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Magnetically Responsive Polymeric Microparticles for Oral Delivery of Protein Drugs

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Purpose

Protein drugs cannot be delivered efficiently through oral routes. To address this challenge, we evaluated the effect of prolonged gastrointestinal transit on the bioavailability of insulin carried by magnetically responsive microparticles in the presence of an external magnetic field.

Methods

Magnetite nanocrystals and insulin were coencapsulated into poly(lactide-co-glycolide) (PLGA) microparticles and their effects on hypoglycemia were evaluated in mice in the presence of a circumferentially applied external magnetic field.

Results

A single administration of 100 U/kg of insulin–magnetite–PLGA microparticles to fasted mice resulted in a reduction of blood glucose levels of up to 43.8% in the presence of an external magnetic field for 20 h (bioavailability = 2.77 ± 0.46 and 0.87 ± 0.29% based on glucose and ELISA assay, respectively), significantly higher than similarly dosed mice without a magnetic field (bioavailability = 0.66 ± 0.56 and 0.30 ± 0.06%, based on glucose and ELISA assay, respectively).

Conclusions

A substantially improved hypoglycemic effect was observed in mice that were orally administered with insulin–magnetite–PLGA microparticles in the presence of an external magnetic field, suggesting that magnetic force can be used to improve the efficiency of orally delivered protein therapeutics.

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References

  1. M. Goldberg I. Gomez-Orellana (2003) ArticleTitleChallenges for the oral delivery of macromolecules Nat. Rev., Drug Discov. 2 289–295 Occurrence Handle10.1038/nrd1067 Occurrence Handle1:CAS:528:DC%2BD3sXisFWkt7s%3D

    Article  CAS  Google Scholar 

  2. A. M. Lowman M. Morishita M. Kajita T. Nagai N. A. Peppas (1999) ArticleTitleOral delivery of insulin using pH-responsive complexation gels J. Pharm. Sci. 88 933–937 Occurrence Handle10.1021/js980337n Occurrence Handle1:CAS:528:DyaK1MXkvVCrsL8%3D Occurrence Handle10479357

    Article  CAS  PubMed  Google Scholar 

  3. K. Iwanaga S. Ono K. Narioka M. Kakemi K. Morimoto S. Yamashita Y. Namba N. Oku (1999) ArticleTitleApplication of surface coated liposomes for oral delivery of peptide: effects of coating the liposome's surface on the GI transit of insulin J. Pharm. Sci. 88 248–252 Occurrence Handle10.1021/js980235x Occurrence Handle1:CAS:528:DyaK1MXivFGisA%3D%3D Occurrence Handle9950646

    Article  CAS  PubMed  Google Scholar 

  4. M. A. Kisel L. N. Kulik I. S. Tsybovsky A. P. Vlasov M. S. Vorob'yov E. A. Kholodova Z. V. Zabarovskaya (2001) ArticleTitleLiposomes with phosphatidylethanol as a carrier for oral delivery of insulin: studies in the rat Int. J. Pharm. 216 105–114 Occurrence Handle10.1016/S0378-5173(01)00579-8 Occurrence Handle1:CAS:528:DC%2BD3MXitFyru7k%3D Occurrence Handle11274812

    Article  CAS  PubMed  Google Scholar 

  5. H. Chen V. Torchilin R. S. Langer (1996) ArticleTitlePolymerized liposomes as potential oral vaccine carriers: stability and bioavailability J. Control. Release 42 263–272 Occurrence Handle10.1016/0168-3659(96)01459-9 Occurrence Handle1:CAS:528:DyaK28XlvFGgsrk%3D

    Article  CAS  Google Scholar 

  6. E. Mathiowitz J. S. Jacob Y. S. Jong G. P. Carino D. E. Chickering P. Chaturvedi C. A. Santos K. Vijayaraghavan S. Montgomery M. Bassett C. Morrell (1997) ArticleTitleBiologically erodable microsphere as potential oral drug delivery system Nature 386 410–414 Occurrence Handle10.1038/386410a0 Occurrence Handle1:CAS:528:DyaK2sXit1Wrt7s%3D Occurrence Handle9121559

    Article  CAS  PubMed  Google Scholar 

  7. G. P. Carino J. S. Jacob E. Mathiowitz (2000) ArticleTitleNanosphere based oral insulin delivery J. Control. Release 65 261–269 Occurrence Handle10.1016/S0168-3659(99)00247-3 Occurrence Handle1:CAS:528:DC%2BD3cXhtl2qsL0%3D Occurrence Handle10699286

    Article  CAS  PubMed  Google Scholar 

  8. A. Fasano S. Uzzau (1997) ArticleTitleModulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model J. Clin. Invest. 99 1158–1164 Occurrence Handle1:CAS:528:DyaK2sXhvFyisLY%3D Occurrence Handle9077522 Occurrence Handle10.1172/JCI119271

    Article  CAS  PubMed  Google Scholar 

  9. T. Uchiyama T. Sugiyama Y. S. Quan A. Kotani N. Okada T. Fujita S. Muranishi A. Yamamoto (1999) ArticleTitleEnhanced permeability of insulin across the rat intestinal membrane by various absorption enhancers: their intestinal mucosal toxicity and absorption-enhancing mechanism of n-lauryl-beta-d-maltopyranoside J. Pharm. Pharmacol. 51 1241–1250 Occurrence Handle1:CAS:528:DC%2BD3cXhslOnug%3D%3D Occurrence Handle10632081

    CAS  PubMed  Google Scholar 

  10. A. Yamamoto T. Okagawa A. Kotani T. Uchiyama T. Shimura S. Tabata S. Kondo S. Muranishi (1997) ArticleTitleEffects of different absorption enhancers on the permeation of ebiratide, an ACTH analogue, across intestinal membranes J. Pharm. Pharmacol. 49 1057–1061 Occurrence Handle1:CAS:528:DyaK2sXnvFWms7Y%3D Occurrence Handle9401937

    CAS  PubMed  Google Scholar 

  11. A. Yamamoto T. Taniguchi K. Rikyuu T. Tsuji T. Fujita M. Murakami S. Muranishi (1994) ArticleTitleEffects of various protease inhibitors on the intestinal-absorption and degradation of insulin in rats Pharm. Res. 11 1496–1500 Occurrence Handle1:CAS:528:DyaK2MXivFalurk%3D Occurrence Handle7855059

    CAS  PubMed  Google Scholar 

  12. G. Ponchel J. M. Irache (1998) ArticleTitleSpecific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract Adv. Drug Deliv. Rev. 34 191–219 Occurrence Handle10.1016/S0169-409X(98)00040-4 Occurrence Handle1:CAS:528:DyaK1cXnsFWlt78%3D Occurrence Handle10837678

    Article  CAS  PubMed  Google Scholar 

  13. C. M. Lehr J. A. Bouwstra W. Kok A. G. Deboer J. J. Tukker J. C. Verhoef D. D. Breimer H. E. Junginger (1992) ArticleTitleEffects of the mucoadhesive polymer polycarbophil on the intestinal-absorption of a peptide drug in the rat J. Pharm. Pharmacol. 44 402–407 Occurrence Handle1:CAS:528:DyaK38XktFCgsbY%3D Occurrence Handle1359054

    CAS  PubMed  Google Scholar 

  14. K. Whitehead Z. C. Shen S. Mitragotri (2004) ArticleTitleOral delivery of macromolecules using intestinal patches: applications for insulin delivery J. Control. Release 98 37–45 Occurrence Handle10.1016/j.jconrel.2004.04.013 Occurrence Handle1:CAS:528:DC%2BD2cXlsFeqtr4%3D Occurrence Handle15245887

    Article  CAS  PubMed  Google Scholar 

  15. U. O. Hafeli (2004) ArticleTitleMagnetically modulated therapeutic systems Int. J. Pharm. 277 19–24 Occurrence Handle10.1016/j.ijpharm.2003.03.002 Occurrence Handle1:CAS:528:DC%2BD2cXktFOisL4%3D Occurrence Handle15158965

    Article  CAS  PubMed  Google Scholar 

  16. H. Chen R. S. Langer (1997) ArticleTitleMagnetically-responsive polymerized liposomes as potential oral delivery vehicles Pharm. Res. 14 537–540 Occurrence Handle1:CAS:528:DyaK2sXjtVWrtrs%3D Occurrence Handle9144746

    CAS  PubMed  Google Scholar 

  17. R. Mehta R. Upadhyay S. Charles C. Ramchand (1997) ArticleTitleDirect binding of protein to magnetic particles Biotechnol. Tech. 11 493–496 Occurrence Handle10.1023/A:1018457915380 Occurrence Handle1:CAS:528:DyaK2sXksF2mt7Y%3D

    Article  CAS  Google Scholar 

  18. T. T. Kararli (1995) ArticleTitleComparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory-animals Biopharm. Drug Dispos. 16 351–380 Occurrence Handle1:CAS:528:DyaK2MXmvFOls70%3D Occurrence Handle8527686

    CAS  PubMed  Google Scholar 

  19. L. Hovgaard H. Jacobs D. E. Wilson S. W. Kim (1996) ArticleTitleStabilization of insulin by alkylmaltosides. B. Oral absorption in vivo in rats Int. J. Pharm. 132 115–121 Occurrence Handle1:CAS:528:DyaK28XjtFSktr4%3D

    CAS  Google Scholar 

  20. A. A. Raoof Z. Ramtoola B. McKenna R. Z. Yu G. Hardee R. S. Geary (2002) ArticleTitleEffect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs Eur. J. Pharm. Sci. 17 131–138 Occurrence Handle1:CAS:528:DC%2BD38XotVerurc%3D Occurrence Handle12393140 Occurrence Handle10.1016/S0928-0987(02)00162-8

    Article  CAS  PubMed  Google Scholar 

  21. G. Pettersson H. Ahlman J. Kewenter (1976) ArticleTitleComparison of small intestinal transit-time between rat and guinea-pig Acta Chir. Scand. 142 537–540 Occurrence Handle1:STN:280:DyaE2s7jtVygsQ%3D%3D Occurrence Handle1020594

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. George Kodokian, Dr. Hongming Chen, Dr. Daniel Kohane, Dr. Jeffrey Karp, and Dr. Yoon Yeo for their helpful discussions. This research was supported by the DuPont–MIT Alliance and the NIH. Ines Sherifi was financially supported by the University of Toronto.

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Authors and Affiliations

  1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Jianjun Cheng, Benjamin A. Teply, Seok Yoon Jeong, Christopher H. Yim, Ines Sherifi & Robert S. Langer

  2. Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Benjamin A. Teply, Ines Sherifi & Omid C. Farokhzad

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Dennis Ho

  4. Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, South Korea

    Sangyong Jon

  5. Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Omid C. Farokhzad, Ali Khademhosseini & Robert S. Langer

  6. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Ali Khademhosseini

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  1. Jianjun Cheng
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  2. Benjamin A. Teply
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  9. Ali Khademhosseini
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  10. Robert S. Langer
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Correspondence to Robert S. Langer.

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Cheng, J., Teply, B.A., Jeong, S.Y. et al. Magnetically Responsive Polymeric Microparticles for Oral Delivery of Protein Drugs. Pharm Res 23, 557–564 (2006). https://doi.org/10.1007/s11095-005-9444-5

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  • DOI: https://doi.org/10.1007/s11095-005-9444-5

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