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Random amphiphilic copolymeric sub-micro particles as a carrier shielding from enzymatic attack for peptides and proteins delivery

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Abstract

The development of peptide drugs and therapeutic proteins is limited by their rapid clearance in liver and other body tissues by proteolytic enzymes, and consequently peptides and proteins are difficult to administer except by injection. There is a growing effort to circumvent these problems by designing strategies to deliver these drugs to specific site of the body. Among them, this peptide carrier presents several advantages for protein therapy including stability in physiological buffer and lack of toxicity. Here, we have been developing a novel bioadhesive polymer matrix that protects entrapped proteins and peptides from degradation by serine protease. Poly(2-lactobionamidoethyl methacrylate-ran-3-acrylamidophenylboronic acid-ran-methoxypolyethylene glycol methacrylate) glycopolymers were synthesized and could self-assemble into the sub-micro particles. The loading capability of insulin, as a drug model, and the insulin release from the particles were assessed. The inhibitory effect of the particles toward trypsin, elastase, and chymotrypsin was evaluated in vitro. Insulin was effectively encapsulated, up to 10%, and could be stained release in vitro. These glycopolymers displayed a strong inhibitory effect toward these exopeptidases. Therefore, novel glycopolymers with excellent inhibitory activity against proteolytic enzymes and reasonable mucoadhesivity might be a useful tool in overcoming the enzymatic barrier to the mucosal delivery (e.g. nasal and buccal) of therapeutic peptides or proteins.

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References

  1. Langguth P, Merkle HP, Amidon GL. Oral absorption of peptides: the effect of absorption site and enzyme inhibition on the systemic availability of metkephamid. Pharm Res. 1994;11:528–35.

    Article  CAS  Google Scholar 

  2. Yamamoto A, Taniguchi T, Rikyuu K, Tsuji T, Fujita T, Murakami M, Muranishi S. Effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats. Pharm Res. 1994;11:1496–500.

    Article  CAS  Google Scholar 

  3. Bernkop-Schnurch A, Pasta M. Intestinal peptide and protein delivery: novel bioadhesive drug-carrier matrix shielding from enzymatic attack. J Pharm Sci. 1998;87:430–4.

    Article  CAS  Google Scholar 

  4. Smoum R, Rubinstein A, Srebnik M. A study of the effect on nucleophilic hydrolytic activity of pancreatic elastase, trypsin, chymotrypsin, and leucine aminopeptidase by boronic acids in the presence of arabinogalactan: a subsequent study on the hydrolytic activity of chymotrypsin by boronic acids in the presence of mono-, di-, and trisaccharides. Bioorg Chem. 2003;31:464–74.

    Article  CAS  Google Scholar 

  5. Tsilikounas E, Kettner CA, Bachovchin WW. Boron-11 NMR spectroscopy of peptide boronic acid inhibitor complexes of alpha-lytic protease. Direct evidence for tetrahedral boron in both boron-histidine and boron-serine adduct complexes. Biochemistry. 1993;32:12651–5.

    Article  CAS  Google Scholar 

  6. London RE, Gabel SA. Fluorine-19 NMR studies of fluorobenzeneboronic acids. Kinetic characterization of the interaction with subtilisin Carlsberg and model ligands. J Am Chem Soc. 1994;116:2570–5.

    Article  CAS  Google Scholar 

  7. Zhong S, Jordan F, Kettner C, Polgar L. Observation of tightly bound 11B nuclear magnetic resonance signals on serine protease. Direct solution evidence for tertrahedral geometry around the boron in the putative transition-state analogues. J Am Chem Soc. 1991;113:9429–35.

    Article  CAS  Google Scholar 

  8. Suenaga H, Yamamoto H, Shinkai S. Screening of boronic acid for strong inhibition of the hydrolytic activity of α-chymotrypsin and for sugar sensing associated with a large fluorescence change. Pure Appl Chem. 1996;68:2179–86.

    Article  CAS  Google Scholar 

  9. Patterson S, Smith BD, Taylor RE. Tuning the affinity of a synthetic sialic acid receptor using combinatorial chemistry. Tetrahedron Lett. 1998;39:3111–4.

    Article  CAS  Google Scholar 

  10. Qureshi S, Al-Shabanah A, Al-Harbi MM, Al-Bekairi AM, Raza M. Boric acid enhances in vivo Ehrlich ascites carcinoma cell proliferation in Swiss albino mice. Toxicology. 2001;165:1–11.

    Article  CAS  Google Scholar 

  11. Lamiral V, Melia E, Haddleton DM. Synthetic glycopolymers: an overview. Eur Polym J. 2004;40:431–49.

    Article  Google Scholar 

  12. Auzély-Velty R, Cristea M, Rinaudo M. Galactosylated N-vinylpyrrolidone-maleic acid copolymers: synthesis, characterization, and interaction with lectins. Biomacromoleculars. 2002;3:998–1005.

    Article  Google Scholar 

  13. Xiao NY, Li AL, Liang H, Lu J. A well-defined novel aldehyde-functionalized glycopolymer: synthesis, micelle formation, and its protein immobilization. Macromoleculars. 2008;41:2374–80.

    Article  CAS  Google Scholar 

  14. Jin XJ, Zhang XG, Wu ZM, Teng DY, Zhang XJ, Wang YX, et al. Amphiphilic random glycopolymer based on phenylboronic acid: synthesis, characterization, and potential as glucose-sensitive matrix. Biomacromoleculars. 2009;10:1337–45.

    Article  CAS  Google Scholar 

  15. Peppas NA, Little MD, Huang Y, Bioadhesive controlled release systems. In: Wise DL, Brannon-Peppas L, Klibanov AM, Langer RL, Mikos AG, Peppas NA, DJ Trantolo, GE Wnek, MJ Yaszemski, editors. Handbook of pharmaceutical controlled release technology. Dekker: New York; 2000. pp. 255–69.

  16. Artursson P, Brown L, Dix J, Goddard P, Petrak K. Preparation of sterically stabilized nanoparticles by desolvation from graft copolymers. J Polym Sci Part A. 1990;28:2651–63.

    Article  CAS  Google Scholar 

  17. He L, Read ES, Armes SP, Adams DJ, Lönngren J. Synthesis of controlled-structure primary amine-based methacrylic polymers by living radical polymerization. Macromolecules. 2007;40:4429–38.

    Article  CAS  Google Scholar 

  18. Williams TJ, Plessas NR, Goldstein IJ. A new class of model glycolipids: synthesis, characterization, and interaction with lectins. Arch Biochem Biophys. 1979;195:145–51.

    Article  CAS  Google Scholar 

  19. Tian Z, Wang M, Zhang A, Feng Z. Preparation and evaluation of novel amphiphilic glycopeptide block copolymers as carriers for controlled drug release. Polymer. 2008;49:446–54.

    Article  CAS  Google Scholar 

  20. Yoon KR, Ramaraj B, Leea SM, Kim DP. Surface initiated-atom transfer radical polymerization of a sugar methacrylate on gold nanoparticles. Surf Interface Anal. 2008;40:1139–43.

    Article  CAS  Google Scholar 

  21. Narain R, Armes SP. Synthesis and aqueous solution properties of novel sugar methacrylate-based homopolymers and block copolymers. Biomacromolecules. 2003;4:1746–58.

    Article  CAS  Google Scholar 

  22. Lee MC, Kabilan S, Hussain A, Yang XP, Blyth J, Lowe CR. Glucose-sensitive holographic sensors for monitoring bacterial growth. Anal Chem. 2004;76:5748–55.

    Article  CAS  Google Scholar 

  23. Kaneko T, Hamada K, Chen MQ, Akashi M. One-step formation of morphologically controlled nanoparticles with projection coronas. Macromolecules. 2004;37:501–6.

    Article  CAS  Google Scholar 

  24. Ohya Y, Cai R, Nishizawa H, Hara K, Ouchi T. Preparation of PEG-g-chitosan nanoparticles as peptide drug carriers. STP Pharm Sci. 2000;10:77–82.

    CAS  Google Scholar 

  25. Miller RA, Presley AD, Francis MB. Self-assembling light-harvesting systems from synthetically modified tobacco mosaic virus coat proteins. J Am Chem Soc. 2007;129:3104–9.

    Article  CAS  Google Scholar 

  26. Ballister ED, Lai AH, Zuckermann RN, Cheng YF, Mougous JD. In vitro self-assembly of tailorable nanotubes from a simple protein building block. Proc Natl Acad Sci USA. 2008;105:3733–8.

    Article  CAS  Google Scholar 

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Acknowledgment

The National Natural Science Foundation of Shandong (Grants ZR2009CM052) and The Science and Technology Project of Jinan City Health Bureau (Grants 2007-32 and 2008-11) are gratefully acknowledged for the financial support to this work.

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Authors and Affiliations

  1. Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Qingyi Meng & Jiaxiang Wang

  2. Department of Vascular Surgery, Affiliated Jinan Central Hospital of Shandong University, Jinan, 250013, China

    Qingyi Meng & Limin Tian

Authors
  1. Qingyi Meng
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  2. Limin Tian
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  3. Jiaxiang Wang
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Correspondence to Jiaxiang Wang.

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Meng, Q., Tian, L. & Wang, J. Random amphiphilic copolymeric sub-micro particles as a carrier shielding from enzymatic attack for peptides and proteins delivery. J Mater Sci: Mater Med 23, 991–998 (2012). https://doi.org/10.1007/s10856-012-4568-8

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  • DOI: https://doi.org/10.1007/s10856-012-4568-8

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