Search

LAT-1, the large neutral amino acid transporter-1, plays a crucial role in cancer growth and proliferation, making it a promising biomarker for imaging and treating human malignancies such as brain cancers. Thus, growing attention is being paid to the development of LAT-targeted drug delivery systems with blood-brain penetration ability [1, 2]. For this purpose, gold nanoparticles (AuNPs) functionalized with L-DOPA have been developed [1]. The great potential of such systems to be used in brain cancer therapy prompts the need for evaluation of the processes occurring at the nano-bio interface [3]. In the presence of gold salts, L-DOPA can undergo various transformations such as oxidation, cyclization, and polymerization [4]. To avoid binding structurally altered molecules to the nanosurface and prevent any negative impact on human health, it is important to consider these transformation patterns. This study aimed to investigate the behavior of L-DOPA upon interaction with a gold nanosurface by using a combination of nuclear magnetic resonance (NMR) spectroscopy and computational methods. Experimental results showed that the final form of L-DOPA on the AuNPs surface is dependent on the molar ratio of reactants used during synthesis. When there was an excess of L-DOPA compared to Au, no alterations in the structure of L-DOPA were observed. However, an excess of Au was found to promote the oxidation of L-DOPA, which could result in various oxidation products being bound to the gold nanosurface. NMR spectra revealed that L-DOPA underwent intramolecular cyclization but could not differentiate oxidation products. On the other hand, computational simulations using density functional theory (DFT) and molecular dynamics (MD) techniques identified the most probable oxidation products for binding to the AuNP surface. The highest affinity to gold nanosurface was obtained for dopachrome compared to its tautomer and leukodopachrome. The obtained results represent valuable mechanistic data about the binding events at the surface of AuNPs to encourage their application as a drug-delivery systems in cancer therapy

The great potential of gold nanoparticles (AuNPs) functionalized with catechols, dopamine and L-DOPA, in biomedical applications prompts the need for evaluation of their interaction at the nano-bio interface.[1] In the presence of gold slats, catechols are known to transform by various pathways including oxidation, cyclization and polymerization.[2] Thus, different transformation patterns should be considered in order to avoid binding the structurally changed molecule to the nanosurface while preventing unpredictable consequences for the health status of an organism. In this study, the fate of functionalization agents upon interaction with gold nanosurface was investigated by combining nuclear magnetic resonance (NMR) spectroscopy and a computational approach. Experimental results revealed that the final form of catechol on the AuNPs nanosurface depends on the molar ratio of reactant used in synthesis. The oxidation of both L-DOPA and dopamine was promoted in the case of molar excess of Au. However, their final products differ as L-DOPA underwent intramolecular cyclization. Computational simulations using density functional theory (DFT) and molecular dynamics (MD) methods revealed the mechanism that stays behind this difference and clarified the most likely candidates, among different oxidation products, for binding to the AuNPs surface. The obtained results represent valuable mechanistic data about the binding events at the surface of AuNPs to encourage their application in biomedicine.

Octapeptins are cyclic lipopeptides that do not exhibit cross-resistance with polymyxins and have a broader spectrum of activity that includes fungi and Gram-positive bacteria. In the present study we investigated the interaction of octapeptin A3 with asymmetric outer membrane models of the Gram-negative pathogen Pseudomonas aeruginosa, using neutron reflectometry, together with fluorimetric and calorimetry methods. For the first time our neutron reflectometry results reveal that the interaction of octapeptin A3 with the Gram-negative outer membrane involves an initial transient polar interaction with the phospholipid and lipid A head groups, followed by the penetration of the entire octapeptin molecule into the fatty acyl core of the outer membrane. This mechanism contrasts that of polymyxin B which specifically targets lipid A, whereas octapeptins appear to target both lipid A and phospholipids. Furthermore, the mechanism of octapeptins does not appear to be highly dependent on an initial complimentary electrostatic interaction with lipid A, which accounts for their ability to bind to the lipid A of polymyxin-resistant Gram-negative bacteria which is modified with cationic moieties that act to electrostatically repel the cationic polymyxin molecule. The presented findings shed new light on the mechanism whereby octapeptins penetrate the outer membrane of polymyxin-resistant Gram-negative pathogens and highlight their potential as candidates for development as new antibiotics against problematic multi-drug resistant pathogens.