Nanotherapeutics to combat infections.
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Date
2019
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Abstract
The rise of drug resistant microorganisms is threatening the ability of antimicrobials to treat
infectious diseases including bacterial infections, thus becoming a significant cause for
premature mortality. Limitations associated with conventional dosage forms are one of the
contributing factors for increasing antimicrobial resistance. Novel nano-drug delivery systems
are showing considerable potential to combat antimicrobial resistance. The application of
advanced novel materials for the efficient delivery of antibiotics is an active research area. The
aim of the study was to design and synthesize advanced materials, and explore nano-based
strategies for preparations of novel drug-delivery systems to treat MRSA infections. In this
study, two sets of novel amphiphiles; fatty acid based pyridinium cationic amphiphiles (FCAs)
and novel hyaluronic acid-oleylamine (HA-OLA) conjugates were synthesized and
characterized. The synthesized novel amphiphiles were employed to formulate two nano-drug
delivery systems for efficient delivery of vancomycin (VCM) to treat S. aureus and MRSA
infections. The synthesized materials were found to have inherent antibacterial activity on
tested bacterial strains and proven to be biosafe after exhibiting cell viability above 75% on all
tested mammalian cell lines using MTT assay. The formulated nano-systems were
characterized in terms of particle sizes, polydispersity indices (PDI), zeta potential (ZP),
surface morphology, in vitro and in vivo (VCM loaded OCA vesicles) antibacterial activity.
Oleic based cationic amphiphile (OCA) was employed to construct VCM loaded OCA vesicles,
and had sizes, PDI, ZP and entrapment efficiency of 132.9 ± 2.5 nm, 0.167 ± 0.02, 18.9 ± 1.2
mV and 61.24 ± 1.8%, respectively. VCM loaded polymersomes prepared using HA-OLA6
had sizes, PDI, ZP and entrapment efficiency of 248.7 ± 3.08 nm, 0.189 ± 0.01, -17.6 ± 0.6 mV
and. 43.12 ± 2.18%, respectively. The drug release from VCM loaded OCA vesicles and VCM
loaded HA-OLA polymersomes (VCM-PS6) was sustained throughout the studied period of
72 h. From in vitro antibacterial studies, both FCAs and HA-OLA conjugates showed
bactericidal activity against the tested bacterial strains. Both VCM loaded OCA vesicles and
VCM-PS6 displayed 4-fold enhanced antibacterial activity against MRSA, when compared to
bare VCM. Furthermore, synergism was observed between VCM and synthesized novel
amphiphiles (FCAs and HA-OLA conjugates) in nano-formulations against MRSA. An in vivo
BALB/c mice skin infection model revealed that, treatment with VCM loaded OCA vesicles
significantly reduced the MRSA burden compared to bare drugs and untreated groups. There was 4.2-fold reduction in the MRSA load in mice skin treated with VCM loaded OCA vesicles
compared to those treated with bare VCM. In summary, synthesized novel materials showed
good biosafety, antibacterial activity and drug delivery potential via nano-systems against
bacterial infections. The data from this study has resulted in one first authored review article,
two first authored and one co-authored research publications.
Description
Doctoral Degree. University of Kwazulu-Natal, Durban.