Pharmacokinetic Properties and Applications as Drug Carriers

As far as dendrimers' pharmacokinetics are concerned, the biodistribution of [14C] labeled PAMAM dendrimers after intravenous injection was determined for generation 3, 5, and 7 PAMAM dendrimers.42 At each generation, the biodistribution characteristics were different. Generation 3 dendrimers showed the highest accumulation in kidney (15% of dose/g tissue over 48 h); however, generation 5 and 7 dendrimers preferentially accumulated in the pancreas (peak level 32% dose/g tissue at 24 h and 20% of dose/g tissue at 2 h, respectively). In addition, generation 7 dendrimers showed extremely high urinary excretion with values of 46 and 74% of dose/g tissue at 2 and 4 h, respectively. These results suggested that the biodistribution of a dendrimer depended on the generation because physicochemical properties were determined by the generation. Other reports described the biodistribution of [3H]-labeled neutral and positively charged generation 5 PAMAM dendrimers in a tumor-bearing mouse model.43 Both neutral and positively charged dendrimers showed a similar biodistribution trend 1 h after intravenous injection; the highest level was found in the lungs, kidney, and liver (positive, 28-6.1% of dose/g tissue; neutral, 5.3-2.9% of dose/g tissue) followed by the tumor, spleen, and pancreas (positive, 3.3-2.6% of dose/g, tissue; neutral 3.4-0.92% of dose/g tissue). Differences between neutral and positively charged dendrimers were observed for accumulation in the lung. A high lung accumulation of cationic dendrimer was found compared with conventional cationic liposomes, and this may be explained by the stacking to the capillary vessels of the lung. Moreover, [14C]-labeling of the dendrimer results in partial neutralization of the dendrimer. Therefore, different biodistribution properties were observed in the lung and liver accumulation between [14C]-and [3H]-labeled dendrimers. These results suggest that the biodistribution properties of radio-labeled dendrimers have to be examined carefully, taking into consideration the surface charge caused by the radio-labeling. As far as tumor accumulation is concerned, this may be explained by the EPR effect.

Drug delivery applications of dendrimers have been studied by Szoka and co-workers.44 The biodistribution of doxorubicin covalently bound via a hydrazone linkage with a polyester dendritic scaffold based on 2,2-bis(hydroxymethyl)propanoic acid was examined. After intravenous injection, doxorubicin was extracted from the tumor and organs. Compared with free doxorubicin, the serum half-life was significantly increased. Therefore, this dendrimer would be a promising drug carrier for cancer therapy.

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