Multimodal photoresponsive nanoassemblies of an amphiphilic calix[4]arene for antibacterial applications

Multimodal Photoresponsive Nanoassemblies of an amphiphilic Calix[4]arene for Antibacterial Applications Ivana Di Bari,a Anna Rita Blanco,b Roberta Picciotto,b Grazia M. L. Consoli,c Salvatore Sortino.a a Department of Drug Science, University of Catania, V.le A. Doria 6, 95125, Catania, Italy; b SIFI S.p.a., Via E. Patti 36, 95020, Lavinaio - Aci S. Antonio, Italy; cCNR-Institute of Biomolecular Chemistry, Via P. Gaifami 18, 95126, Catania, Italy. ivanadibari@hotmail.it. Photodynamic Therapy (PDT) is based on the administration of a photosensitizing agent (PS) that generates mainly the highly reactive singlet oxygen (1O2), leading to oxidative damage and cell death. However, many PSs have a hydrophobic nature, which favors their aggregation in aqueous medium strongly precluding their photochemical behavior.1 The entrapment of PS in nanocarriers permits to overcome these drawbacks and ensures protection from degradation, site-specific delivery, enhanced bioavailability, increased local concentration. Combination of PDT with other photogenerated cytotoxic species such as nitric oxide (NO) is particularly attractive, as NO possesses excellent anticancer and antibacterial properties. 1O2 and NO are able to react with different biological substrates, do not suffer multidrug resistance problems and, due to their short half-life in blood (<1s), lack of charge and small sizes, they can diffuse in the cellular environment over short distances (<200 ?m), confining their region of action and reducing side effects. Moreover, since the NO photorelease from NO photodonors is independent from O2 availability it can potentially very well complement the 1O2 effects at the onset of hypoxic conditions typical of some tumors and infections by anaerobic bacteria.2 Synthetic versatility and good biocompatibility are crucial requisites which make the calixarene macrocycles appealing in pharmaceutical and biomedical field.3 In the search of novel antibacterial strategies designed to simultaneously address problems of antibiotic resistance and biofilm formation, we achieved the first example of calixarene (CA)-based nanocontainers incorporating multiple photoresponsive agents (Fig. 1). The capability of the obtained nanosystems to generate 1O2 and/or NO upon to irradiation was investigated directly and in real time by means infrared luminescence spectroscopy and photoamperometric techniques. The light-stimulated bactericidal effect was successfully tested on Gram positive and Gram negative bacteria. Enhancement of NO photorelease, due to the action of the CA assembly as a nanoreactor, size, and the presence of targeting groups on the surface of CA the open new perspectives for antibacterial application in nanomedicine. Figure 1. Schematic representation of a CA-based photoresponsive nanosystem. 1.K. Lang, J. Monsinger, D. M. Wagnerovà, Coordin. Chem. Rev., 2004, 248, 321. 2.A. Fraix, N. Marino, S. Sortino, Topics Curr. Chem., 2016, 370, 225. 3.S. B. Nimse, T. Kim, Chem. Soc. Rev., 2013, 42, 366.