Controlled-Release Drugs with Bacteriophages
Sustained/Controlled-Release Drug Devices Containing Bacteriophages Based on New Biodegradable Poly (ester amide)s
Tech Area / Field
- CHE-POL/Polymer Chemistry/Chemistry
3 Approved without Funding
Georgian Academy of Sciences / Institute of Bacteriophage, Microbiology and Virology, Georgia, Tbilisi
- Georgian Technical University / Research Center for Medical Polymers and Biomaterials, Georgia, Tbilisi
Project summarySpecific aim – development of technology for a new generation of biocomposite materials:
– based on biodegradable poly(ester amide)s as a matrix;
– using bacteriophages as an bactericidal substance, acting in a sustained/controlled release fashion.
Such products provide a novel approach to management of poorly healing and poorly vascularized wounds (i.e, diabetic foot ulcers, pressure ulcers in nursing home patients, trophic ulcers, etc.). As with any novel technology, there is a need for initial research support to move the project to a point where commercialization is possible; we are requesting funding for such a high risk but potentially high yield project.
In medicine, poorly healing wounds, such as those seen in diabetic patients with foot ulcers, and in bedridden patients with pressure sores, represent a major (and very expensive) management problem. Use of antibiotics in this setting is generally not efficacious: because of poor vascularization, antibiotics seldom can penetrate to affected areas at high enough levels to eradicate infection; and, because of the recurrent courses of antibiotics that these patients have received, bacterial pathogens causing the infections are often antibiotic resistant.
Biocomposites, mediating a sustained/controlled release of appropriate therapeutic agents, have proven to be especially efficacious for healing infected wounds and cavities. Film materials (so called “Artificial skin”), prepared from these biocomposites, have important therapeutic effects:
– polymer material, when applied to the surface of such wounds, acts as a protector from external actions (mechanical, etc.) and bacterial invasion, and prevents heat and moisture loss that occur as a result of uncontrolled water evaporation from the injured surface;
– the slow-release properties of the compound can be exploited to promote appropriate, steady release of anti-bacterial agents at the site of infection.
Use of biocomposite “artificial skin” does not require immobilization, promoting/permitting a return to daily activities of life, an important consideration in this class of patients.
A key element in the management of chronically infected wounds is the suppression of pathogenic bacterial flora. With biocomposite materials, this can be achieved by introducing bacteriocidal substances into the biocomposition structure. Antibiotics may be used in this setting, but their efficacy is increasingly limited by the development of antibiotic resistance. More recently, there has been interest in the introduction into biocomposites of such bactericidal substances as silver sulfadiazine, furagin and chlorohexydine. However, utilization of such compounds may be limited by their inherent toxicity, particularly for patients with underlying kidney or liver disease.
Incorporation of bacteriophages into such biocomposite materials provides an alternative approach. Bacteriophage are viruses that kill specific bacteria. The lysis of microorganisms by viruses was discovered at the beginning of the 20th century. Any one phage tends to be highly specific for certain bacteria, requiring that therapy be carefully targeted (i.e., there is no analogy to the broad-spectrum antibiotics which can “kill everything”). However, this also means that phage therapy can be used to lyse specific pathogens without disturbing normal bacterial flora.
Preliminary studies in the Republic of Georgia have indicated that this approach to therapy can be efficacious – and cost effective. However, for this product to continue to move toward commercialization, there is a need to focus research efforts on development and selection of the polymer matrix, and – if bacteriophages are to be used as the active antibacterial agent – on interactions between the matrix and bacteriophage with the desired antibacterial spectrum.
The scientific team in Georgia, lead by Prof. R. Katsarava, has more than 20 years of experience in research on the chemical synthesis and study of new macromolecular systems, including ones composed of naturally occurring a-amino acids and other non-toxic building blocks. At a practical level, it has been shown by this team that these polymers are ideal as matrices for constructing biocomposites, acting in drug sustained/controlled release fashion.
The expertise of Dr. Katsarava’s group is complemented by Prof. A. Meipariani and his colleagues,,who have more than 40 years of experience in phage therapy. Phages have been reported to be effective in treating skin infections caused by Pseudomonas, Staphylococcus, Klebsiella, Proteus, E. coli, and other pathogenic species; success rates in these studies have ranged from 75 to 100%, depending on the pathogen. However, for these studies bacteriophages were introduced in a variety of vehicles: liquid preparations (i.e. water solutions), aerosols and creams. The authors of the present project were the first to explore the utility of bacteriophages as drug devices in polymeric biocomposites. A basic composition was produced and patented in Georgia as “PhageDerm”. Various modifications of “PhageDerm” have been recommended for clinical trials being carried out in Georgia for treatment of infected surface or poorly vascularized wounds. Interest in this product has been expressed by Intralytix, Inc., a Baltimore company working on commercialization of bacteriophage products.
Notwithstanding the success achieved to date, the created products are not optimal since they contain admixtures like components of bacterial lysis (which are formed during growing bacteriophages on the corresponding bacteria-target), which can be toxic and/or cause immune reactions. To be able to move forward with commercialization, it is necessary to create biocomposites free of such admixtures. This, in turn, requires the availability of highly purified phage preparations. Purification work will be conducted together with the U.S. team (University of Maryland), headed by Prof. Glenn Morris, and with scientists at Intralytix.
Immediate basic goals of the current project will include:
– synthesis and selection of biodegradable PEAs’ with optimal mechanical and biochemical properties;
– separation and purification of bacteriophages;
– elaboration of the technology of creating basic biocomposites containing purified bacteriophages, using various approaches, and to obtained film materials (“Artificial skin”) suitable to manage superficial wounds;
– in vitro study of polymer biodegradation/bacteriophage release kinetics from the biocomposite films;
– study of issues related to sterilization and sterile packaging of the final products (“Artificial skin”).
Specific technical tasks of the project are:
– refinement of film casting method with solvent recuperation (and development of necessary associated equipment);
– making perforated large-size films (20×30 cm2) and manufacturing a perforator for this purpose;
– development of small-size, laboratory scale equipment for spray-drying of bacteriophages.
The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.
ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.