Physicochemical characterization and membrane binding properties of camptothecin

Area of Science:

• Pharmacology
• Physical Chemistry
• Drug Formulation

Background:

• Camptothecin (CPT) is an important anti-cancer agent with limited clinical use due to poor solubility.
• Understanding CPT's physicochemical properties, especially in acidic environments, is crucial for improving its therapeutic efficacy.

Purpose of the Study:

• To investigate the solubility and membrane interaction of camptothecin (CPT) lactone form in acidic pH.
• To explore how CPT's properties at acidic pH can inform novel formulation strategies for enhanced anti-tumor activity.

Main Methods:

• Determined intrinsic and equilibrium solubility of CPT-lactone at varying temperatures and pH.
• Estimated the intrinsic partition coefficient (P) of CPT-lactone.
• Measured association constants (K(f)) with zwitterionic (DOPC) and negatively charged (DOPG) lipid bilayers using fluorescence anisotropy.

Main Results:

• CPT-lactone solubility increased with temperature and decreased pH, reaching 3.44 and 5.11 microM at 22 and 37°C, respectively.
• The intrinsic partition coefficient (log P) was 1.65, indicating good absorption potential.
• CPT showed preferential binding to negatively charged membranes (K(f) = 93.1 M⁻¹) compared to zwitterionic ones (K(f) = 35.4 M⁻¹).

Conclusions:

• At acidic pH, CPT exists as a soluble lactone form with increased affinity for negatively charged membranes.
• These pH-dependent properties offer opportunities for developing advanced CPT formulations.
• Optimizing CPT solubility and membrane binding in acidic conditions may enhance its anti-tumor efficacy.