El-Sayed Mohamed, Ginski Mark, Rhodes Christopher, Ghandehari Hamidreza
University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, 20 N. Pine Street, Baltimore, MD 21201, USA.
J Control Release. 2002 Jun 17;81(3):355-65. doi: 10.1016/s0168-3659(02)00087-1.
The objective of this study was to investigate the influence of physiochemical parameters (such as size, molecular weight, molecular geometry, and number of surface amine groups) of poly (amidoamine) (PAMAM) dendrimers, on their permeability across Caco-2 cell monolayers. The permeability of a series of PAMAM dendrimers, generations 0-4 (G0-G4), was investigated across Caco-2 cell monolayers in both the apical to basolateral (AB) and basolateral to apical (BA) directions. The influence of PAMAM dendrimers on the integrity, paracellular permeability, and viability of Caco-2 cell monolayers was also monitored by measuring the transepithelial electrical resistance (TEER), mannitol permeability, and leakage of lactate dehydrogenase (LDH) enzyme, respectively. G0, G1 and G2 demonstrated similar AB permeabilities, which were moderate several fold higher than the AB permeability of higher generations. The AB and BA permeability of G0-G4 typically increased with the increase in donor concentration and incubation time. Permeability values are not reported at generations, concentrations or incubation times that the dendrimers were toxic to Caco-2 cells. TEER values decreased and mannitol permeability increased as a function of donor concentration, incubation time, and generation number. LDH results for G3 and G4 indicate that Caco-2 cell viability was reduced with increasing donor concentration, incubation time, and generation number. The appreciable permeability of G0-G2, coupled with their nontoxic effects on Caco-2 cells, suggest their potential as water-soluble polymeric drug carriers for controlled oral drug delivery.
本研究的目的是调查聚（酰胺胺）（PAMAM）树枝状大分子的物理化学参数（如尺寸、分子量、分子几何形状和表面胺基数量）对其跨Caco-2细胞单层通透性的影响。研究了0-4代（G0-G4）一系列PAMAM树枝状大分子在顶侧到基底侧（AB）和基底侧到顶侧（BA）两个方向上跨Caco-2细胞单层的通透性。还分别通过测量跨上皮电阻（TEER）、甘露醇通透性和乳酸脱氢酶（LDH）泄漏，监测了PAMAM树枝状大分子对Caco-2细胞单层完整性、细胞旁通透性和活力的影响。G0、G1和G2表现出相似的AB通透性，比更高代数的AB通透性高几倍，属于中等水平。G0-G4的AB和BA通透性通常随着供体浓度和孵育时间的增加而增加。在树枝状大分子对Caco-2细胞有毒性的代数、浓度或孵育时间下，未报告通透性值。TEER值随着供体浓度、孵育时间和代数的增加而降低，甘露醇通透性则增加。G3和G4的LDH结果表明，随着供体浓度、孵育时间和代数的增加，Caco-2细胞活力降低。G0-G2的可观通透性，以及它们对Caco-2细胞的无毒作用，表明它们作为用于口服控释给药的水溶性聚合物药物载体具有潜力。
