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Molecularly Imprinted Polymer Nanocarriers for Sustained Release of Erythromycin

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Abstract

Purpose

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

Methods

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.

Results

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.

Conclusions

Sustained release of erythromycin in physiological buffer was demonstrated.

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Abbreviations

AIBN:

2,2’-azobisisobutyronitrile

BET:

Brunauer, Emmett, and Teller

BJH:

Barrett, Joyner, and Halenda

Boc:

Tert-butyloxycarbonyl

DLS:

Dynamic light scattering

EDMA:

Ethylene glycol dimethacrylate

ERY:

Erythromycin

HPLC:

High-performance liquid chromatography

MAA:

Methacrylic acid

MeOH:

Methanol

MIP:

Molecularly imprinted polymer

NIP:

Non-imprinted polymer

PBS:

Phosphate buffered saline

Phe:

Phenylalanine

PLS:

Partial least square

PRESS:

Predicted residual sums of squares

RSS:

Residual sum of squares

SPE:

Solid-phase extraction

TEM:

Transmission electron microscope

TFA:

Trifluoroacetic acid

TRIM:

Trimethylolpropane trimethacrylate

UV:

Ultraviolet

References

  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.

    Chapter  Google Scholar 

  2. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23(3):590–615.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  6. Shinkai M, Henke MO, Rubin BK. Macrolide antibiotics as immunomodulatory medications: Proposed mechanisms of action. Pharmacol Ther. 2008;117(3):393–405.

    Article  CAS  PubMed  Google Scholar 

  7. Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ transplantation. Drugs. 2007;67(3):369–91.

    Article  CAS  PubMed  Google Scholar 

  8. Ruygrok PN, Muller DW, Serruys PW. Rapamycin in cardiovascular medicine. Int Med J. 2003;33(3):103–9.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Chapter  Google Scholar 

  14. Alvarez-Lorenzo C, Concheiro A. Molecularly imprinted materials as advanced excipients for drug delivery systems. Biotechnol Annu Rev. 2006;12:225–68.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Kempe H, Kempe M. Influence of salt ions on binding to molecularly imprinted polymers. Anal Bioanal Chem. 2010;396(4):1599–606.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  29. Kempe M, Mosbach K. Receptor binding mimetics: a novel molecularly imprinted polymer. Tetrahedron Lett. 1995;36(20):3563–6.

    Article  CAS  Google Scholar 

  30. Kempe M. Antibody mimicking polymers as chiral stationary phases in HPLC. Anal Chem. 1996;68(11):1948–53.

    Article  CAS  PubMed  Google Scholar 

  31. Ye L, Cormack PAG, Mosbach K. Molecularly imprinted monodisperse microspheres for competitive radioassay. Anal Commun. 1999;36(2):35–8.

    Article  CAS  Google Scholar 

  32. Connolly ML. Computation of molecular volume. J Am Chem Soc. 1985;107(5):1118–24.

    Article  CAS  Google Scholar 

  33. Sibrian-Vazquez M, Spivak DA. Molecular imprinting made easy. J Am Chem Soc. 2004;126(25):7827–33.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  39. Chen Z, Ye L. Controlling size and uniformity of molecularly imprinted nanoparticles using auxiliary template. J Mol Recognit. 2012;25(6):370–6.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

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.

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Authors and Affiliations

  1. Nanomedicine and Biomaterials, Department of Experimental Medical Science, Lund University, Biomedical Center, D11, 22184, Lund, Sweden

    Henrik Kempe, Anna Parareda Pujolràs & Maria Kempe

Authors
  1. Henrik Kempe
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  2. Anna Parareda Pujolràs
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  3. Maria Kempe
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Corresponding author

Correspondence to Maria Kempe.

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Kempe, H., Parareda Pujolràs, A. & Kempe, M. Molecularly Imprinted Polymer Nanocarriers for Sustained Release of Erythromycin. Pharm Res 32, 375–388 (2015). https://doi.org/10.1007/s11095-014-1468-2

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  • DOI: https://doi.org/10.1007/s11095-014-1468-2

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