DOI: 10.1002/asia.201200640 A Host–Guest Supramolecular Complex with Photoregulated Delivery of Nitric Oxide and Fluorescence Imaging Capacity in Cancer Cells Noufal Kandoth, [a] Milo Malanga, [b] Aurore Fraix, [a] Lµszló Jicsinszky, [b] Éva Fenyvesi,* [b] Tiziana Parisi, [c] Ivana Colao, [c] Maria Teresa Sciortino, [c] and Salvatore Sortino* [a] Introduction Nitric oxide (NO) is one of the most appealing and studied molecules in the fascinating realm of the biomedical scien- ces. [1] Besides its pivotal role in the maintenance and biore- gulation of vital functions including neurotransmission, hor- mone secretion, and vasodilatation in living bodies, [2] this ephemeral free radical has recently stimulated an upsurge of interest because of its promising antioxidant, antibacterial, and anticancer activity. [3–5] These exciting discoveries have made the development of new strategies and methods for NO delivery a hot topic [6] with the intriguing prospect to tackle important diseases, especially cancer. [7] The biological effects of NO have been shown to be highly site-, concentra- tion-, and dosage-dependent, creating a complex role for this molecule in opposing beneficial and deleterious events. [8] This dichotomy has made the light-controlled NO donors much more appealing than those based on spontane- ous thermolysis for potential use in nanomedicine. [9] Light is in fact the most elegant and finely tunable external input for the non-invasive introduction of therapeutic agents in a de- sired biological environment, mimicking an “optical syringe” with an exquisite spatiotemporal control. [10] In addition to providing fast reaction rates, light triggering represents a “bi- ofriendly” and easily manipulated reactant, and offers the great benefit of not affecting physiological parameters such as temperature, pH, and ionic strength, a fundamental requi- site for biomedical applications. [10] Due to its half-life of approximately 5 seconds in tissues, its very small size, its lack of charge, and its lipophilic char- acter, NO is capable to diffuse some micrometers (40– 200 mm) in the cellular environment. Therefore, this radical species offers the advantage to confine its reactivity in the restricted region of space where it has been photogenerated. Furthermore, the NO radical is able to attack biological sub- strates of different nature like the plasma membrane, [11] the mitochondria, [12] and the cell nucleus, [13] thus representing a multitarget cytotoxic agent and avoiding problems of mul- tidrug resistance encountered with several conventional an- ticancer drugs. Finally, since the NO release from NO pho- todonors is independent from O 2 availability, the NO-photo- stimulated therapy can potentially very well complement the photodynamic therapy, in which the phototoxicity mech- anism is entirely dependent on the presence of oxygen, [14] at the onset of hypoxic conditions. The cell-penetrating property of the NO photodonors is another indispensable prerequisite to be fulfilled in NO- based therapy. This issue has inspired an intense research activity devoted to develop biocompatibile vehicles. [6a, 9a] Cy- Abstract: Herein we report the design, preparation, and properties of a supra- molecular system based on a tailored nitric oxide (NO) photodonor and a rhodamine-labeled b-cyclodextrin conjugate. The combination of spectro- scopic and photochemical experiments shows the absence of significant inter- chromophoric interactions between the host and the guest in the excited states. As a result, the complex is able to re- lease NO under the exclusive control of visible light, as unambiguously dem- onstrated by direct detection of this transient species through an ampero- metric technique, and exhibits the typi- cal red fluorescence of the rhodamine appendage. The supramolecular com- plex effectively internalizes in HeLa cancer cells as proven by fluorescence microscopy, shows a satisfactory bio- compatibility in the dark, and induces about 50 % of cell mortality upon irra- diation with visible light. The conver- gence of all these properties in one single complex makes the present host–guest ensemble an appealing can- didate for further delevopment of pho- toactivatable nanoscaled systems ad- dressed to photostimulated NO-based therapy. Keywords: cyclodextrins · fluores- cence · nitric oxide · phototherapy · supramolecular chemistry [a] N. Kandoth, Dr. A. Fraix, Prof. S. Sortino Laboratory of Photochemistry, Department of Drug Sciences University of Catania Viale Andrea Doria 6, I-95125 Catania (Italy) Fax: (+ 39) 095-580138 E-mail : ssortino@unict.it [b] M. Malanga, Dr. L. Jicsinszky, Dr. É. Fenyvesi CycloLab Ltd. Illatos fflt 7, H-1097 Budapest (Hungary) E-mail: fenyvesi.e@cyclolab.hu [c] T. Parisi, I. Colao, Dr. M. T. Sciortino Dipartimento di Scienze della Vita Sezione di Scienze Microbiologiche Genetiche e Molecolari Università di Messina Salita Sperone, I-98166 Messina (Italy) 2888 # 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2012, 7, 2888 – 2894 FULL PAPER