Pharmaceutical Research

, Volume 14, Issue 11, pp 1568–1573 | Cite as

The Mechanism of Uptake of Biodegradable Microparticles in Caco-2 Cells Is Size Dependent

  • Manisha P. Desai
  • Vinod Labhasetwar
  • Elke Walter
  • Robert J. Levy
  • Gordon L. Amidon


Purpose. To study the uptake of biodegradable microparticles in Caco-2 cells.

Methods. Biodegradable microparticles of polylactic polyglycolic acid co-polymer (PLGA 50:50) of mean diameters 0.1 μm, 1 μm, and 10 μm containing bovine serum albumin as a model protein and 6-coumarin as a fluorescent marker were formulated by a multiple emulsion technique. The Caco-2 cell monolayers were incubated with each diameter microparticles (100 μg/ml) for two hours. The microparticle uptake in Caco-2 cells was studied by confocal microscopy and also by quantitating the 6-coumarin content of the microparticles taken up by the cells. The effects of microparticle concentration, and incubation time and temperature on microparticle cell uptake were also studied.

Results. The study demonstrated that the Caco-2 cell microparticle uptake significantly depends upon the microparticle diameter. The 0.1 μm diameter microparticles had 2.5 fold greater uptake on the weight basis than the 1 μm and 6 fold greater than the 10 μm diameter microparticles. Similarly in terms of number the uptake of 0.1 μm diameter microparticles was 2.7 × 103 fold greater than the 1 μm and 6.7 × 106 greater than the 10 μm diameter microparticles. The efficiency of uptake of 0.1 μm diameter microparticles at 100 μg/ml concentration was 41% compared to 15% and 6% for the 1 μm and the 10 μm diameter microparticles, respectively. The Caco-2 cell microparticle (0.1 μm) uptake increased with concentration in the range of 100 μg/ml to 500 μg/ml which then reached a plateau at higher concentration. The uptake of microparticles increased with incubation time, reaching a steady state at two hours. The uptake was greater at an incubation temperature of 37°C compared to at 4°C.

Conclusions. The Caco-2 cell microparticle uptake was microparticle diameter, concentration, and incubation time and temperature dependent. The small diameter microparticles (0.1 μm) had significantly greater uptake compared to larger diameter microparticles. The results thus suggest that the mechanism of uptake of microparticles in Caco-2 cell is particle diameter dependent. Caco-2 cells are used as an in vitro model for gastrointestinal uptake, and therefore the results obtained in these studies could be of significant importance in optimizing the microparticle-based oral drug delivery systems.

drug carrier oral drug delivery vaccine absorption bioavailability endocytosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J. Kreuter. J. Anat. 189:503–505, 1996.Google Scholar
  2. 2.
    R. Bodmeier, H. G. Chem, and O. Paeratakul. Pharm. Res. 6:413–417 (1989).Google Scholar
  3. 3.
    C. Michel, M. Aprahamain, L. Defontaine, P. Couvreur, and C. Damge. J. Pharm. Pharmacol. 43:1–5 (1991).Google Scholar
  4. 4.
    A. T. Florence, A. M. Hillery, N. Hussain, and P. U. Jani. J. Controlled Release 36:39–46 (1995).Google Scholar
  5. 5.
    D. Shah and W. C. Shen. J. Pharm. Sci. 85:1306–1311 (1996).Google Scholar
  6. 6.
    P. Maincent, R. Le Verge, P. A. Sado, P. Couvreur, and J. P. Devissaguet. J. Pharm. Sci. 75:955–958 (1986).Google Scholar
  7. 7.
    P. A. Kramer and T. Burnstein. Life Sci. 19:515–520 (1976).Google Scholar
  8. 8.
    O. Strannegard and A. Yurchison. Int. Arch. Allergy 35:579–590 (1969).Google Scholar
  9. 9.
    J. H. Eldridge, C. J. Hammond, J. A. Muelbroek, J. K. Staas, R. M. Gilley, and T. R. Tice. J. Controlled Release 11:205–214 (1990).Google Scholar
  10. 10.
    C. A. Gilligan and A. Li Wan Po. Int. J. Pharm. 75:1–24 (1991).Google Scholar
  11. 11.
    A. Li Wan Po, E. Rogers, M. Shepphard, and E. M. Scott. Adv. Drug. Del. Rev. 18:101–109 (1995).Google Scholar
  12. 12.
    I. J. Hidalgo and J. B. Li. Adv. Drug. Del. Rev. 22:53–66 (1996).Google Scholar
  13. 13.
    C.-M. Lehr and V. H. L. Lee. Pharm. Res. 10(12):1796–1799 (1993).Google Scholar
  14. 14.
    K. L. Audus, R. L. Bartel, I. J. Hidalgo, and R. T. Borchardt. Pharm. Res. 7(5):435–451 (1990).Google Scholar
  15. 15.
    M. P. Desai, V. Labhasetwar, G. L. Amidon, and R. J. Levy. Pharm. Res. 13:1838–1845 (1996).Google Scholar
  16. 16.
    R. H. Muller. Colloidal Carriers for Controlled Drug Delivery and Targeting CRC Press, Boston, 1991.Google Scholar
  17. 17.
    V. Labhasetwar, B. Chen, D. W. M. Muller, J. Bonadio, K. Ciftci, K. March, and R. J. Levy. Adv Drug Del Rev. 24:109–120 (1997).Google Scholar
  18. 18.
    P. Artursson. J. Pharm. Sci. 79(6):476–482 (1990).Google Scholar
  19. 19.
    D. C. Kim, P. S. Burton, and R. T. Borchardt. Pharm. Res. 10(12):1710–1714 (1993).Google Scholar
  20. 20.
    P. Artursson and J. Karlsson. Biochem. Biophys. Res. Comm. 175(3):880–885 (1991).Google Scholar
  21. 21.
    G. F. Beck, W. J. Irwin, P. L. Nicklin, and S. Akhtar. Pharm. Res. 13(7):1028–1036 (1996).Google Scholar
  22. 22.
    E. Walter, S. Janich, B. J. Roessler, J. M. Hilfinger, and G. L. Amidon. J. Pharm. Sci. 85:1070–1076 (1996).Google Scholar
  23. 23.
    A. M. Hillery, P. U. Jani, and A. T. Florence. J. Drug Targetting 2:151–156 (1994).Google Scholar
  24. 24.
    M. Aprahamian, C. Michel, W. Humbert, J. Devissaguet, and C. Damge. Biol. Cell 61:69–76 (1987).Google Scholar
  25. 25.
    P. Couvreur and F. Puisieux. Adv. Drug. Del. Rev. 10:141–162 (1993).Google Scholar
  26. 26.
    J. Kreuter. Adv. Drug. Del. Rev. 7:71–86 (1991).Google Scholar
  27. 27.
    J. Mastecky, Z. Moldoveanu, M. Novak, W.-Q Huang, R. M. Gilley, J. K. Staas, D. Schafer, and R. W. Compans. J. Controlled Release 28:131–141 (1994).Google Scholar
  28. 28.
    M. Manganaro, P. L. Ogra, and P. B. Ernst. Int. Arch. Allerg. Immuno. 103:223–233 (1994).Google Scholar
  29. 29.
    K. E. Carr, R. A. Hazzard, S. Reid, and G. M. Hodges. Pharm. Res. 13:1205–1209 (1996).Google Scholar
  30. 30.
    T. Uchida and S. Goto. Bio. Pharm. Bull. 17:1272–1276 (1994).Google Scholar
  31. 31.
    T. H. Ermak, E. P. Dougherty, H. R. Bhagat, Z. Kabok, and J. Pappo. Cell Tissue Res. 279:433–436 (1995).Google Scholar
  32. 32.
    J. C. Leroux, R. M. Cozens, J. L. Roesel, B. Galli, E. Doelker, and R. Gurny. Pharm. Res. 13:485–487 (1996).Google Scholar
  33. 33.
    A. M. Hillery, I. Toth, and A. T. Florence. J. Controlled Release 42:65–73 (1996).Google Scholar
  34. 34.
    H. Sato, Y. Sugiyama, A. Tsuji, and I. Horikoshai. Adv. Drug. Del. Rev. 19:445–467 (1996).Google Scholar

Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  • Manisha P. Desai
    • 1
  • Vinod Labhasetwar
    • 1
  • Elke Walter
    • 1
  • Robert J. Levy
    • 1
    • 2
  • Gordon L. Amidon
    • 1
  1. 1.College of PharmacyUniversity of MichiganAnn Arbor
  2. 2.Department of Pediatric CardiologyUniversity of MichiganAnn Arbor

Personalised recommendations