Innovative self-assembling nanodelivery systems to combat bacterial infections.
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Date
2020
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Abstract
The rising surge of bacterial resistance puts an immense economic and social strain on the
healthcare system worldwide. Unfortunately, the production of new antibiotics is
significantly outstripped by existing therapies that are losing their effectiveness. Limitations
associated with conventional dosage forms are one of the main contributing factors for
increasing antimicrobial resistance. Novel nano-drug delivery systems have immense
potential for overcoming antimicrobial resistance. This study broadly aimed to design
advanced materials and explore nano-based strategies for preparation of self-assembling
delivery systems to combat Staphylococcus aureus (S. aureus) and methicillin-resistant
Staphylococcus aureus (MRSA) infections. In this study, three novel self-assembling
systems; supramolecular amphiphilic Beta-cyclodextrin and Oleyl amine (BCD-OLA),
supramolecular self-assembled drug delivery system (SADDs) for enhancement of
vancomycin (VCM) delivery, and self-assembling PEGylated Fusidic acid (PEG-FA) as a
polymer therapeutic were designed, synthesized and employed for the formulation of nanodrug delivery systems for efficient delivery of antibiotics. All the newly synthesized systems
were confirmed and characterized by FTIR, DSC, NMR and molecular dynamic (MD)
simulations. The synthesized materials and the formulated delivery system were found to be
biosafe after exhibiting cell viability above 75% in all human cell lines tested using the MTT
assay. The formulated nano-based systems were evaluated for sizes, polydispersity indices
(PDI), zeta potential (ZP), surface morphology, drug release, in vitro and in vivo antibacterial
activity. The formulated BCD-OLA nanovesicles size was shown to be 119.8 ± 1.12 nm with
a PDI of 0.220 ± 3.98, and ZP of 25.8 ± 6.96 mV. The formulated SADDs for VCM delivery
displayed a size of 85.15 ± 0.4 nm with PDI of 0.131 ± 0.017 and ZP of -27 ± 1.3 mV. The
encapsulation efficiency of VCM in both formulated BCD-OLA and VCM/TS nano-system
was 40.2 ± 4.5% and 68.8 ± 2.8%, respectively. The release profile of the encapsulated drug
from both systems was found to have sustained release over a 48 h period. The selfassembled PEG-FA conjugate showed an average hydrodynamic diameter of 149.3 ± 0.21 nm
with PDI of 0.267 ± 0.012 and ZP of 5.97 ± 1.03 mV. HRTEM images revealed vesicular
structure for supramolecular BCD-OLA, and a homogenous spherical morphology for
formulated VCM/TS and PEG-FA nanoparticels (NPs). In vitro antibacterial activity for the
BCD-OLA nanovesicles, VCM/TS NPs and PEG-FA (NPs) showed enhancement in
antibacterial activity by 2- to 4-fold reduction in MIC against S. aureus and MRSA when
compared to the bare drug. Further intracellular and macrophage studies showed that VCM-
loaded BCD-OLA nanovesicles had an 8- and 459-fold reduction of intracellular bacteria
compared to the bare drug, respectively. There was a 9.5-fold reduction in the MRSA load in
mice skin treated with VCM/TS NPs in comparison with bare VCM (p = 0.0077). Human
serum albumin (HSA) binding studies using in silico molecular docking and Microscale
Thermophoresis showed that PEG-FA had very weak or no interaction with HSA (Kd =
14999 µM), which could prevent bilirubin displacement and reduce side effects. In summary,
these novel nano-drug delivery systems show potential for improving the treatment of
bacterial infections, which will be useful for addressing the crisis of resistant bacteria and
declining new antibiotics. The data from this study has resulted in three first-authored
international publications.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.