Antimicrobial resistance threatens the effective treatment of increasing range of bacterial infections and it is increasingly becoming a serious threat to public health. Without new effective antibiotic formulations, the success of major surgery and cancer chemotherapy would be compromised. For instance, patients with MRSA (methicillin-resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection. Nano drug delivery systems like nanoparticles have earned enormous importance in biomedical research due to their ease of synthesis, versatile functionalization and advancing theranostics. They can also enhance antibiotic therapy and overcome bacterial resistance mechanisms by targeting the drug to the infection site. New generation nanoparticles are further being developed to be specifically responsive to the acidic conditions at infection sites to improve targeting, reduce drug loss and increase expsoure of bacteria to the drug.
University of KwaZulu-Natal researchers in South Africa led by Professor Thirumala Govender and Dr. Rahul Kalhapure successfully synthesized a novel gemini surfactant, AGS 7, based on oleic acid tails (hydrophobic portion) and anionic sodium carboxylate head groups (hydrophilic portion). They found AGS 7 a good solubilizer and stabilizer for colloidal formulations and therefore they used it in formulating vancomycin in chitosan nanoparticles. Their study was the first to report the use of gemini surfactant in developing a pH-responsive antibiotic delivery system. In the current studies, a series of experiments were conducted in vitro and in vivo for the charactrization of the new formulation and its antibacterial activity.
When the authors tested their AGS 7 in an array of cell lines (MCF7 human breast adenocarcinoma, A549 human alveolar basal epithelial adenocarcinomia cells and HepG2 human liver hepatocellular carcinoma cell lines) no toxicity was observed. These results opened the way for exploring AGS 7 in preparation of pH-responsive vancomycin loaded chitosan nanoparticles for biological applications.
When the research team looked at the cumulative amount of vancomycin free base released from the formulation at acidic pH 6.5 and the physiological pH 7.4 they observed 3-fold greater cumulative drug release in acidic pH than physiological pH after just 30 min. The larger drug release at acidic pH continued at prolong time of 24 hour incubation. Vancomycin release was found to be concentation independent at both pH values with zero order kinetics suggesting a constant release rate.
The advantageous criteria of having pH-responsive drug release was possibily due to the decrease in ionization of their surfactant AGS 7 under mildly acidic conditions, resulting in a destabilization of the nanoparticles’ structure
When the resesarch team tested the formulation against S. aureus and their resistant counter (methicillin-resistant Staphylococus aureus, MRSA) at different pH conditions, they found a pronounced antibacterial activity. In acidic pH the vancomycin loaded chitosan nanoparticles stabilized by AGS 7 triggered the release of more vancomycin making it 4 -times potent against S. aureus at acidic pH than at physiological pH. Moreover, the effect was larger in the clinically relevant MRSA where the concentration released resulted in 8 times more activity at acidic pH compared to pH 7.4. The authors also conducted animal studies in skin infection mice disease model to confirm the in vitro results. The injected formulation showed 8 times less MRSA colonies and reduced tissue skin inflammation than control (vancomycin alone). The researchers explained the positive results of the enhanced therapeutic activity of their formulation to the decrease in the ionization of AGS7 in acidic pH at the infection site. Moreover, the attachment of protonated amino groups to the negatively charged bacterial cell wall which will trigger vancomycin release from destablized nanoparticle structure.
Prof Govender acknowledged her research team for the succesful development of the novel and safe ionic gemini surfactant, AGS 7, that can be used in formulating pH sensitive nanoantibiotics which can be used to overcome the challenges with rising antimicrobial resistance.
Rahul S. Kalhapure
Dr. Rahul S. Kalhapure earned his PhD from Institute of Chemical Technology (ICT), Mumbai, India. His area of research is on the development of novel biocompatible materials (heterolipids, surfactants, polymers and dendrimers) and complexes of small drug molecules for performance efficient nano drug delivery systems and novel transdermal permeation enhancers. He is currently a researcher at the University of Texas at El Paso, USA. Based on his research accomplishments, University of KwaZulu-Natal, Durban, South Africa has appointed him as an Honorary Research Fellow. In South Africa he was the recipient of prestigious NRF-DST Innovation Postdoctoral Fellowship awarded in recognition of research excellence. His current main areas of interests are synthesis of novel biocompatible excipients, dendritic materials and formulation development of nano drug delivery systems with enhanced performance. Dr. Kalhapure is therefore uniquely skilled both in synthetic chemistry and formulation of novel drug delivery systems. Dr. Kalhapure was bestowed with the “ICT Golden Jubilee Innovative PhD (Tech.) Thesis award” from the ICT, Mumbai, for the best thesis in chemical technology. At this early career level, Dr. Kalhapure has 39 publications in discipline-specific high impact factor journals and several presentations in local and international conferences. He also continues to be a reviewer for several leading international peer-reviewed journals.
Thirumala Govender completed a PhD in Nanotechnology at University of Nottingham (UK) after being awarded a Commonwealth Scholarship. Her current research on novel delivery systems focuses on nanotechnology and alternate routes of drug delivery. She has published widely in top ranked international journals on the successful formulation of various novel drug delivery systems as well as the design of new pharmaceutical excipients for various communicable and non-communicable disease conditions. She is currently Professor of Pharmacy in the Discipline of Pharmaceutical Sciences, Head of the Drug Delivery Research Unit and Head of the NanoHealth Pillar of the UKZN Nanotechnology Platform at UKZN. In recognition of her scientific expertise in pharmaceutical technology, Prof Govender is currently appointed as an Expert Evaluator on the Medicines Control Council of South Africa for the quality evaluation of new medicines for regulatory approval. Prof Govender is also a past Vice Chair of the Academy of Pharmaceutical Sciences of South Africa. She has won several awards locally and internationally for excellence in research and teaching.
Kalhapure, R. S., Jadhav, M., Rambharose, S., Mocktar, C., Singh, S., Renukuntla, J., & Govender, T. (2017). pH-responsive chitosan nanoparticles from a novel twin-chain anionic amphiphile for controlled and targeted delivery of vancomycin. Colloids and Surfaces B: Biointerfaces, 2017, 158, 650-657.