Communications Journal of Pharmacy and Pharmacology JPP 2001, 53: 541–547  2001 The Authors Received October 31, 2000 Accepted January 15, 2001 ISSN 0022-3573 Interactions among proteins and hydrophobically modified polyelectrolytes L. E. Bromberg Abstract A special class of hydrophobically modified polyelectrolytes was studied wherein poly(acrylic acid) (PAA) was conjugated with Pluronic F127 NF surfactant. The Pluronic-PAA copolymer solutions form gels at low concentrations when exposed to body temperature. Such gels possess enhanced retention in topical applications. Circular dichroism spectra indicate that tertiary structures of human insulin, haemoglobin, and albumin were stabilized in solutions of Pluronic- PAA. Aggregation of insulin in gelled solutions of Pluronic-PAA was impeded as demonstrated in shaking tests. The presence of Pluronic-PAA hindered the insulin degradation by α- chymotrypsin by at least 7-fold. Extraction of calcium ions from trypsin by Pluronic-PAA led to the dramatic changes in the tertiary structure and total loss of enzymatic activity, suggesting that Pluronic-PAA could inhibit tryptic degradation of proteins. Introduction Poly(acrylic acid) (PAA) and its cross-linked derivatives can be considered as safe drug carriers, as they are not absorbed through the mucosa and thus are devoid of systemic side effects, when applied in topical drug delivery (Junginger et al 2000). In addition, PAA and its hydrogels are mucoadhesive and show enhanced retention in body cavities (Felt et al 1999). Finally, since PAAs act as adsorption and penetration enhancers they have been suggested for use as facilitators of the paracellular permeation of the hydrophilic peptides (Junginger et al 2000). We have recently discovered a new class of PAA-based copolymers and gels, whereby PAA is modified with a triblock copolymer of poly(ethylene oxide) (PEO) and poly- (propylene oxide) (PPO) (Pluronic, or Poloxamer), which is attached to PAA via carbon–carbon bond (Bromberg 1998a–e ; Bromberg & Ron 1998 ; Bromberg & Barr 1999 ; Bromberg & Magner 1999 ; Bromberg & Salvati 1999 ; Bromberg & Temchenko 1999 ; Bromberg 2001a, b). The copolymers of PAA and Pluronics (termed Pluronic-PAA herein) possess properties beneficial for topical delivery that complement mucoadhesion of PAA, such as the ability to self-assemble in aqueous solutions forming micelle-like aggregates (Bromberg 1998c, d ; Huibers et al 1999). The Pluronic-PAA micelles are capable of solubilizing hydrophobic drugs in aqueous solutions (Bromberg & Temchenko 1999). The copolymers are muco- adhesive (Bromberg 1999), non-irritating (Bromberg & Ron 1998), and enhance bioavailability of drugs (Bromberg 2001a). In this study, we concentrated on Pluronic-PAA as protein formulation aids. It appears that when Pluronic-PAA and model protein solution forms a gel at 37C, the protein aggregation is impeded, while the tertiary structure of human proteins such as insulin, haemoglobin and Department of Physics and Center for Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA L. E. Bromberg Correspondence : L. E. Bromberg, 15 Sherwood Road, Swampscott, MA 01907, USA. E-mail cpbrolevyahoo.com 541 Downloaded from https://academic.oup.com/jpp/article/53/4/541/6149749 by guest on 18 July 2022