Bacteria-responsive materials for drug delivery

Doctoral thesis, 2015

The number of diabetics, obese individuals and other patients carrying other lifestyle diseases is increasing worldwide. At the same time the population is ageing. These patients all suffer from poor blood circulation, which often gives rise to non-healing, or chronic, wounds. Thus, the number of chronic wounds is also increasing at a fast pace. Such wounds often carry infection since the wound environment is favorable for bacteria. The wounds cause pain, odor and can lead to amputation or even death. Hence, the patients are treated with systemic and topical antimicrobial substances, e.g. antibiotics. However, the overexposure and misuse of such drugs has created another issue worldwide: bacterial resistance. There are already some infections that are difficult to treat due to the rapid development of bacterial resistance and fewer working drugs. Our work has focused on a release platform that can administer drugs only when a wound shows signs of infection. By sensing the type of infection at hand, the release system should break down and expose a suitable antimicrobial substance to the bacteria. Such a release system would not only combat the infection but also decrease the risk of bacterial resistance and other side effects on the patient, since it would be administered locally and only when it is needed. Two bacteria were chosen as targets, Staphylococcus aureus and Pseudomonas aeruginosa, which often are pathogenic in chronic wounds. Both bacteria exude very substrate specific proteases, i.e. V8 and Protease IV, respectively. Hence, nanofilms corresponding to each protease were assembled via the layer-by-layer route. V8 readily degrades peptide bonds involving poly-L-glutamic acid (PLGA), which also was the main component in the release system against S. aureus, while Protease IV degrades bonds involving poly-L-lysine, which hence was used as component in the release system against P. aeruginosa. The nanofilms were found not to be degraded by normal human enzymes; however, each bacterial protease ruptured their respective film if they reached a concentration similar to the concentration found in a chronic wound. Consequently, the drug was released or exposed only when in contact with the bacterial enzymes. Such release systems could be used to fight infection while avoiding bacterial resistance and misuse of antimicrobials.