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Bioinspired filomicelles for the effective delivery of antibiotics

Primary Supervisor: Dr Kogularamanan (Rama) Suntharalingam, Department of Chemistry

Secondary supervisor: Dr James Hodgkinson

PhD project title: Bioinspired filomicelles for the effective delivery of antibiotics

University of Registration: University of Leicester

Project outline:

Background. Antibiotics are drugs that are used to prevent and treat bacterial infections. Antibiotic resistance occurs when bacteria modify their response to antibiotics, making them less effective or even redundant. According to the World Health Organization, antibiotic resistance is a major, unmet health challenge. There is now a growing list of bacterial infections namely, pneumonia, tuberculosis, blood poisoning, gonorrhoea and foodborne diseases that are becoming harder to treat due to the ineffectiveness of antibiotics at their administered doses. One of the reasons for this is the relatively long courses needed to treat infections. This is borne from the inability to safely administer shorter courses with higher doses. Most antibiotics are not designed to specifically target bacterial infection sites, but instead have a global effect, and thus can suffer from systematic toxicity. Therefore if antibiotics can be safely delivered to bacterial infection sites at higher doses, the course of treatment can be reduced.

Nanoscale technologies offer a method to unambiguously deliver antibiotics to their site(s) of action.[1] Further, nano-systems increase drug solubility, bioavailability, and extend drug half-life over small molecule antibiotics. Several nanoparticle formulations have been investigated for drug delivery, including those based on iron oxide, carbon, gold, hydrogels, liposomes, and polymers. Polymeric nanoparticles are of particular interest due to their biocompatibility, synthetic versatility, and tuneable properties. We have previously used polymeric nanoparticles to successfully deliver anticancer agents to target cells.[2,3] Most polymer-based nanoparticles are spherical, however, biometric studies have shown that filomicelles, inspired by naturally occurring filament-like filoviruses, benefit from longer circulation time, higher accumulation into disease site(s), and enhanced active target delivery compared to conventional spheroidal nanoparticles.[4,5]

Objectives and methods. This project will develop “worm-like” nanoparticles (filomicelles), based on naturally occurring viruses like Ebola and Marburg, to delivery high doses of antibiotics to bacterial infection sites. The filomicelles will be made up of polymers functionalised with different permutations and ratios of antibodies specific for proteins on the outer membrane of specific bacteria strains. This will enable pattern based recognition of specific bacteria strains, and facilitate safe, selective, and personalised delivery. The streamline nature of the filomicelles will also enable deeper penetration into bacterial infection sites (and more generally, entry into areas in the human body that is inaccessible to traditional antibiotics). The long-term outcomes of this project will inform the way antibiotics are administered to patients.

Biocompatible and biodegradable amphiphilic polymers will be used to construct the filomicelles. Filomicelles will be self-assembled and loaded with clinically-used and investigational antibiotics using biophysical techniques. The antibiotic encapsulation efficiency will be determined by spectroscopic and analytic methods (UV-Vis and ICP-MS). Filomicelle size and polydispersity will be probed using spectroscopic (DLS) and high-resolution imaging techniques (at the Advanced Microscopy Facility and the Midlands Regional Cryo-EM Facility). Antibiotic release, under physiological conditions, will be studied by dynamic dialysis. To specifically deliver drugs to bacterial strains, differences between the membrane surface of given bacterial strains and other cell types will be exploited. Filomicelles will be prepared with different permutations and ratios of antibodies specific for bacterial membrane proteins, enabling pattern based recognition, with the potential for personalised drug delivery. Specificity will be evaluated by measuring uptake by bacterial strains, and comparing this to other cell types.

References:

  1. Farokhzad OC, Langer R, “Impact of Nanotechnology on Drug Delivery” ACS Nano, 2009, 3, 16-20.
  2. Eskandari A, Boodram JN, Lu C, Bruno PM, Hemann M, Suntharalingam K, “The breast cancer stem cell potency of copper(II) complexes bearing nonsteroidal anti-inflammatory drugs and their encapsulation using polymeric nanoparticles” Dalton Transactions, 2016, 45, 17867-17873.
  3. Eskandari A, Suntharalingam K, “A reactive oxygen species-generating, cancer stem cell-potent manganese(II) complex and its encapsulation into polymeric nanoparticles” Chemical Science, 2019, 10, 7792-7800.
  4. Oltra NS, Swift J, Mahmud A, Rajagopal K, Loverde SM, Discher DE, “Filomicelles in nanomedicine – from flexible, fragmentable, and ligand-targetable drug carrier designs to combination therapy for brain tumors” Journal of Materials Chemistry B, 2013, 1, 5177-5185.
  5. Truong NP, Quinn JF, Whittaker MR, Davis TP, “Polymeric filomicelles and nanoworms: two decades of synthesis and application” Polymer Chemistry, 2016, 7, 4295-4312.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology. Integrated Understanding of Health: Pharmaceuticals

Techniques that will be undertaken during the project:

  • Chemistry: Polymer synthesis and purification, bioconjugation, analytical and spectroscopic characterisation.
  • Microbiology: Bacterial culture, phage biology, biofilm studies.
  • Biochemistry / Molecular Biology: Human cell culture, in vitro cytotoxicity assays, cellular uptake studies, immunoblotting, immunofluorescence, flow cytometry.
  • Microscopy / Electro-physiology: Scanning electron microscopy, cryo-electron microscopy, fluorescent microscopy, live cell imaging.

Contact: Dr Kogularamanan (Rama) Suntharalingam, University of Leicester