Modulating Potency: Physicochemical Characteristics are a Determining Factor of TLR4-Agonist Nanosuspension Activity
| Autor: | Jeff Guderian, James Chesko, Christopher B. Fox, Magdalini Moutaftsi, Quinton M. Dowling, Thomas S. Vedvick, Ryan M. Kramer, Sandra J. Sivananthan |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Agonist
1 2-Dipalmitoylphosphatidylcholine Chemical Phenomena Surface Properties medicine.drug_class Acylation medicine.medical_treatment Pharmaceutical Science Excipient Disaccharides Lipid A Adjuvants Immunologic Suspensions In vivo medicine Humans Transition Temperature Potency Particle Size Phosphorylation Blood Cells Myristates Chemistry Osmolar Concentration Biological activity In vitro Nanostructures Toll-Like Receptor 4 Drug Combinations Biochemistry Cytokines lipids (amino acids peptides and proteins) Adjuvant Interferon-gamma Release Tests medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 103:879-889 |
| ISSN: | 0022-3549 |
| Popis: | Activity of adjuvanted vaccines is difficult to predict in vitro and in vivo. The wide compositional and conformational range of formulated adjuvants, from aluminum salts to oil-in-water emulsions, makes comparisons between physicochemical and immunological properties difficult. Even within a formulated adjuvant class, excipient selection and concentration can alter potency and physicochemical properties of the mixture. Complete characterization of physicochemical properties of adjuvanted vaccine formulations and relationship to biological response is necessary to move beyond a guess-and-check paradigm toward directed development. Here we present a careful physicochemical characterization of a two-component nanosuspension containing synthetic TLR-4 agonist glucopyranosyl lipid adjuvant (GLA) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) at various molar ratios. Physicochemical properties were compared with potency, as measured by stimulation of cytokine production in human whole blood. We found a surprising, nonlinear relationship between physicochemical properties and GLA-DPPC ratios that corresponded well with changes in biological activity. We discuss these data in light of the current understanding of TLR4 activation and the conformation-potency relationship in development of adjuvanted vaccines. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text