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PANG Report Summary

Project ID: 690836
Funded under: H2020-EU.1.3.3.

Periodic Reporting for period 1 - PANG (Pathogen and Graphene)

Reporting period: 2016-01-01 to 2017-12-31

Summary of the context and overall objectives of the project

While complications related to infectious diseases have significantly reduced due to the availability of a broad-range of antibiotics and a wide variety of antimicrobial agents, the number of death related to infections is only declining every year by only 1 %, with a forecast of 13 million deaths due to these cases in 2050. While the development of vaccinations and novel anti-bacterial drugs and treatments are at the forefront of research, excessive use of antibiotics and antimicrobial agents increased significantly the number of multi-drug resistant (MDR) bacteria and has resulted in a serious threat to public health. According to published data in 2011, 25.000 patients die annually in the EU as a result of infections caused by antibiotic-resistant bacteria, with two thirds of these deaths due to Gram-negative pathogens. The costs incurred by drug resistant infections amount to an estimated €1.5 billion annually, due to increases in healthcare expenditure costs. The situation is all the more serious as antimicrobials have become an essential tool for modern medicine and many surgical operations could not be performed without them.
The inexorable rise in the incidence of antibiotic resistance in bacterial pathogens, coupled with the low rate of emergence of new clinically useful antibiotics, has refocused attention on finding alternatives to overcome antimicrobial resistance. Among the various approaches, the use of nanomaterials is currently considered a highly promising strategy due to their small size, which allows packaging multiple antimicrobial agents on the same nanoparticle making the development of resistance unlikely. This project is thus exploring the utility of novel graphene based nanocomposites and surfaces for the management and better understanding of microbial infections. The anti-microbical potential of the novel graphene based nanomaterials, the possibility of using such structures for the development of non-invasive therapies together with the understanding of the mechanism of action are the main focal points of the project entitled “PANG”, relating to Pathogen and Graphene.

The objectives of PANG are:
1. The development of graphene-based antibacterial matrixes though chemical functionalization of these structures using antibacterial peptides and antibiotics and to test these novel nanomaterials for their bactericidal potential in particular against AMR strains
2. The development of graphene-based skin patches for the treatment of skin infections. In the case of skin infection, the wound is covered by exudate making it impermeable to topical antibiotics. The development of a flexible patch allowing a rapid and highly efficient treatment of subcutaneous wound infections using the photothermal properties of graphene is aimed at
3. In parallel, the project aims in obtaining a deeper understanding of the effects of the graphene nanostructures on the immune system. Notably, the interaction of graphene with neutrophils and the eventual formation of neutrophil extracellular traps will be investigated. In the case of interaction of graphene with neutrophils, strong localized inflammation can result with induced immune responses.
4. Considering vaccinations, the adjuvant properties of graphene using ovalbumin (OVA) as model antigen will be determined and compared to currently used adjuvants such as aluminum- hydroxide (alum), complete Freund’s Adjuvant (CFA) and Incomplete Freund’s Adjuvant (IFA). Indeed, the benefits flowing from adjuvant incorporation into any vaccine formulation have to be balanced with the risk of adverse reactions. The toxicity of aluminum is still controveral, but considered neurotoxic for animals and humans. Unfortunately, the potent CFA and IFA adjuvants are correlated with increased toxicity and were lately banned due as considered too toxic for human used. One of the major challenges in adjuvant research is thus to gain potency while minimizing toxicity. The difficulty

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Until now the main results are following
1. Development of mucosal surfaces to study bacterial interaciton by surface plasmon resonance based
2. Development of light activatable skin patch for the treatment of skin infections
3. Demonstration of the theranostic potential of anti-fimbrial modified magnetic rGO nanocomposites for a magnetic-separation based body fluid purification approach of E. coli UTI89.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The focus of the next 24 monthese are mainly on two issues, important to progress beyong the state of the art on these issues:

1. Transdermal delivery of antimicrobial peptides on demand to treat wound infections
There are several highly important results to be expected until the end of the project. One thematic concerns the integration of antimicrobial peptides into hydrogels which are loaded with rGO and where the antimicrobial peptide can be released upon heating. The effect of heat on the transdermal delivery of these peptides will be studies in parallel. The first in vivo experiments are underway to proof the viability of this strategy. In case of success the socio-impact is large as such an approach might be unique in allowing the treatment not only of wound infections but also of diabetic food ulcers and other infections.

2. Immunological response of graphene nanostructures
Adjuvants in vaccine formulations aim to enhance, accelerate and prolong the immunogenicity of antigens that have insufficient immune-stimulatory capabilities. However, available adjuvant such as aluminum compounds (aluminum hydroxide, phosphate, sulfate) and oil-in-water emulsions (Freund’s incomplete adjuvant, FIA) have sever drawbacks that limit their application for vaccines targeting pathogens killed by antibodies and in the case of FIA are too reactogenic for use in humans. Modern adjuvants need to be designed to limit associated healthy risks and to prevent infectious diseases of global significance for which successful vaccines have not been possible using traditional technologies. We will investigate the potential of graphene nanostructures in this respect. Indeed, we have found that modified nanodiamonds are particular promising candidates and a patent application is currently under consideration between University of Lille (USTL) and Danylo Halytsky Lviv National Medical University (LNBMU). This will ensure the wider societal implication of the project. Indeed, the practical outcomes of enhanced immune responses are a reduction in the quantity of antigen needed for vaccination and vaccine dose reduction to achieve immunity.
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