A major limitation of the clinical efficacy of the 7-ethyl-10-hydroxycamptothecin (SN38) therapy is its facile conversion of the active lactone form into a less active carboxylate species at physiological pH and limited aqueous solubility. The present manuscript embodies a detailed description of several physicochemical properties of SN38 and further details the thermodynamic basis for its poor aqueous solubility. The ionization and increased solubility of the drug in highly acidic media were subsequently employed to efficiently load the positively charged drug in its biologically active lactone form into mesoporous silica material of type MCM-41, achieving a maximum loading of 250 mg of SN38 per gram of silicate. It was also found that the equilibrium association constant K(A) varies with the extent of drug adsorption. At low and high drug load, corresponding to one SN38 molecule bound for every 70 and 13 -SiO(2)-, K(A) was determined to be 1253.5 and 127.39 M(-1), respectively.

To accurately derive the kinetic and thermodynamic parameters governing the hydrolysis of the lactone ring at physiological pH, a derivative spectrophotometric technique was used for the simultaneous estimation of lactone and carboxylate forms of camptothecin (CPT). The hydrolysis of the CPT-lactone and the lactonization of CPT-carboxylate at 310.15 K followed a first-order decay with apparent rate constants equal to 0.0279 ± 0.0016 min −1 and 0.0282 ± 0.0024 min −1 , respectively. The activation energy associated with the hydrolysis of the CPT-lactone and the lactonization of the CPT-carboxylate as calculated from the Arrhenius equation was 89.18 ± 0.84 and 86.49 ± 2.7 kJ mol −1 , respectively. The enthalpy and entropy of the thermodynamically favored hydrolysis reaction were on average 10.49 kJ mol −1 and 48.00 J K −1 mol −1 , respectively. The positive enthalpy and entropy values of the CPT-lactone hydrolysis indicate that the reaction is endothermic and entropically driven. The stability of CPTlactone in the presence of human serum albumin (HSA) was also analyzed. Notwithstanding the much faster hydrolysis of the CPT-lactone in the presence of HSA at various temperatures, the energy of activation was determined to be similar to the one estimated in the absence of HSA, suggesting that HSA does not catalyze the hydrolysis reaction, but it merely binds, sequesters, and stabilizes the CPT-carboxylate species. C 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 704-

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