, depending on the compounds' structure and charge. We are also developing reporter assays that provide functional information on various essential cellular processes to elucidate both the mechanism of action and potential off-target, off-mechanism toxicity.

2-2   10:25  Heptamethine Cyanine Near-IR Uncaging Chemistry: Discovery and Applications MJ Schnermann*, National Cancer Institute ; RN Nani, National Cancer Institute; AP Gorka, National Cancer Institute

Abstract: Many key fundamental and applied questions in biology require unraveling issues relating to the spatial and temporal organization of multi-cellular systems. While the combination of photocaged small molecule probes and the spatially controlled application of light could in principle provide key insights, existing photoremovable caging groups are often not suitable, particularly for organismal applications. This is due to the general requirement of UV or blue light, which suffers from associated toxicity and poor tissue penetrance. By contrast, light between 650 and 900 nm, often referred to as the near-IR window, is cytocompatible and exhibits much improved tissue penetration. We have developed a single photon uncaging reaction initiated by 690 nm light using readily synthesized C4'-dialkylamine-substituted heptamethine cyanines. Release occurs through a reaction sequence comprising regioselective photooxidative C-C cleavage and then hydrolysis of the C4'-amine. The oxidative cleavage step was known to be the basis of cyanine photobleaching and our efforts are the first to deliberately apply this remarkable reactivity for small molecule delivery. The precisely controlled introduction of biological stimuli will enable studies within complex model organisms that address cell-cell interactions or control/monitor cell fate. In this area, we are developing advanced tools to spatially pattern gene expression. From a medical perspective, the ability to release therapeutic molecules using the targeted application of near-IR light will facilitate the creation of innovative drug delivery strategies. In this area, we are developing antibody-based theranostic tools with the goal of treating otherwise unresectable tumors and micrometastases. Details regarding the development of this approach, our mechanistic studies, and long-term goals will be discussed.

2-3   10:50  Metal Coordination Complexes as Photosensitizers for Photodynamic Therapy SA McFarland*, Acadia University

Abstract: Photodynamic therapy (PDT), a method that combines a photosensitizer (PS) and light in the presence of oxygen to destroy tumors, was first used in the field of oncology more than 40 years ago. Despite its vast potential and some isolated success, PDT remains underutilized as a cancer treatment. The number of variables that must be optimized with respect to the light component and the absence of large, comparative randomized clinical trials have been implicated as well as drawbacks associated with the organic PSs that have been traditionally employed for PDT. Metal coordination complexes for light-mediated cancer therapy are an attractive alternative to their organic counterparts. These systems possess a variety of excited state configurations that can be accessed through rational and systematic changes to their very modular, yet structurally diverse, architectures. These excited states can be tuned to participate in oxygen and oxygen-independent photoprocesses through catalytic and stoichiometric reactions, and offer many additional advantages over purely organic PSs. Our group has developed ruthenium (Ru)- and osmium (Os)-based coordination complexes for photoactivated cancer therapy, with a lead compound entering human clinical trials for treating bladder cancer this year. Herein we will discuss the attributes of Ru and Os PSs for PDT, the development process, and future directions.

2-4   11:15  Multifunctional Prodrugs for the Spatiotemporal Combination of Photodynamic Therapy and Site-Specific Chemotherapy Youngjae You*, University of Oklahoma Health Sciences Center

Abstract: A non-invasive or minimally invasive tumor ablation method is an attractive tool for controlling local and regional tumors. This approach can be complementary to primary treatment options without causing systemic side effects or severe physical burdens from the treatments. Photodynamic therapy (PDT) is one such a regimen, which has been used in the clinic for various tumors. However, the therapeutic efficacy of PDT is limited by various factors leading to incomplete tumor ablation for certain cases. The spatial and temporal limits of the major effector of PDT, singlet oxygen, have been suggested as potential causes of incomplete ablation in highly heterogeneous tumor and PDT. We recently developed a prodrug strategy that could overcome these limits by using a unique combination of PDT and site-specific chemotherapy. The prodrug is composed of a photosensitizer and anticancer drugs via a singlet oxygen-cleavable linker. In particular, we designed the prodrugs using fluorescent photosensitizers. Thus, the prodrugs can be imaged using optical imaging both in vitro and in vivo. Upon illumination, the prodrugs cause immediate PDT damage and sustained damage by locally released anticancer drugs, which are released during the illumination at the target. Recent progress in our research will be presented including mechanistic proofs of the dual damage and targeted multifunctional prodrugs.

2-5   11:40  Photooxidative Crosslinking and Affinity Labeling of Proteins Using Naphthalene Imides SL Sova*, University of Maryland Baltimore County

Abstract: Determining protein structures and interactions are crucial to understanding their biological function. Photoaffinity labeling and oxidative crosslinking have been demonstrated by us using naphthaldiimide and naphthalimide derivatives as a new structural probes of proteins. N-(4-Hydroxyphenyl propionic acid)-1,8-naphthalene imide (NI-Tyr) and N-3,4-dihydroxyphenyl propionic acid)-1,8-naphthalene imide (NI-Dopa) actively target the binding site of mushroom tyrosinase. Enzymatic oxidation was accompanied by the recovery of fluorescence intensity in both cases. Competitive kinetic assays showed mixed inhibition of the monophenolase activity and activation of the diphenolase activity, indicating these naphthalimides were oxidized within the active site; however no permanent covalent linkage was observed. Despite failing to label mushroom tyrosinase, these compounds do oxidatively crosslink proteins such as lysozyme. Though the location of the crosslink has not been determined, the compounds are viable for probing transient protein interactions. In separate work, N,N'-bis[2-(ethanoic acid)]-1,4,5,8-naphthalene diimide does nonspecifically label bovine serum albumin. To make this diimide more site specific, asymmetric naphthaldiimides containing a site-specific substrate or inhibitor are being synthesized as new photoaffinity labels with molar extinction coefficients nearly 1000-fold higher than traditional benzophenone-based compounds.

2-6   11:50  An Unusual Photooxygen-Atom Exchange Reaction of Nitrosamines with Molecular Oxygen: Dependence on Nitrosamine Substituents AA Ghogare*, Brooklyn College and Graduate Center of the City University of New York ; C Debaz, Brooklyn College; I Abramova, Brooklyn College; E Greer, Baruch College; MS Oliveira, University of Sao Paulo; FM Prado, University of Sao Paulo; P Di Mascio, University of Sao Paulo; A Greer, Brooklyn College and Graduate Center of the City University of New York

Abstract: Despite the decades-long interest in N-nitrosamine organic chemistry and toxicity, no photochemical oxygen atom exchange process with molecular oxygen has been reported. Little is known of the peroxy intermediates involved in the direct photolysis of nitrosamines in the presence of molecular oxygen. This presentation describes results on scrambling of oxygen atoms in the photolysis of two of four nitrosamines in the presence of 18-O labeled oxygen gas. HPLC/MS and HPLC-MS/MS data show that 18-O labeled nitrosamines were generated for N-nitrosodiphenylaniline and N-nitroso-N-methylaniline. In contrast, nitrosamines N-butyl-N-(4-hydroxybutyl)nitrosamine and N-nitrosodiethylamine do not exchange the 18-O label and instead decomposed to amines and/or imines under the conditions. Our mechanistic proposal is the formation of nitrooxide, hexaoxadiazocane and trioxazetidine intermediates followed by an oxygen extrusion process to account for exchange of the oxygen atom label.



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