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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, RWQYVPGKFTVQRGD (hairpin-RGD). Levels of integrin αβ 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 αβ-expressing cells. Molecular modeling was performed to support experimental results using MOE. Results: Prodrugs recognized and bound to integrin αβ-expressing cells in integrin αβ 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 αβ-expressing cells. Conclusions: Binding-induced conformation change of hairpin peptide can be used to design integrin-targeted drug delivery system. [ABSTRACT FROM AUTHOR]

Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward. [ABSTRACT FROM AUTHOR]

Lipid-based nanocarriers or liposomes have been proven successful in the delivery of chemotherapeutic agents and are currently applied clinically in the treatment of various types of cancer. Liposomes offer the advantage of a high drug payload, decreased drug toxicity and enhanced drug accumulation at tumor sites. Increased accumulation is due to the relatively leaky tumor vasculature that allows liposome extravasation. Between different types of tumors and even within one tumor, vascular permeability and thus liposome extravasation may differ greatly. Furthermore, upon accumulation of liposomes in the tumor area, drug bioavailability is not guaranteed. At present, these are the major issues for clinically used liposomal drugs. Mild hyperthermia (HT), the heating of tumor tissue to temperatures of up to 43°C, has been developed in the past decades as an established and efficacious treatment modality in combination with chemo- and radiotherapy. HTcan be used to further improve liposomal chemotherapy in two ways: HT is known to increase vascular permeability in solid tumors and may therefore increase levels of liposome accumulation, and thermosensitive liposomes have been developed that can be triggered to release their contents upon hyperthermia. By applying these two strategies, drug delivery to tumors can be strongly enhanced. [ABSTRACT FROM AUTHOR]

Purpose: To develop cationic lipid-coated magnesium phosphate nanoparticles (LPP) for intracellular catalase (CAT) delivery. Methods: Magnesium phosphate nanoparticles (MgP NP) were prepared by micro-emulsion precipitation and mixed with catalase-loaded cationic liposomes (DOTAP/cholesterol) to yield LPP formulation of catalase (LPP-CAT). The size and ζ-potential of LPP-CAT were measured by dynamic light scattering. The pH-sensitivity of LPP-CAT was determined by monitoring their degradation of hydrogen peroxide (H2O2) and their morphologies under transmission electron microscopy (TEM) at pH 7.4 and 5.5. The ability of LPP-CAT to protect MCF-7 cells against hydrogen peroxide was measured by MTS assay. ROS levels in EA.hy926 cells were measured after treatment with LPP-CAT. Results: LPP-CAT were successfully prepared and carried an average diameter of <300 nm and ζ -potential of about +40 mV. At pH 5.5, LPP-CAT degraded H2O2 almost 4-fold as fast as pH 7.4 and displayed drastic morphological changes of an osmotic explosion. LPP-CAT protected MCF-7 cells from lethal level of exogenous H2O2 and significantly lowered the ROS levels in EA.hy926 cells. A lipid with a pH-sensitive conformational switch (flipid) further enhanced the protein delivery of LPP-CAT. Conclusion: LPP represents a promising nano-system for intracellular protein delivery. [ABSTRACT FROM AUTHOR]