Effects of amphiphilic block copolymers on the equilibrium lactone fractions of camptothecin analogues at different pHs

Camptothecin (CPT) and its analogues constitute one of the most important families of anticancer drugs. However, the CPT-family members have to confront the severe problem of hydrolysis from lactone form, the only form capable of antitumor efficacy, to the carboxylate form, leading to a significant decrease in therapy efficiency as well as severe side effects. Herein, two CPT analogues with different water solubilities, 10-hydrocamptothecin (HCPT) and topotecan (TPT), and four poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) (PEG-PPG-PEG, Pluronic) copolymers of varied hydrophilic-lipophilic balance (HLB) values, were examined with emphasis on the change of the equilibrium lactone fraction (f(lactone)) of the drugs after addition of the copolymers. In all cases, f(lactone) was enhanced. For weak water-soluble HCPT, the enhancement extent was significantly increased with decrease of the copolymer HLB, which is influenced by the block chain length for a given series of amphiphilic block copolymers. The effect was less significant for TPT, a more hydrophilic drug. The fluorescence experiments confirmed the assembly of the drugs into polymeric micelles. A series of pH titrations were also carried out, which quantified the shift of pH(1/2) (pH when f(lactone) = 0.5) after addition of the copolymers. The optimal or most sensitive pH, pH(opt), which gave the maximum enhancement of f(lactone) by the polymers, was found to depend upon the type of drug, the HLB value of copolymer, and also the polymer concentration. Hence, this work has indicated the universality of the enhancement effect of polymeric micelles on the equilibrium lactone fractions of CPT analogues, and meanwhile revealed the dependence of the enhancement extent upon the HLB values of the copolymer and hydrophilicity of the drug. The concept of optimal pH has also been put forward for the first time.