NO-releasing cyclodextrins

Nitric oxide (NO) is a signaling molecule produced by almost all types of organisms ranging from bacteria to plants and animal cells. It is a neurotransmitter with important role in vasodilation, respiration, inflammation, defensive reaction of the organism.

NO is known to have both pro- and antineoplastic effects. Low concentrations of NO are reported to promote tumor growth, whereas high NO influx acts as a potent tumor repressor, leading to cytotoxicity and apoptosis. [1] There is increasing interest in developing NO-releasing materials as potent anti-tumor agents in which high and localized concentrations of NO may be directly released in a sustained manner to the tumor site. NO-releasing CDs, especially the stimuli-responsive systems have been in the focus of research in the past few years, because they represent dual effects: in addition to NO-release they act as drug delivery systems via complexation of the active ingredient in the CD cavity.

The earliest publication reported on S-nitroso-N-acetylpenicillamine-β-cyclodextrin, which demonstrated excessive NO release causing the disruption of blood-brain barrier (BBB), typical in neurodegenerative diseases such as meningitis. [2]

6‐Mono‐ and 6‐multi‐S‐nitroso‐β‐cyclodextrins release NO upon thermal and photochemical trigger and release the encapsulated drug molecules upon dilution.[3] The recently published N-diazeniumdiolate-modified CD derivatives capable of delivering promethazine is another example for the bimodal action. [4]

NO-releasing nanovehicle was obtained by the assembly of α-CD-modified MoS₂ nanosheets with a heat‐sensitive NO donor N,N′‐di‐sec‐butyl‐N,N′‐dinitroso‐1,4‐phenylenediamine (BNN6). [5] When stimulated by laser irradiation, the MoS₂‐BNN6 nanovehicle not only exhibits efficient photothermal therapy but also can precisely control NO release, generating oxidative/nitrosative stress resulting in antibacterial and wound-repairing functions.

Even a third function was incorporated into β-CD conjugate bearing an anthracene moiety and a nitroaniline derivative within the primary side and positively charged functions (quaternary amino moieties) on the secondary side to ensure solubility. [2,6] It shows anticancer and antibacterial effect through the visible light-controlled release of NO and singlet oxygen and can also deliver anticancer drugs or antibacterial agents complexed within the CD cavity to further strengthen the favorable therapeutic effects. The anthracene moiety has another important role: its fluorescence is used for imaging to follow the fate of this drug delivery system within living cells and organisms. This multifunctional system with fluorescence reporting is a promising candidate in biopharmaceutical research.

Another multifunctional β-CD derivative was prepared by conjugating the NO-releaser nitroaniline and a bimannoside moiety as a targeting unit for mannose binding receptors on a β-CD scaffold. The interesting feature of this derivative, that it shows supramolecular aggregation in aqueous solution which directly leads to increased NO-release upon laser-irradiation and to enhanced receptor binding. Due to these advantageous properties this derivative holds great promises in the development of photoactive antimicrobials against antibiotic resistant bacteria. [7]

1. Saebra, A.B., de Lima, R., Calderón, M. Nitric oxide releasing nanomaterials for cancer treatment. Current status and perspectives. Current Topics in Medicinal Chemistry 2015, 15, 298–308.
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2. Boje, K.M.K., Lakhman, S.S. Nitric oxide redox species exert differential permeability effects on the blood-brain barrier. Journal of Pharmacology and Experimental Therapeutics 2000, 293(2), pp. 545-550
3. Piras, L., Theodossiou, T.A., Manouilidou, M.D., Sortino, S., Yannakopoulou, K. S-nitroso-β-cyclodextrins as new bimodal carriers: Preparation, detailed characterization, nitric-oxide release, and molecular encapsulation Chemistry – An Asian Journal 2013, 8(11), pp. 2768-2778. https://doi.org/10.1002/asia.201300543
4. Jin, H., Yang, L., Ahonen, M.J.R., Schoenfisch, M.H. Nitric Oxide-Releasing Cyclodextrins. Journal of the American Chemical Society 2018, 140, 14178–14184. https://pubs.acs.org/doi/10.1021/jacs.8b07661
5. Gao, Q., Zhang, X., Yin, W., Ma, D., Xie, C., Zheng, L., Dong, X., Mei, L., Yu, J., Wang, C., Gu, Z., Zhao, Y. Functionalized MoS₂ Nanovehicle with Near-Infrared Laser-Mediated Nitric Oxide Release and Photothermal Activities for Advanced Bacteria-Infected Wound Therapy. Small 2018, 1802290. https://doi.org/10.1002/smll.201802290
6. Benkovics, G., Perez-Lloret, M., Afonso, D., Darcsi, A., Béni, Sz., Fenyvesi, É., Malanga, M., Sortino, S. A multifunctional β-cyclodextrin-conjugate photodelivering nitric oxide with fluorescence reporting. International Journal of Pharmaceutics 2017, 531(2), 614-620. https://doi.org/10.1016/j.ijpharm.2017.05.023
7. Cutrone, G., Benkovics, G., Malanga, M., Sortino, S., García-Fuentes, L., Casas-Solvas, J. M., Fenyvesi, E., Vargas-Berenguel, A. Mannoside and 1,2-mannobioside β-cyclodextrin-scaffolded NO-photodonors for targeting antibiotic resistant bacteria
   Carbohydrate Polymers, 2018, 199, 649-660. https://doi.org/1016/j.carbpol.2018.07.018