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Biologic Drug Substance and Drug Product Manufacture
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Ajit S. Narang, Mary E. Krause, Shelly Pizarro, Joon Chong Yee
Salts increase protein hydrophobicity by neutralizing and shielding the ionizable surface functional groups. In addition to salt, solution pH closer to the pI and the neutral pH range promotes protein surface hydrophobicity and adsorption with the HIC column. The relative propensity of salts for increasing the hydrophobicity and tendency for the salting out effect is indicated by the Hofmeister series, also known as the lyotropic series. The Hofmeister series is a rank ordering of the ability of ions to precipitate or crash out proteins from their solutions. At lower concentrations, these ions impact the stability of the secondary and tertiary structure of proteins, thus exposing hydrophobic groups that interact with the HIC column.
Introduction to Bioresponsive Polymers
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Deepa H. Patel, Drashti Pathak, Neelang Trivedi
A major family of physical ion-responsive materials is ion-exchange resins, which are often used for different purposes such as to mask the taste of the bitter drug, as a counter ion-responsive drug release carrier, and to achieve sustained drug release [76]. These resins are typically insoluble polymers consists of a cross-linked polystyrene backbone with side chains containing ion-active groups such as sulfonic acid and carboxylic acid. The counter ions present in the saliva and gastrointestinal fluids stimulate drug release, which is directed by an equilibrium exchange reaction via oral administration. For illustration, cationic polymers holding quaternary ammonium groups show sensitivity towards ions in the saliva [77]. Polymers displaying a lower critical solution temperature (LCST) also show definite sensitivity towards ionic strength [78]. The LCST can be moved, generally to a lower temperature, in the existence of salt, following the Hofmeister series [78]. Polyion complex micelles signify another foremost family of ionic strength-sensitive materials. Reversible development and dissociation of polyion complex micelles over an alteration in salt concentration (and thus ionic strength) have been used for the release of cargo in a controlled manner [79]. In addition to responding physically to variations of ionic strength, materials can also react to specific ion types, normally by establishing complexes. In the recently reported investigation, metal-ion-responsive adhesive hydrogel, modified with β-cyclodextrin and hydrophobic 2,2’-bipyridyl moieties, the chemically selective adhesion property could be changed by governing the inclusion of inhibitory metal ligands to host moieties [80].
A molecular dynamics approach towards evaluating osmotic and thermal stress in the extracellular environment
Published in International Journal of Hyperthermia, 2018
David Fuentes, Nina M. Muñoz, Chunxiao Guo, Urzsula Polak, Adeeb A. Minhaj, William J. Allen, Michael C. Gustin, Erik N. K. Cressman
Although initial efforts established the concept of TCA [10,11], a better understanding of the fundamental mechanisms of cell death resulting from combined hyperthermal and hyperosmotic stresses implemented in vivo is needed to optimize delivery protocols. Salts are frequently added to proteins in solution to manipulate either biomolecular stability or ligand-binding affinity [12–15]. Also, the free energy change of stabilization is a function of the polar surface area of an added osmolyte [16]. Molecular dynamics studies have demonstrated salt-induced strengthening of hydrophobic interactions that leads to stabilization of compact conformations [17]. With respect to the Hofmeister series, the salts used for TCA may be selected to function as kosmotropes. These kosmotropes preferentially hydrate extracellular proteins and are preferentially excluded from the protein-solvent interface [18]. The increased water concentration near the protein interface is expected to stabilize folded and misfolded protein structures through increased Van der Waals forces for hiding hydrophobic residues. Similarly, the increased water concentration near a protein–ligand interface is expected to alter intermolecular forces from ionic bonds, hydrogen bonds and Van der Waals interactions that govern protein–ligand binding [18].
Modification of the kinetic stability of immunoglobulin G by solvent additives
Published in mAbs, 2018
Jonas V. Schaefer, Erik Sedlák, Florian Kast, Michal Nemergut, Andreas Plückthun
In contrast, the effect of ions (including arginine) is in many respects different from that of polyols and methylamines. We have investigated the influence of three different salts that were chosen based on the position of their anions in the so-called Hofmeister series of anions.54 Perchlorate, due to its preferential binding to a protein surface, belongs to the chaotropic, chloride to the neutral and sulfate, being preferentially excluded from the protein surface, to the kosmotropic anions, judged by their effects on the thermodynamic stabilities of proteins.53,54 In fact, perchlorate is the only additive in our study with a significantly destabilizing effect on the kinetic stability of all studied IgGs and Fabs alike. Although arginine is not a typical salt, we included it into this group due to its similar effect on the IgG's thermal denaturation. Arginine is known as an amino acid with the ability to suppress protein-protein interactions without significantly affecting the protein stability, and for this reason it is frequently used as an additive in refolding reactions.63,64 It has a small negative effect on the kinetic stability of both IgGs and Fabs, even though the transition temperature is slightly higher for all constructs in its presence.