Browsing by Author "Omolo, Calvin Andeve."
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Item Design of advanced materials and nano delivery approaches for enhancing activity against Methicillin resistant Staphylococcus aureus.(2018) Omolo, Calvin Andeve.; Govender, Thirumala.; Mocktar, Chunderika.Infectious diseases, including bacterial infections, continue to be a significant cause of morbidity and mortality globally, antimicrobial resistance has further made them fatal. Limitations of conventional dosage forms have been found to be one of the contributing factors to antimicrobial resistance. Novel nano delivery systems are showing potential to combat antimicrobial resistance. The search for novel materials for 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 SA and MRSA infections. In this study two novel materials; a linear polymer dendrimer hybrid star polymer (3-mPEA) comprising of a generation one poly (ester-amine) dendrimer (G1-PEA) and copolymer of methoxy poly (ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL) and oleic acid based quaternary lipid (QL) were synthesized and characterized and Poloxamer 188 (P188) material available in the market were employed to formulate three nano drug delivery systems for efficient and targeted delivery of antibiotics. The synthesized materials and the drug delivery system were found to be biosafe after exhibiting cell viability above 75% in all the cell lines tested on using 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. Nanovesicles were formulated from 3-mPEA and they had sizes, PDI, ZP and entrapment efficiency of 52.48 ± 2.6 nm, 0.103 ± 0.047, -7.3 ± 1.3 mV and 76.49 ± 2.4%. respectively. QL lipid was employed to formulate vancomycin (VCM) loaded liposomes with Oleic acid based ‘On’ and ‘Off’” pH responsive switches for infection site and intracellular bacteria targeting. They were found to have the size of 98.88 ± 01.92 at pH 7.4. and exhibited surface charge switching from negative at pH 7.4 to positive charge accompanied by faster drug release at pH 6.0. Fusidic acid nanosuspension (FA-NS) with size, PDI and ZP of 265 ± 2.25 nm, 0.158 ± 0.026 and -16.9 ± 0.794 mV respectively was formulated from P188. The drug release profile from both the nanovesicles and liposomes was found to have sustained release. In vitro antibacterial activity for the nanovesicles, FA-NS and liposomes showed 8, 6 and 4-fold better activity at pH 7.4, while the liposome being a pH responsive antibacterial system at pH 6 showed 8- and 16- fold better activity against both Methicillin susceptible (MSSA) and resistant Staphylococcus aureus (MRSA) respectively when compared with the bare drugs. An in vivo BALB/c mice, skin infection model revealed that treatment with VCM-loaded nanovesicles, liposomes and FA-Ns significantly reduced the MRSA burden compared to bare drugs and untreated groups. There was a 20, 6.33 and 76-fold reduction in the MRSA load in mice skin treated with nanovesicles, liposomes and FA-NS respectively compared to those treated with bare VCM and fusidic acid. In summary, synthesized material showed to be biosafe and potential for the development of nano-based drug delivery systems of antibiotics against bacterial infections. The data from this study has resulted in one book chapter and 3 first authored and 3 co-authored research publications.Item Formulation of pH-responsive lipid-polymer hybrid nanoparticles for co-delivery and enhanced antibacterial activity of 18β-glycyrrhetinic acid and vancomycin against MRSA.(2020) Jaglal, Yajna.; Govender, Thirumala.; Omolo, Calvin Andeve.Background: Due to the rise in antimicrobial resistance and the challenges accompanied by conventional antibiotic dosage forms, there is a need for developing drug delivery systems that enhance, protect and potentiate the current antibiotics in the market. Furthermore, natural derivatives from plants have proven to be potent antimicrobial agents. Therefore, their combination with antibiotics could be effective in overcoming antimicrobial resistance. Aim: The aim of this study was to co-deliver vancomycin and 18β-glycyrrhetinic acid via pH-responsive lipid-polymer hybrid nanoparticles (VCM-GAPAH-LPHNPs) formulated from polyallylamine and oleic acid (OA) and to explore its potential for enhanced activity and targeted delivery. Methods: Molecular dynamics and stability studies were used to determine the stability of the oil and water phases independently as well as VCM-GAPAH-LPHNPs as a complex. VCM-GAPAH-LPHNPs were prepared using the micro-emulsion technique. The size, polydispersity index and zeta potential of VCM-GAPAH-LPHNPs were determined using the dynamic light scattering technique. Transmission electron microscopy analysis was conducted to determine the morphology of VCM-GAPAH-LPHNPs. The entrapment efficiency and drug loading were determined using the ultrafiltration method. Differential scanning calorimetry was used to determine the thermal profiles of VCM-GAPAH-LPHNPs and its components. In vitro drug release studies were performed using the dialysis bag technique. Drug release kinetics were analysed using the DDSolver program. Cytotoxicity of VCM-GAPAH-LPHNPs were determined using the MTT assay. Haemolysis of VCM-GAPAH-LPHNPs were performed at different concentrations using sheep blood. In vitro antibacterial activity of VCM-GAPAH-LPHNPs were determined against SA and methicillin-resistant Staphylococcus aureus (MRSA) at pH 6 and 7.4. Time killing assay was performed using the plate colony count method. MRSA biofilm study was performed using the crystal violet assay. Results: Molecular dynamics indicated VCM-GAPAH-LPHNPs to be stable. VCM-GAPAH-LPHNPs were successfully prepared using the micro-emulsion technique. VCM-GAPAH-LPHNPs size, polydispersity index, zeta potential and encapsulation efficiency were found to be 198.4 ± 0.302 nm, 0.255 ± 0.003, - 3.8 ± 0.335 mV and 69.46 ± 2.52 % respectively. Thermal profiles of lyophilized VCM-GAPAH-LPHNPs showed transformation from crystallization to amorphous form. In vitro drug release studies revealed that VCM-GAPAH-LPHNPs released 60% of VCM after 24 h whereas bare VCM released 90% of VCM after 24 h hence VCM-GAPAH-LPHNPs showed sustained drug release compared to bare VCM. At pH 6 VCM-GAPAH-LPHNPs released 82% of VCM after 24 h whereas at pH 7.4 VCM-GAPAH-LPHNPs released 60% of VCM after 24 h indicating VCM-GAPAH-LPHNPs had a faster drug release at pH 6 compared to pH 7.4. The Weibull model was considered the best fit model for VCM-GAPAH-LPHNPs. The MTT assay revealed 75% > cell viability which indicated VCM-GAPAH-LPHNPs to be non-cytotoxic. At 0.5 mg/ml VCM-GAPAH-LPHNPs showed < 1% haemolysis. Stability studies at 4 °C and room temperature indicated VCM-GAPAH-LPHNPs to be stable. In vitro antibacterial activity against MRSA treated with VCM-GAPAH-LPHNPs demonstrated a 16-fold lower minimum inhibitory concentration than bare VCM at acidic conditions. The time-killing assay study at 12 h revealed that VCM-GAPAH-LPHNPs eliminated 100% of MRSA cells whereas bare VCM eliminated 55% of MRSA cells. The crystal violet assay analysis revealed VCM-GAPAH-LPHNPs ability to eliminate MRSA biofilms. Conclusion: VCM-GAPAH-LPHNPs could effectively treat MRSA infections at a faster rate as compared to bare VCM. Therefore, this novel pH-responsive LPHNPs may serve as a promising nanocarrier for enhancing antibiotic delivery and antibacterial activity.