Abstract
Purpose. Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl).
Methods. This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (Kobs, ΔH, and N) were determined.
Results. As the KC1 concentration was increased, Kobs decreased thus establishing the salt dependence of the interaction. The linear variation of ΔGobs with ΔSobs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KC1 concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HC1 was greater than those of the electrostatic attractions.
Conclusions. We have shown that the interaction between PAA and procaine HC1 is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HC1 molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HC1 complex.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
M. R. Jenquin and J. W. McGinity. Characterisation of acrylic resin matrix films and mechanisms of drug-polymer interactions. Int. J. Pharm. 101:23–34 (1994).
A. Harada and K. Kataoka. Novel polyion complex micelles entrapping enzyme molecules in the core: Preparation of narrowly distributed micelles from lysozyme and poly (ethylene glycol)-poly(aspartic acid) block copolymer in aqueous medium. Macromolecules 31:288–294 (1998).
E. Allémann, R. Gurny, and E. Doelker. Drug loaded nanoparticles: Preparation methods and drug targeting issues. Eur. J. Pharm. Biopharm. 39:173–191 (1993).
S. S. Davis. Biomedical applications of nanotechnology-implications for drug targeting and gene therapy. Trends Biotechnol. 15:217–224 (1997).
T. Govender, S. Stolnik, M. C. Garnett, L. Illum, and S. S. Davis. PLGA nanoparticles prepared by nanoprecipitation: Drug loading and release studies of a water soluble drug. J. Contr. Rel. 57:171–185 (1999).
P. R. Dash, V. Toncheva, E. Schacht, and L. W. Seymour. Synthetic polymers for vectorial delivery of DNA: characterisation of polymer-DNA complexes by photon correlation spectroscopy and stability to nuclease degradation and disruption by polyanions in vitro. J. Contr. Rel. 48:269–276 (1997).
T. Wiseman, S. Williston, J. F. Brandts, and L. N. Lin. Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal. Biochem. 179:131–137 (1989).
M. L. Doyle. Characterisation of binding interactions by isothermal titration calorimetry. Curr. Opin. Biotechnol. 8:31–35 (1997).
M. F. Lu, S. Borodkin, L. Woodward, P. Li, C. Diesner, L. Hernandez, and M. Vadnere. A polymer carrier system for taste masking of macrolide antibiotics. Pharm. Res. 8:706–712 (1991).
B. O. Haglund, R. Joshi, and K. J. Himmelstein. An in situ gelling system for parenteral delivery. J. Contr. Rel. 41:229–235 (1996).
J. R. Robinson and W. J. Bologna. Vaginal and reproductive system treatments using a bioadhesive polymer. J. Contr. Rel. 28:87–94 (1994).
T. Lundback and T. Hard. Salt dependence of free energy, enthalpy, and entropy of nonsequence specific DNA binding. J. Phys. Chem. 100:17690–17695 (1996).
G. S. Manning. The molecular theory of polyelectrolyte solutions with applications to the electrostatic properties of polynucleotides. Quart. Rev. Biophys. 2:179–246 (1978).
G. S. Manning. Limiting laws and counterion condensation in polyelectrolyte solutions. I. Colligative properties. J. Phys. Chem. 51:924–933 (1969).
G. S. Manning. On the application of polyelectrolyte limiting laws to the helix-coil transition of DNA. I. Excess univalent cations. BIPMA. 11:937–949 (1972).
M. T. Jr. Record, C. F. Anderson, and T. M. Lohman. Thermodynamic analysis of ion effects on the binding and conformational equilibria of proteins and nucleic acids: the roles of ion association or release, screening, and ion effects on water activity. Quart. Rev. Biophys. 2:103–178 (1978).
M. T. Jr. Record, M. T. Lohman, and P. de Haseth. Ion effects on ligand-nucleic acid interactions. J. Mol. Bio. 107:145–158 (1976).
I. Haq, P. Lincoln, D. Suh, B. Norden, B. Z. Chowdhry, and J. B. Chairs. Interaction of Δ-and Λ-[Ru(Phen)2DPPZ]2+ with DNA: A calorimetric and equilibrium binding study. J. Am. Chem. Soc. 117:4788–4796 (1995).
T. Lundback, H. Hansson, S. Knapp, R. Ladenstein, and T. Hard. Thermodynamic characterization of non-sequence-specific DNA-binding by the sso7d protein from sulfolobus solfataricus. J. Mol. Biol. 276:775–786 (1998).
T. M. Lohman, P. L. de Haseth, and M. T. Jr. Record. Pentalysine-deoxyribonucleic acid interactions: A model for the general effects of ion concentrations on the interactions of proteins with nucleic acids. Biochemistry 19:3522–3530 (1980).
T. M. Lohman and D. P. Mascotti. Thermodynamics of ligand-nucleic acid interactions. Methods Enzymol. 221:400–424 (1992).
L. B. Overman, W. Bujalowski, and T. M. Lohman. Equilibrium binding of Escherichia coli single-strand binding protein to single-strand nucleic acids in the (SSB)65 binding mode. Cation and anion effects and polynucleotide specificity. Biochemistry 27:456–471 (1988).
L. B. Overman and T. M. Lohman. Linkage of pH, anion and cation effects in protein-nucleic acid equilibria. J. Mol. Biol. 236:165–178. (1994).
D. P. Mascotti and T. M. Lohman. Thermodynamics of single-strand RNA binding to oligosines containing tryptophan. Biochemistry 31:8932–8946 (1992).
H. Aki and M. Yamamoto. Biothermodynamic characterization of monocarboxylic and dicarboxylic aliphatic acids binding to human serum albumin: A flow microcalorimetric study. Biophys. Chem. 46:91–99 (1993).
H. Aki, M. Goto, and M. Yamamoto. Thermodynamic aspects of the molecular recognition of drugs by human serum albumin. Thermochimica Acta 251:379–388 (1995).
J. D. McGhee and P. J. Hippel. Theoretical aspects of DNA-protein interactions: Co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. J. Mol. Biol. 86:469–489 (1974).
A. C. Moffat, J. V. Jackson, M. S. Moss, and B. Widdop Clarke's isolation and identification of drugs, The Pharmaceutical Press, London, 1986.
C. B. Black and J. A. Cowan. Quantitative evaluation of electrostatic and hydrogen-binding contributions to metal cofactor binding to nucleic acids. J. Am. Chem. Soc. 116:1174–1178 (1994).
J. J. Kiefer, P. Somasundaran, and K. P. Ananthapadmanabhan. Interaction of tetradecyltrimethylammonium bromide with poly (acrylic acid) and poly (methacrylic acid). Effect of charge density. Langmuir 9:1187–1192 (1993).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Govender, T., Ehtezazi, T., Stolnik, S. et al. Complex Formation Between The Anionic Polymer (PAA) and a Cationic Drug (Procaine HC1): Characterization by Microcalorimetric Studies. Pharm Res 16, 1125–1131 (1999). https://doi.org/10.1023/A:1018912522342
Issue Date:
DOI: https://doi.org/10.1023/A:1018912522342