Supramolecular amphiphiles of Beta-cyclodextrin and Oleylamine for enhancement of vancomycin delivery

Abstract

The global threat of antimicrobial resistant strains calls for innovative strategies to utilize nano drug delivery systems to enhance the delivery of antibiotics, thus reducing the development of resistance. Supramolecular amphiphiles that can self-assemble into nanostructures are one such nano delivery system, that are showing potential for effective drug delivery. The aim of this study was to synthesize and formulate a novel sugar-based cationic amphiphile (BCD-OLA) derivative from a Beta-cyclodextrin (BCD) head and long C18 carbon chain with a terminal amine; oleylamine (OLA), using inclusion complexation for application in antibiotic delivery. A suspension method was used for preparing the BCD-OLA amphiphile, which was then utilized for the formulation of nanovesicles. The complexation of BCD-OLA was confirmed by FTIR, ¹H NMR, 2D NMR NOESY spectrum and molecular dynamic (MD) simulations. Thereafter, biosafety was evaluated using the in vitro MTT cytotoxicity assay. Size, zeta potential (ZP), polydispersity index (PDI), entrapment efficiency, in vitro drug release and antimicrobial activity of BCD-OLA-loaded nanovesicles was also evaluated. MD of the BCD-OLA simulation showed that the mechanism responsible for amphiphile formation was through hydrophobic inclusion of OLA in BCD. MTT results showed cell viability of 75-100%, thus affirming biosafety of BCD-OLA complex. TEM images showed the self-assembled structures to be vesicles. The formulated nanovesicles size was shown to be 125.1 ± 8.30 nm with a PDI of 0.231 ± 0.05, and ZP of 19.3 ± 9.20mv. The encapsulation efficiency of vancomycin was 40.2 ± 4.5%. Vancomycin release from the nanovesicles was found to be sustained, with an 80% release over a 48 h period. The in vitro antibacterial test showed that the BCD-OLA had a 2- and 4-fold lower MIC against Staphylococcus aureus (SA) and Methicillin-resistant Staphylococcus aureus (MRSA), respectively, compared to bare vancomycin. Further, intracellular and macrophage studies showed that the system had a 459-fold reduction of intracellular bacteria using infected human embryotic kidney cells (HEK), and an 8-fold reduction in infected macrophages, contrast with bare vancomycin. These discoveries affirmed the potential of the BCD-OLA complex as a promising biosafe effective nanocarrier for antibiotic delivery.

Keywords: Cyclodextrin; Inclusion complex; MRSA; Nanovesicles; Supramolecular amphiphiles.