Designed positively charged cyclodextrin hosts with enhanced binding of penicillins as carriers for the delivery of antibiotics: The case of oxacillin

Marco Agnes; Angelos Thanassoulas; Polychronis Stavropoulos; George Nounesis; Georgios Miliotis; Vivi Miriagou; Evita Athanasiou; Gabor Benkovics; Milo Malanga; Konstantina Yannakopoulou

doi:10.1016/j.ijpharm.2017.04.080

Designed positively charged cyclodextrin hosts with enhanced binding of penicillins as carriers for the delivery of antibiotics: The case of oxacillin

Int J Pharm. 2017 Oct 15;531(2):480-491. doi: 10.1016/j.ijpharm.2017.04.080. Epub 2017 May 1.

Affiliations

¹ Institute of Nanoscience and Nanotechnology, National Center for Scientific Research "Demokritos", Patr. Grigoriou E' & 27 Neapoleos str., 15341, Agia Paraskevi, Greece.
² Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety, National Center for Scientific Research "Demokritos", Patr. Grigoriou E' & 27 Neapoleos str., 15341, Agia Paraskevi, Greece.
³ Laboratory of Bacteriology, Hellenic Pasteur Institute, Vas. Sophias 127, Athens, 11521, Greece.
⁴ Laboratory of Cellular Immunology, Hellenic Pasteur Institute, Vas. Sophias 127, Athens, 11521, Greece.
⁵ CycloLab SA, Cyclodextrin R&D Ltd., H-1097 Illatos út 7, Budapest, Hungary.
⁶ Institute of Nanoscience and Nanotechnology, National Center for Scientific Research "Demokritos", Patr. Grigoriou E' & 27 Neapoleos str., 15341, Agia Paraskevi, Greece. Electronic address: k.yannakopoulou@inn.demokritos.gr.

PMID: 28473235
DOI: 10.1016/j.ijpharm.2017.04.080

Abstract

In an effort to identify the optimal cyclodextrin (CD) host for delivery of penicillins to mammalian cells that will also offer protection against β-lactamase-induced hydrolysis, nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC) have been employed to study the inclusion complexes formed in aqueous solution between designed CD derivatives and two aminopenicillins, ampicillin and amoxicillin, and two antistaphylococcal penicillins, methicillin and oxacillin. Anionic and cationic thioether-substituted-β- and -γCD derivatives were thus synthesized and compared with the neutral, parent CDs for complexation with the penicillins. The synthesized derivatives were shown to present ∼20% elongated cavity space in solution. Moreover, the cationic ones are >98% protonated at physiological pH. The most efficient host was the positively charged octakis[6-(2-aminoethylthio)-6-deoxy]-γ-CD (γCys) that formed the strongest complex with oxacillin (K_b ∼1700M^-1) in an enthalpically and entropically favorable process (ΔH_b=-10.5kJ/mol,TΔS_b=8.0kJ/mol). In vitro biological tests demonstrated that γCys reduces 2.3-fold the rate of hydrolysis of oxacillin in the presence of oxa-1 β-lactamase while displaying cell crossing capability and efficient internalization into macrophages as well as a sufficiently safe cytotoxicity profile. Overall, γCys could be considered as a promising vehicle for protection and delivery of oxacillin.

Keywords: Amoxicillin (PubChem CID: 33613); Ampicillin (PubChem CID: 6249); ITC; Methicillin (PubChem CID: 6087); NMR; Octakis[6-(2-carboxyethyl)thio-6-deoxy]-γ-CD (γPSP, Sugammadex: PubChem CID:6918584); Oxa-1 beta-lactamase; Oxacillin; Oxacillin (PubChem CID: 6196); Penicillins; Positively charged cyclodextrin; pK(a); β-cyclodextrin (PubChem CID: 444041); γ-cyclodextrin (PubChem CID: 5287407).

MeSH terms

Animals
Anti-Bacterial Agents / administration & dosage*
Cell Line
Cyclodextrins / chemistry*
Drug Carriers / chemistry*
Macrophages
Mice
Oxacillin / administration & dosage*
beta-Lactamases

Substances

Anti-Bacterial Agents
Cyclodextrins
Drug Carriers
beta-lactamase OXA-2
beta-Lactamases
Oxacillin