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Novel integrin-targeted binding-triggered drug delivery system for methotrexate
Phanidhara Kotamraj1, Wade A Russu, Bhaskara Jasti
1Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California 95211, USA.
Pharmaceutical Research
|June 23, 2011
Summary
A novel drug delivery system utilizes a hairpin peptide that changes conformation upon binding to integrin α(V)β(3), triggering methotrexate release. This system shows feasibility for targeted drug delivery, enhancing therapeutic potential.
Area of Science:
- Biomedical Engineering
- Drug Delivery Systems
- Molecular Biology
Background:
- Integrin α(V)β(3) is a key target for drug delivery due to its role in various diseases.
- Targeted drug delivery aims to improve efficacy and reduce side effects by concentrating drugs at the disease site.
- Developing stimuli-responsive systems enhances drug release control.
Purpose of the Study:
- To design a drug delivery system that undergoes a binding-induced conformation change for targeted delivery of methotrexate.
- To demonstrate the feasibility of using a hairpin peptide structure for binding-triggered drug delivery.
- To investigate the targeting and drug release capabilities of methotrexate prodrugs conjugated to RGD or hairpin peptides.
Main Methods:
- Synthesized methotrexate prodrugs conjugated to Arg-Gly-Asp (RGD) or a hairpin peptide (hairpin-RGD) using solid-phase peptide synthesis.
- Modulated integrin α(V)β(3) levels in HUVEC cells using adenoviral systems and siRNA.
- Assessed prodrug stability and methotrexate release in plasma, with and without integrin α(V)β(3)-expressing cells.
- Utilized molecular modeling to analyze conformational changes and support experimental findings.
Main Results:
- Prodrugs exhibited integrin α(V)β(3) expression level-dependent binding to target cells.
- The hairpin peptide prodrug demonstrated resistance to enzymatic hydrolysis from Streptomyces griseus-derived glutamic acid-specific endopeptidase (SGPE) and plasma enzymes.
- Drug release was successfully triggered by the presence of HUVEC cells and SGPE.
- Conformational analysis indicated that binding to integrin α(V)β(3) induced a conformational change in the MTX-hairpin-RGD prodrug, exposing a labile linkage.
Conclusions:
- A hairpin peptide's binding-induced conformation change is a viable strategy for designing integrin-targeted drug delivery systems.
- This approach enables controlled drug release triggered by specific cellular interactions.
- The developed system holds promise for targeted delivery of methotrexate and other therapeutic agents.
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