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A novel microbial infection-responsive drug release system
M Tanihara1, Y Suzuki, Y Nishimura
1Graduate School of Materials Science, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan. mtanihar@ms.aist-nara.ac.jp
Abstract:
The aim of this study was to construct a novel drug delivery system suitable for controlled release of antibiotics. There is a need for devices that release antibiotics only during microbial infection, because prophylactic or prolonged use of antibiotics leads to serious problems, such as renal and liver toxicity and the emergence of drug-resistant bacteria (e.g., meticillin-resistant Staphylococcusaureus). We found previously that Staphylococcus aureus-infected wound fluid showed high thrombin-like activity; therefore, in this study we designed an antibiotic release system triggered by thrombin activity. We synthesized an insoluble polymer-drug conjugate in which gentamicin was bound to poly(vinyl alcohol) hydrogel through a newly developed thrombin-sensitive peptide linker. The conjugate released gentamicin when it was incubated with Staphylococcus aureus-infected wound fluid, with thrombin and leucine aminopeptidase, or with human plasma and Ca2+, whereas no biologically active gentamicin was released when the conjugate was incubated with noninfected wound fluid, with leucine aminopeptidase alone, with thrombin alone, or with plasma. Furthermore, the conjugate reduced the bacterial number in an animal model of Staphylococcus aureus infection. These results demonstrated that the conjugate has sufficient specificity and excellent potential as a stimulus-responsive, controlled drug release system.
Insights
This study developed a novel antibiotic delivery system that releases gentamicin only when triggered by infection-specific thrombin activity. This targeted approach minimizes toxicity and combats antibiotic resistance.
Area of Science:
- Biomaterials Science
- Drug Delivery Systems
- Infectious Diseases
Background:
- Prophylactic or prolonged antibiotic use leads to toxicity and antimicrobial resistance.
- Meticillin-resistant Staphylococcus aureus (MRSA) infections pose a significant clinical challenge.
- A need exists for smart drug delivery systems that respond to infection-specific cues.
Purpose of the Study:
- To develop a novel, controlled antibiotic release system.
- To design a system that releases antibiotics specifically during microbial infection.
- To create a stimulus-responsive drug delivery platform triggered by thrombin activity.
Main Methods:
- Synthesized an insoluble polymer-drug conjugate of gentamicin and poly(vinyl alcohol) hydrogel.
- Utilized a newly developed thrombin-sensitive peptide linker for gentamicin conjugation.
- Tested the conjugate's release profile in vitro using infected wound fluid, thrombin, leucine aminopeptidase, and human plasma with Ca2+.
- Evaluated the conjugate's efficacy in an animal model of Staphylococcus aureus infection.
Main Results:
- The gentamicin conjugate specifically released the antibiotic in the presence of Staphylococcus aureus-infected wound fluid, thrombin with leucine aminopeptidase, or plasma with Ca2+.
- No significant gentamicin release was observed with non-infected wound fluid, thrombin alone, leucine aminopeptidase alone, or plasma alone.
- The conjugate demonstrated a significant reduction in bacterial load in a Staphylococcus aureus infection animal model.
Conclusions:
- The developed conjugate functions as a highly specific, stimulus-responsive drug delivery system.
- This system shows excellent potential for controlled release of antibiotics, targeting infection sites.
- The findings suggest a promising strategy to mitigate antibiotic-related toxicity and combat antimicrobial resistance.