Pharmaceutical Research

, Volume 32, Issue 2, pp 375–388 | Cite as

Molecularly Imprinted Polymer Nanocarriers for Sustained Release of Erythromycin

  • Henrik Kempe
  • Anna Parareda Pujolràs
  • Maria Kempe
Research Paper



To develop and evaluate molecularly imprinted nanocarriers for sustained release of erythromycin in physiological buffer media.


Erythromycin-imprinted poly(methacrylic acid–co–trimethylolpropane trimethacrylate) nanocarriers and corresponding control nanocarriers were prepared by free-radical precipitation polymerization. The nanocarriers were characterized by transmission electron microscopy, dynamic light scattering, and nitrogen sorption analysis. Binding studies were carried out with erythromycin and five structurally unrelated drugs. Molecular descriptors of the drugs were computed and correlated to measured binding data by multivariate data analysis. Loading with erythromycin and in vitro release studies were carried out in physiological buffer media. Kinetic models were fitted to drug release data.


The template affected the size and morphology of the nanocarriers. Binding isotherms showed that erythromycin-imprinted nanocarriers had a higher erythromycin binding capacity than corresponding control nanocarriers. Multivariate data analysis, correlating binding to molecular descriptors of the drugs, indicated a molecular imprinting effect. Erythromycin loading capacity was 76 mg/g with a loading efficiency of 87%. Release studies in physiological buffer showed an initial burst release of a quarter of loaded erythromycin during the first day and an 82% release after a week. The release was best described by the Korsmeyer-Peppas model.


Sustained release of erythromycin in physiological buffer was demonstrated.


antibiotics drug delivery molecular imprinting nanoparticles sustained release 





Brunauer, Emmett, and Teller


Barrett, Joyner, and Halenda




Dynamic light scattering


Ethylene glycol dimethacrylate




High-performance liquid chromatography


Methacrylic acid




Molecularly imprinted polymer


Non-imprinted polymer


Phosphate buffered saline




Partial least square


Predicted residual sums of squares


Residual sum of squares


Solid-phase extraction


Transmission electron microscope


Trifluoroacetic acid


Trimethylolpropane trimethacrylate





This work was supported by Greta och Johan Kocks Stiftelser, Stiftelsen Syskonen Svenssons fond för Medicinsk forskning, and Magnus Bergvalls Stiftelse. Dr. Eric Carlemalm and Ms. Birgitta Lindén is acknowledged for help with TEM and BET analysis, respectively.

Supplementary material

11095_2014_1468_MOESM1_ESM.docx (726 kb)
ESM 1 (DOCX 726 kb)


  1. 1.
    Xu Z-Q, Flavin MT, Eiznhamer DA. Macrolides and ketolides. In: Dougherty TJ, Pucci MJ, editors. Antibiotic Discovery and Development. New York: Springer; 2012. p. 181–228.CrossRefGoogle Scholar
  2. 2.
    Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23(3):590–615.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Fumimori T, Honda S, Migita K, Hamada M, Yoshimuta T, Honda J, et al. Erythromycin suppresses the expression of cyclooxygenase-2 in rheumatoid synovial cells. J Rheumatol. 2004;31(3):436–41.PubMedGoogle Scholar
  4. 4.
    Ren W, Blasier R, Peng X, Shi T, Wooley PH, Markel D. Effect of oral erythromycin therapy in patients with aseptic loosening of joint prostheses. Bone. 2009;44(4):671–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Suzuki J, Ogawa M, Hishikari K, Watanabe R, Takayama K, Hirata Y, et al. Novel effects of macrolide antibiotics on cardiovascular diseases. Cardiovasc Ther. 2012;30(6):301–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Shinkai M, Henke MO, Rubin BK. Macrolide antibiotics as immunomodulatory medications: Proposed mechanisms of action. Pharmacol Ther. 2008;117(3):393–405.PubMedCrossRefGoogle Scholar
  7. 7.
    Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ transplantation. Drugs. 2007;67(3):369–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Ruygrok PN, Muller DW, Serruys PW. Rapamycin in cardiovascular medicine. Int Med J. 2003;33(3):103–9.CrossRefGoogle Scholar
  9. 9.
    Bosnjakovic A, Mishra MK, Ren W, Kurtoglu YE, Shi T, Fan D, et al. Poly (amidoamine) dendrimer-erythromycin conjugates for drug delivery to macrophages involved in periprosthetic inflammation. Nanomedicine. 2011;7(3):284–94.PubMedCrossRefGoogle Scholar
  10. 10.
    Doadrio JC, Sousa EMB, Izquierdo-Barb I, Doadrio AL, Perez-Pariente J, Vallet-Regí M. Functionalization of mesoporous materials with long alkyl chains as a strategy for controlling drug delivery pattern. J Mater Chem. 2006;16(5):462–6.CrossRefGoogle Scholar
  11. 11.
    Portilla-Arias JA, Camargo B, García-Alvarez M, de Ilarduya AM, Muñoz-Guerra S. Nanoparticles made of microbial poly(γ-glutamate)s for encapsulation and delivery of drugs and proteins. J Biomat Sci. 2009;20(7–8):1065–79.CrossRefGoogle Scholar
  12. 12.
    Alexander C, Andersson HS, Andersson LI, Ansell RJ, Kirsch N, Nicholls IA, et al. Molecular imprinting science and technology: a survey of the literature for the years up to and including 2003. J Mol Recognit. 2006;19(2):106–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Kempe H, Kempe M. Molecularly imprinted polymers. In: Albericio F, Tulla-Puche J, editors. The Power of Functional Resins in Organic Synthesis. Weinheim: Wiley; 2008. p. 15–44.CrossRefGoogle Scholar
  14. 14.
    Alvarez-Lorenzo C, Concheiro A. Molecularly imprinted materials as advanced excipients for drug delivery systems. Biotechnol Annu Rev. 2006;12:225–68.PubMedCrossRefGoogle Scholar
  15. 15.
    Kryscio DR, Peppas NA. Mimicking biological delivery through feedback-controlled drug release systems based on molecular imprinting. AIChE J. 2009;55(6):1311–24.CrossRefGoogle Scholar
  16. 16.
    Fernández-González A, Guardia L, Badía-Laíño R, Díaz-García ME. Mimicking molecular receptors for antibiotics – analytical implications. Trends Anal Chem. 2006;25(10):949–57.CrossRefGoogle Scholar
  17. 17.
    Cederfur J, Pei Y, Zihui M, Kempe M. Synthesis and screening of a molecularly imprinted polymer library targeted for penicillin G. J Comb Chem. 2003;5(1):67–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Benito-Pena E, Moreno-Bondi MC, Aparicio S, Orellana G, Cederfur J, Kempe M. Molecular engineering of fluorescent penicillins for molecularly imprinted polymer assays. Anal Chem. 2006;78(6):2019–27.PubMedCrossRefGoogle Scholar
  19. 19.
    Kempe H, Kempe M. Influence of salt ions on binding to molecularly imprinted polymers. Anal Bioanal Chem. 2010;396(4):1599–606.PubMedCrossRefGoogle Scholar
  20. 20.
    Kempe H, Kempe M. QSRR analysis of β-lactam antibiotics on a penicillin G targeted MIP stationary phase. Anal Bioanal Chem. 2010;398(7–8):3087–96.PubMedCrossRefGoogle Scholar
  21. 21.
    Levi R, McNiven S, Piletsky SA, Cheong S-H, Yano K, Karube I. Optical detection of chloramphenicol using molecularly imprinted polymers. Anal Chem. 1997;69(11):2017–21.PubMedCrossRefGoogle Scholar
  22. 22.
    Mirzaei M, Najafabadi SAH, Abdouss M, Azodi-Deilami S, Asadi E, Hosseini MRM, et al. Preparation and utilization of microporous molecularly imprinted polymer for sustained release of tetracycline. J Appl Poly Sci. 2013;128(3):1557–62.Google Scholar
  23. 23.
    Shi Y, Lv H, Lu X, Huang Y, Zhang Y, Xue W. Uniform molecularly imprinted poly (methacrylic acid) nanospheres prepared by precipitation polymerization: the control of particle features suitable for sustained release of gatifloxacin. J Mater Chem. 2012;22(9):3889–98.CrossRefGoogle Scholar
  24. 24.
    Siemann M, Andersson LI, Mosbach K. Separation and detection of macrolide antibiotics by HPLC using macrolide-imprinted synthetic polymers as stationary phases. J Antibiot. 1997;50(1):89–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Song S, Wu A, Shi X, Li R, Lin Z, Zhang D. Development and application of molecularly imprinted polymers as solid-phase sorbents for erythromycin extraction. Anal Bioanal Chem. 2008;390(8):2141–50.PubMedCrossRefGoogle Scholar
  26. 26.
    Geng L, Kou X, Lei J, Su H, Maa G, Su Z. Preparation, characterization and adsorption performance of molecularly imprinted microspheres for erythromycin using suspension polymerization. J Chem Technol Biotechnol. 2012;87(5):635–42.CrossRefGoogle Scholar
  27. 27.
    Kou X, Lei J, Geng L, Deng H, Jiang Q, Zhang G, et al. Synthesis, characterization and adsorption behavior of molecularly imprinted nanospheres for erythromycin using precipitation polymerization. J Nanosci Nanotechnol. 2012;12(9):7388–94.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang Z, Yang X, Zhang H, Zhang M, Luo L, Hu Y, et al. Novel molecularly imprinted polymers based on multi-walled carbon nanotubes with binary functional monomer for the solid-phase extraction of erythromycin from chicken muscle. J Chromatogr B. 2011;879(19):1617–24.CrossRefGoogle Scholar
  29. 29.
    Kempe M, Mosbach K. Receptor binding mimetics: a novel molecularly imprinted polymer. Tetrahedron Lett. 1995;36(20):3563–6.CrossRefGoogle Scholar
  30. 30.
    Kempe M. Antibody mimicking polymers as chiral stationary phases in HPLC. Anal Chem. 1996;68(11):1948–53.PubMedCrossRefGoogle Scholar
  31. 31.
    Ye L, Cormack PAG, Mosbach K. Molecularly imprinted monodisperse microspheres for competitive radioassay. Anal Commun. 1999;36(2):35–8.CrossRefGoogle Scholar
  32. 32.
    Connolly ML. Computation of molecular volume. J Am Chem Soc. 1985;107(5):1118–24.CrossRefGoogle Scholar
  33. 33.
    Sibrian-Vazquez M, Spivak DA. Molecular imprinting made easy. J Am Chem Soc. 2004;126(25):7827–33.PubMedCrossRefGoogle Scholar
  34. 34.
    Ray RS, Mehrotra S, Shankar U, Suresh Babu G, Joshi PC, Hans RK. Evaluation of UV-induced superoxide radical generation potential of some common antibiotics. Drug Chem Toxicol. 2001;24(2):191–200.PubMedCrossRefGoogle Scholar
  35. 35.
    Jedliński Z, Paprotny J. Synthesis and polymerisation of some N-alkylolacryl-amides. III. Polymerization of 2-methacrylamido-2-methyl-propanediol-l,3 and 2-methacrylamido-2-methylpropanol-1. J Polym Sci Part A-1. 1967;5(11):2957–60.CrossRefGoogle Scholar
  36. 36.
    Karlsson JG, Karlsson B, Andersson LI, Nicholls IA. The roles of template complexation and ligand binding conditions on recognition in bupivacaine molecularly imprinted polymers. Analyst. 2004;129(5):456–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang Y, Song D, Lanni LM, Shimizu KD. Importance of functional monomer dimerization in the molecular imprinting process. Macromolecules. 2010;43(15):6284–94.CrossRefGoogle Scholar
  38. 38.
    Cacho C, Turiel E, Martin-Esteban A, Pérez-Conde C, Cámara C. Characterisation and quality assessment of binding sites on a propazine-imprinted polymer prepared by precipitation polymerization. J Chromatogr B. 2004;802(2):347–53.CrossRefGoogle Scholar
  39. 39.
    Chen Z, Ye L. Controlling size and uniformity of molecularly imprinted nanoparticles using auxiliary template. J Mol Recognit. 2012;25(6):370–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Henrik Kempe
    • 1
  • Anna Parareda Pujolràs
    • 1
  • Maria Kempe
    • 1
  1. 1.Nanomedicine and Biomaterials, Department of Experimental Medical ScienceLund UniversityLundSweden

Personalised recommendations