External electrostatic interaction versus internal encapsulation between cationic dendrimers and negatively charged drugs: Which contributes more to solubility enhancement of the drugs?

Relationships of electrostatic interaction and encapsulation between poly(amidoamine) (PAMAM) dendrimers and negatively charged drug molecules have been investigated by aqueous solubility and NMR (¹H NMR and two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY)) studies. PAMAM dendrimers significantly increased the solubilities of phenobarbital and sulfamethoxazole, but scarcely influenced those of primidone and trimethoprim. Moreover, ¹H NMR and 2D-NOESY measurements indicated that few phenobarbital or sulfamethoxazole molecules were entrapped in the cavities of low-generation dendrimers (generation 3, G3). These results suggest that external electrostatic interaction contributes more to the solubility enhancement of drugs than internal encapsulation.