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As the EU has pointed out, “Infectious diseases ... represent a very significant burden on healthcare systems worldwide and in particular for developing nations. Bacterial diseases such as Tuberculosis or infections with bacteria like MRSA often cannot be prevented by vaccination, lack early-stage diagnosis and treatment options. A major problem is the fact that bacteria are increasingly resistant to antibiotics”. The worldwide spread of antibiotic-resistant microorganisms can be viewed as an ecological consequence of the systematic use of antimicrobial agents (over one million tons). Resistance to antibiotics represents a major public health problem which needs to be urgently addressed.
Developing new drugs to combat the increasingly resistant bacteria takes years. In this context, the Cyclon Hit network proposed a short-term alternative to confront the fast development of resistance to antibiotics, that is, the development of novel strategies to deliver the well-documented existing drugs in an optimized fashion to: i) protect the drugs toward degradation; ii) increase antibiotic bioavailability; iii) reduce drug toxic side effects; iv) increase patient compliance to the treatment and iv) reduce treatment duration and related costs. This is of tremendous interest for drugs used to treat tuberculosis, Salmonella Typhimurium, Staphyloccocus aureus and hospital infections.
CycloN Hit, an FP7 MSCA ITN project (2014-2018), gathered 11 full partners and 6 associated partners, of which 7 are SMEs. 11 Early Stage and 6 young Experienced Researchers (ESRs and ERs) were employed and received extensive interdisciplinary training. The teams demonstrated that nanocarriers based on cyclodextrins (CDs) are particularly appealing for the optimized delivery of antibiotics. CDs are a family of biocompatible cyclic oligosaccharide nanocages. They are made of α-D-glucopyranose units joined in a circular way to form a ring with a hydrophilic exterior and a hydrophobic cavity, in which antibiotics were hosted. Thus, CDs improved the solubility, stability and bioavailability of these drugs, and facilitated their administration. Moreover, partners in CycloN Hit engineered CDs endowed with antibacterial properties. CycloN Hit took full advantage of nanotechnology and of the high level interdisciplinary expertise of the partners to efficiently encapsulate and protect antibiotics in nanocarriers for both intracellular and extracellular delivery to combat resistant bacteria, and study the mechanisms in biological systems using state-of-the art techniques.
Researchers engineered CD-based carriers for antibiotics for the treatment of tuberculosis and more tailored alternative therapeutic approaches for several MDR microorganisms. Some examples are shown in Figure 1. For instance, positively charged CD nanocarriers, were able to cross cell membranes and form inclusion complexes with β-lactam antibiotics in situ offering protection of the drugs against hydrolytic activity of bacterial enzymes. Self-assembled CD-based nanoparticles were also developed, entrapping more than one type of therapeutic agent.
The various CD-based systems were labelled with fluorescent molecules to study their fate in biological media as well as in biofilms. Silica nanoparticles were coated with CDs to control drug release. The interactions between the CD-based carriers and the drugs were thoroughly studied by advanced spectroscopic methodologies. These techniques allows deeper understanding on how a different degree of hydrophilicity in mesoporous silica particles affects the released amount of loaded antibiotic (clofazimine) in their pores. Simple modification of the carrier’s properties allows to control the release and adapt to the requirements of the treatment.
Nanoparticulate drug carriers were tailored to track pathogens in their hideouts. For instance, drug-loaded nanoparticles were engineered to act as “Trojan horses” to enter infected cells and deliver their cargoes to kill intracellular bacteria (Figure 1E). Considering that the current regimen for tuberculosis and other infectious diseases consists of a cocktail of drugs, the CycloN Hit approach could be employed to encapsulate synergic drugs, considerably simplifying the treatment and increasing patient compliance. In particular, researchers focused in the case of tuberculosis on pulmonary administration of the nanoparticles loading both drug and booster since lungs are the primary site of Mycobacterium tuberculosis infection. This approach also helps to overcome certain technical bottlenecks inherent to the physico-chemical properties of the two compounds, achieving higher concentrations at the target site and less systemic side effects. Following treatment in an animal model for tuberculosis, researchers observed a 1000 decrease in lung mycobacterial load.

Figure 1. Examples of engineered antibiotic nanocarriers studied in the CycloN Hit project:
CD-antibiotic complexes (A); structures of drug-loaded CD particles with s of controlled sizes (B); silica nanoparticles loaded with antibiotics (C); CD-based drug carriers efficiently penetrate inside cells (D, E) or in biofilms (F).

So far, the CycloN Hit consortium published around 70 articles in peer reviewed journals, organized three workshops, two summer schools and numerous outreach activities. The training activities were complemented by the uploading six freely accessible e-classes on Advanced Drug Delivery topics on the CycloN Hit website increasing its visibility that counts more than 156000 visits, up to now. The involved teams went even beyond their initial objectives by organising a congress in Pasteur Institute in Paris in 2015, whereas in 2018, a “brokerage and pitching” event took part in Orsay, gathering several EU projects. A special issue dedicated on CDs (International Journal of Pharmaceutics) was co-edited by two Cyclon Hit partners.
Exploiting the most recent advances in the nanomedicine field, CycloN Hit partners paved the way to alternative therapeutic approaches for several resistant microorganisms. ‘Intelligent’ nanoparticles capable of delivering drugs to the site of infection with minimal side effects can certainly be envisioned as a disruptive and groundbreaking choice to drive innovation in the future.

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