Studies On Hydroxycamptothecin Loaded Cerasomes

Hydroxycamptothecin (HCPT) is a trace alkaloid extracted from a Chinese special tree Camptotheca acuminata Decne. It is a marketing anti-cancer drug in China and the clinical formulation is the sodium carboxylate of HCPT with high toxicity. Novel controlled-release formulations have been developed to overcome the tough problem of severe toxicity and poor absorption. Cerasomes are self-assembled from cerasome-forming lipids (CFLs), with siloxane network structure on the surface which possess remarkable stability, water dispersibility and biocompatibility. In the present dissertation HCPT loaded cerasomes were fabricated and the corresponding bio safety was evaluated.HCPT loaded cerasomes and composite cerasomes (formed by CFLs and phospholipid) were prepared. The drug loading content, encapsulation efficiency, Size distribution, morphologies and the structural stability were analyzed. The particle sizes ranged from 189.5 to 231.8 nm, and the encapsulation efficiencies were between 40.6-85.0%. Comparing with HCPT loaded liposomes, the stability of HCPT loaded cerasomes were improved significantly.The in vivo toxicity of cerasomes was evaluated. After i.v. administered blank cerasomes and composite cerasomes containing 70% CFL to Wistar rats at two different doses of 25 and 50 mg/kg, respectively, the body weight and serum biochemistry tests were performed. The acute toxicity of cerasomes was observed by the loss of body weight and relative weight of the liver after 24 h administration of cerasomes at a higher dose of 50 mg/kg, whereas no visualized tissue injuries were found and the rats were fully recovered after 14d of administration. No side effects were observed after the administration of composite cerasomes containing 70% CFL at a lower dose of 25 mg/kg, suggesting a good biosafety.The plasma pharmacokinetic study was performed after intravenous administration of HCPT loaded cerasomes. The rat plasma concentration-time curves profiles matched two-compartment models. Along with the increase of CFL content, the initial concentration Co decreased while the area under the curve AUC0-∞, distribution half-life, elimination half-life and the average residence time increased. HCPT loaded composite cerasomes containing 70% CFL showed a better AUCo-∞ and lower Cmax, implying longer HCPT retention with lower concentration and controlled release of HCPT.The freezing drying process for HCPT loaded cerasomes were studied as well. Using HCPT loaded composite cerasomes containing 70% CFL, mannitol as the cryoprotectants and the concentrations of HCPT loaded composite cerasomes and mannitol at 4 mg/mL and 8 mg/mL respectively. The resuspended HCPT loaded composite cerasomes after freeze-drying process showed optimal shape, over 95% of in vitro release, and similar pharmacokinetic parameters of in vivo release comparing with fresh prepared HCPT loaded composite cerasomes.