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Influence of Surface Chemistry of Poly(Amidoamine) Dendrimers on Caco-2 Cell Monolayers

University of Maryland School of Pharmacy Department of Pharmaceutical Sciences 20 N. Pine Street Baltimore, Maryland 21201-1180, USA, Present address: University of Washington Department of Bioengineering Box: 352255, AERL 341A Seattle, Washington 98195, USA

Mark Ginski

Guilford Pharmaceuticals, Inc. Department of Pharmaceutics 6411 Beckley Street Baltimore, Maryland 21224, USA, Present address: Shire Laboratories, Inc., Department of Preformulation Sciences 1550 East Gude Drive Rockville, Maryland 20850, USA

Christopher A. Rhodes

Guilford Pharmaceuticals, Inc. Department of Pharmaceutics 6411 Beckley Street Baltimore, Maryland 21224, USA

Hamidreza Ghandehari

University of Maryland School of Pharmacy Department of Pharmaceutical Sciences 20 N. Pine Street Baltimore, Maryland 21201-1180, USA

The objective of this research was to investigate the effect of surface charge of poly(amidoamine), PAMAM, dendrimers on the integrity, paracellular permeability, and viability of Caco-2 cell monolayers by monitoring the transepithelial electrical resistance (TEER), mannitol permeability, and leakage of lactate dehydrogenase (LDH) enzyme, respectively. Neutral PAMAMOH, generations 2-4 (G2-G4), and anionic PAMAM-COOH (G-0.5-G4.5) dendrimers were incubated with Caco-2 cell monolayers at donor concentrations of 0.1, 1.0, and 10.0 mM for 90, 150, and 210 min. Neutral G2-G4 and anionic G-0.5, G0.5, G1.5 and G4.5 dendrimers did not cause any significant change in TEER or mannitol permeability across Caco-2 cell monolayers. Anionic G2.5 and G3.5 dendrimers, however, caused an incubation time-dependant decline in TEER values and up to a 6-fold increase in mannitol permeability. All anionic PAMAM-COOH dendrimers caused an incubation time-, concentration-, and generation-dependant LDH leakage that was not observed with neutral PAMAM-OH dendrimers. These studies suggest a size and/or charge "window" where anionic dendrimers may enhance paracellular transport across Caco-2 cell monolayers further confirming their potential as drug carriers and permeation enhancers for oral drug delivery.

Key Words: poly(amidoamine) dendrimers • water-soluble polymers • Caco-2 cells • transepithelial transport • oral drug delivery

Journal of Bioactive and Compatible Polymers, Vol. 18, No. 1, 7-22 (2003)
DOI: 10.1177/0883911503018001002


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