Abstract 5656: Sustained delivery of CZ48, a lactone-stabilized camptothecin, by nanosuspensions.
Authors: Chow Diana S-L , Dong Dong , Giovanella Beppino C. , Liu Xin , Hsiao Cheng-Hui , Teng Yang 
Published: August 2014

Background: CZ48, a prodrug of camptothecin (CPT), shows promising antitumor activity as a topoisomerase I (Topo-I) inhibitor after its biotransformation to CPT in vivo. Studies establish that a prolonged exposure of Topo-I inhibitors with low concentrations is more efficacious in cancer treatment than a short term exposure with high concentrations, due to the S-phase cell cycle specific mechanism. However, poor solubility and the effective delivery challenges have been the obstacles for clinical applications of CZ48 to patients.

Objectives: The research was to achieve the following objectives: (1) to prepare by wet media milling method and characterize CZ48 nanosuspensions (NSs); (2) to determine the pharmacokinetics (PK) of CZ48 and CPT from CZ48 NSs in Swiss nude mouse model; (3) to demonstrate the proof-of-concept efficacy of CZ48 NS in tumor-bearing athymic mouse model.

Methods: CZ48 NSs of different sizes were formulated by media milling method. The in vitro release kinetics in plasma and phosphate buffered saline (PBS) solution (pH 7.4) were characterized, respectively, using the dialysis bag diffusion technique. The PK of CZ48 and CPT were evaluated in male Swiss nu-nu mice by intravenous (i.v.) doses of 5 and 25 mg/kg for cosolvent reference and NSs, respectively. The PK parameters of CZ48 and CPT were derived by WinNonlin 3.0. The proof-of-concept efficacy was performed in the subcutaneous tumor model of Non-small Cell Lung Cancer (NSCLC) H460 cell line in the nude mouse model. ANOVA with Tukey's post-hoc and Kaplan-Meier survival analysis were used for comparisons of PK modifications and efficacy of the CZ48 from NSs using the cosolvent as reference.

Results: CZ48 NSs of particle sizes of 200 nm (NS-S) and 600 nm (NS-L) were successfully formulated and extensively characterized. The in vitro sustained release of CZ48 from NSs in plasma was achieved with 0.60 ± 0.12 %/h release rate and less than 40 % total release at 48 h, compared with 6.48 ± 0.29 %/h release rate and complete release by 28 h from cosolvent. NS-S and NS-L prolonged the blood circulation of CZ48 by 8.00, and 5.58 h, respectively, compare to 0.70 h from cosolvent. More importantly, NS-S yielded CPT with the longest half-life (12.51, 5.81 vs. 0.40 h) and largest AUC (19.78, 10.95 vs. 8.29 nM*h/(mg/kg)) than NS-L and cosolvent. CZ48-loaded NS-S exhibited significant tumor growth rate suppression compared to cosolvent (0.08 ± 0.03 vs. 0.18 ± 0.06/day) with a higher tolerable dose (25 vs. 5 mg/kg), and an improved survival rate (80% vs. 10%).

Conclusion: This study is the first report to demonstrate the NS as a viable pharmaceutical carrier to deliver CZ48 in a sustained manner, achieving significant tumor growth suppression at a higher tolerable dose. The study provides a formulation strategy of great potentials to overcome the delivery barriers for other anticancer drugs. We anticipate that the CZ48 NS will be a lead candidate for the future clinical trials of CZ48.

Citation Format: Diana S-L Chow, Dong Dong, Beppino C. Giovanella, Xin Liu, Cheng-Hui Hsiao, Yang Teng. Sustained delivery of CZ48, a lactone-stabilized camptothecin, by nanosuspensions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5656. doi:10.1158/1538-7445.AM2013-5656