1.
Synthesis and characterization of a pH responsive folic acid functionalized polymeric drug delivery system.
Li, X, McTaggart, M, Malardier-Jugroot, C
Biophysical chemistry. 2016;:17-26
Abstract
We report the computational analysis, synthesis and characterization of folate functionalized poly(styrene-alt-maleic anhydride), PSMA for drug delivery purpose. The selection of the proper linker between the polymer and the folic acid group was performed before conducting the synthesis using Density Functional Theory (DFT). The computational results showed the bio-degradable linker 2, 4-diaminobutyric acid, DABA as a good candidate allowing flexibility of the folic acid group while maintaining the pH sensitivity of PSMA, used as a trigger for drug release. The synthesis was subsequently carried out in multi-step experimental procedures. The functionalized polymer was characterized using InfraRed spectroscopy, Nuclear Magnetic Resonance and Dynamic Light Scattering confirming both the chemical structure and the pH responsiveness of PSMA-DABA-Folate polymers. This study provides an excellent example of how computational chemistry can be used in selection process for the functional materials and product characterization. The pH sensitive polymers are expected to be used in delivering anti-cancer drugs to solid tumors with overly expressed folic acid receptors.
2.
Novel integrin-targeted binding-triggered drug delivery system for methotrexate.
Kotamraj, P, Russu, WA, Jasti, B, Wu, J, Li, X
Pharmaceutical research. 2011;(12):3208-19
Abstract
PURPOSE To design a binding-induced conformation change drug delivery system for integrin-targeted delivery of methotrexate and prove the feasibility of using hairpin peptide structure for binding triggered drug delivery. METHODS Methotrexate prodrugs were synthesized using solid phase peptide synthesis techniques by conjugating methotrexate to Arg-Gly-Asp (RGD) or a hairpin peptide, RWQYV(D)PGKFTVQRGD (hairpin-RGD). Levels of integrin α(V)β(3) in HUVEC were up-regulated using adenoviral system and knocked down using siRNA. Stability of prodrugs and methotrexate release from prodrugs were evaluated in plasma, in presence or absence of integrin α(V)β(3)-expressing cells. Molecular modeling was performed to support experimental results using MOE. RESULTS Prodrugs recognized and bound to integrin α(V)β(3)-expressing cells in integrin α(V)β(3) expression level-dependent manner. Prodrug with hairpin peptide could resist Streptomyces griseus-derived glutamic acid-specific endopeptidase (SGPE) and plasma enzyme hydrolysis. Drug release was triggered in presence of HUVEC cells and SGPE. Analysis of conformation energy supported that conformational change in MTX-hairpin-RGD led to exposure of labile link upon binding to integrin α(V)β(3)-expressing cells. CONCLUSIONS Binding-induced conformation change of hairpin peptide can be used to design integrin-targeted drug delivery system.