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Bioinspired filomicelles for the effective delivery of antibiotics


Department of Genetics and Genome Biology

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Dr K Suntharalingam No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Leicester United Kingdom Immunology Microbiology Molecular Biology Structural Biology

About the Project

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.

Entry requirements:

• Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.

• Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.

• Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.

• Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.

• Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above

For further information please contact [Email Address Removed]

Application advice:

To apply please refer the application instructions at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp

You will need to apply for the PhD place and also submit your online application notification to MIBTP. Links for both are on the above web page.

Project / Funding Enquiries: For further information please contact [Email Address Removed]

Application enquiries to [Email Address Removed]


Funding Notes

All MIBTP students will be provided with a 4 years studentship.
Tuition Fees at UK fee rates
- a tax free stipend of at least £15,295 p.a (to rise in line with UKRI recommendation)
- a travel allowance in year 1
- a travel / conference budget
- a generous consumables budget
- use of a laptop for the duration of the programme

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.
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