Camptothecin in Sterically Stabilized Phospholipid Nano-Micelles: A Novel Solvent pH Change Solubilization Method

Camptothecin (CPT) is a topoisomerase I inhibitor that acts against a broad spectrum of cancers. Unfortunately clinical application of CPT is limited by insolubility, instability, and toxicity problems. To circumvent these delivery problems of CPT, we propose biocompatible, targeted sterically stabilized micelles (SSM) as nanocarriers for CPT (CPT-SSM). SSM composed of polyethylene glycol (PEGylated) phospholipids are attractive nanocarriers for CPT delivery because they are sufficiently small to extravasate through the leaky microvasculature of tumor and inflamed tissues for passive targeting. The purpose of this study was to develop a novel method of preparing CPT-SSM based on its pH dependent, reversible carboxylate-lactone conversion chemistry. CPT carboxylate was added to SSM at pH 5 that favored the formation of active but hydrophobic CPT lactone for spontaneous association with SSM. The kinetics of CPT conversion and CPT-SSM formation, and the effect of varying CPT-PEGylated phospholipid molar ratio on CPT-SSM properties and CPT solubilization were evaluated. CPT converted gradually from the carboxylate form to lactone, and CPT-SSM were formed after 12 h incubation. The mean size of CPT-SSM was ∼14 nm. CPT solubilization (∼12 μg/ml) and other CPT-SSM micelle properties did not change significantly with increasing CPT to PEGylated phospholipid molar ratios using this novel method, unlike the coprecipitation/reconstitution technique previously reported. This reproducible CPT solubilization in SSM was attributed to avoidance of drug aggregate formation by this method. The advantages of our solvent pH change method to prepare CPT-SSM support further investigations of this approach to other hydrophobic drugs similar to CPT in chemistry and also CPT molecular solubilization in other nanocarriers.