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We have synthesized and characterized a novel phosphorothioate CpG oligodeoxynucleotide (CpG ODN)-Ficoll conjugated nanoparticulate adjuvant, termed DV230-Ficoll. This adjuvant was constructed from an amine-functionalized-Ficoll, a heterobifunctional linker (succinimidyl-[(N-maleimidopropionamido)-hexaethylene glycol] ester) and the CpG-ODN DV230. Herein, we describe the evaluation of the purity and reactivity of linkers of different lengths for CpG-ODN-Ficoll conjugation, optimization of linker coupling, and conjugation of thiol-functionalized CpG to maleimide-functionalized Ficoll and process scale-up. Physicochemical characterization of independently produced lots of DV230-Ficoll reveal a bioconjugate with a particle size of approximately 50 nm and covalent attachment of more than 100 molecules of CpG per Ficoll. Solutions of purified DV230-Ficoll were stable for at least 12 months at frozen and refrigerated temperatures and stability was further enhanced in lyophilized form. Compared to nonconjugated monomeric DV230, the DV230-Ficoll conjugate demonstrated improved in vitro potency for induction of IFN-α from human peripheral blood mononuclear cells and induced higher titer neutralizing antibody responses against coadministered anthrax recombinant protective antigen in mice. The processes described here establish a reproducible and robust process for the synthesis of a novel, size-controlled, and stable CpG-ODN nanoparticle adjuvant suitable for manufacture and use in vaccines.

READ……http://pubs.acs.org/doi/full/10.1021/acs.bioconjchem.6b00107

Optimization, Production, and Characterization of a CpG-Oligonucleotide-Ficoll Conjugate Nanoparticle Adjuvant for Enhanced Immunogenicity of Anthrax Protective Antigen

Bob Milley^*^†, Radwan Kiwan^†, Gary S. Ott^†, Carlo Calacsan^†, Melissa Kachura^†, John D. Campbell^†, Holger Kanzler^‡, and Robert L. Coffman^†

^† Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, United States

^‡ MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland 20878, United States

Bioconjugate Chem., Article ASAP

DOI: 10.1021/acs.bioconjchem.6b00107

Publication Date (Web): April 13, 2016

*E-mail: bmilley@dynavax.com. Phone: (510) 665-7227. Fax: (510) 848-1327.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

//////Optimization, Production, Characterization, CpG-Oligonucleotide-Ficoll Conjugate Nanoparticle Adjuvant, Enhanced Immunogenicity, Anthrax Protective Antigen

Volume 441, Issues 1–2, Pages 1-834 (30 January 2013)

Delivery of venlafaxine hydrochloride with thermosensitive chitosan hydrogels system: diffusion controlled release and kinetic gelation mechanism is nucleation and growth.

http://www.sciencedirect.com/science/article/pii/S0378517312010125

doi:10.1016/j.ijpharm.2012.11.005

Abstract

Chitosan/glycerophosphate disodium (GP) thermosensitive hydrogels were prepared for the sustained delivery of venlafaxine hydrochloride (VH) and optimization of this formulation was mainly studied. Release mechanism was investigated by applying various mathematical models to the in vitro release profiles. Overall, drug release from the hydrogels showed best fit in first-order model and drug release mechanism was diffusion-controlled release. Optimization of VH chitosan/GP thermosensitive hydrogels was conducted by using a three-level three-factorial Box–Behnken experimental design to evaluate the effects of considered variables, the strength of the formulation, chitosan concentration and GP amount, on the selected responses: cumulative percentage drug release in 1 h, 24 h and the rate constant. It presented that higher strength and GP concentration resulted in higher initial release and rate constant, which supported the hypothesis that the kinetic gelation mechanism of this system was nucleation and growth. Drug release profiles illustrated that controlled drug delivery could be obtained over 24 h, which confirmed the validity of optimization. In vivo pharmacokinetic study was investigated and it demonstrated that compared with VH solution, chitosan/GP thermosensitive hydrogels had a better sustained delivery of VH.

///////Optimization, thermosensitive chitosan hydrogels, sustained delivery, venlafaxine hydrochloride