Researchers from the Georgia Tech and Emory University have developed a novel biodegradable class of polymer known as polyketals, that facilitate rapid drug delivery to specific sites in several disease conditions. Scott Wilson, a graduate student, presented the details and clinical significance of these polyketals and their derivatives at the 236th American Chemical Society National Meeting, held during 18th to 20th August 2008, in Philadelphia.
Niren Murthy, Assistant Professor at the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, and his colleagues are currently investigating these polyketals and their derivatives for delivery of drugs, proteins, and snips of ribonucleic acid, for the treatment of inflammatory bowel disease, acute liver failure, lung injury and heart attacks. As therapeutic carriers, polyketal microparticles have some distinctive features such as:
• Degradation into FDA-approved membrane-permeable compounds that diffuse out of the cells and tissues, thereby preventing its accumulation, which could lead to additional inflammation
• Stability in acidic and basic media, and degradation in presence of reactive oxygen species such as superoxides, which are found in and around inflamed tissues
• For the treatment of acute liver failure, the superoxide detoxifying enzyme, superoxide dismutase can be incorporated inside the polyketal–poly (cyclohexane-1,4-diyl acetone dimethylene ketal), enabling rapid release into the acidic environment
• Immobilization of the protein on the surface of polyketals to overcome the limitation of protein disruption with the use of organic solvents.
Three patent applications for the polyketal drug delivery system have been filed to the Food and Drug Administration by Georgia Tech, Emory and the University of Rochester.
Yang SC and colleagues (Bioconjugate Chemistry, 2008) had reported polyketal copolymers as a new option of acid-sensitive delivery system for acute inflammatory diseases. They demonstrated that by increasing the hydrophobic/hydrophilic balance the hydrolysis kinetics of aliphatic polyketals could be further accelerated. The researchers synthesized a polyketal, PK3, with appropriate hydrolysis kinetics for the treatment of inflammatory diseases and encapsulated the anti-inflammatory drug, imatinib, into microparticles formulated with PK3. In vivo studies showed that the efficacy of imatinib in the treatment of acute liver failure improved with the use of PK3. Based on their findings, the researchers look forward to the potential applications of aliphatic polyketals in treating acute inflammatory diseases in view of their pH sensitivity, adjustable hydrolysis kinetics, and biocompatible degradation products.
Previous researches have found that although the currently available aliphatic polyketals are acid sensitive, capable of passively targeting therapeutics to macrophages, and degradable into biocompatible products, they are inappropriate for the treatment of acute inflammatory diseases owing to the release of inflammation-causing acid on degradation and a longer half-life period, resulting in a longer time for hydrolysis. By manipulating the rate of polyketal hydrolysis, the delivery of drugs can be accelerated for acute cases such as liver failure where the delay in drug assimilation could be lethal to patients.
Further validation for the efficacy and safety of this new class of drug delivery polymers needs to be achieved through preclinical and clinical studies. Accelerated delivery of therapeutics to the patients would help in improving the treatment options of inflammatory diseases like inflammatory bowel disease, acute liver failure, lung injury where the rapidity of drug delivery is imperative to the survival of the patient.
References
1. Biodegradable Polymers May Improve Treatment of Inflammatory Diseases. News Release. Georgia Tech. Last accessed August 25, 2008.
2. Yang SC, Bhide M, Crispe IN, Pierce RH, Murthy N. Polyketal copolymers: a new acid-sensitive delivery vehicle for treating acute inflammatory diseases. Bioconjug Chem. 2008 Jun;19(6):1164-9. Epub 2008 May 24.
3. Paramonov SE, Bachelder EM, Beaudette TT, et al. Fully acid-degradable biocompatible polyacetal microparticles for drug delivery. Bioconjug Chem. 2008 Apr;19(4):911-9. Epub 2008 Mar 29.
