CZ-48

9-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca acuminata, and have been confirmed to possess high anti-cancer properties. In the present study, 9NC was identified as the major metabolite of CZ112 in rat plasma through HPLC/photodiode array detection (PDA) and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. A highly sensitive LC-MS/MS method was developed and validated for the simultaneous analysis of CZ112 and 9NC in rat plasma, and camptothecin-20-O-acetate (CZ44) was used as an internal standard (IS). The calibration curves were linear (r² > 0.999) over concentrations from 2.5 to 320 ng/mL for both CZ112 and 9NC. The method had an accuracy of 96.7-109.6%, and the intra- and inter-day precision (RSD%) were 10.9% or less for CZ112 and 9NC. The stability data showed no significant degradation occurred under the experimental conditions. This method was successfully applied to the pharmacokinetic study of CZ112 and its metabolite 9NC in rat plasma after intravenous and intragastric administration. The oral bioavailability of CZ112 was 6.2 ± 3.3% (n = 6).

CZ48, a prodrug of camptothecin (CPT) with derivative resistant to lactone hydrolysis, suffers from limited application for cancer treatment due to poor water-solubility, thus causing its low bioavailability and absorption in vivo. To echo this problem, CZ48 was incorporated into poly (lactic acid) (PLA) microbubbles via a double emulsion technique (W/O/W), and the successful loading was confirmed by X-ray diffraction (XRD) patterns and confocal laser scanning microscope (CLSM). The obtained CZ48-loaded microbubbles had a diameter ranging from 0.5 to 6.7 μm, and the encapsulation efficiency and drug-loading content were as high as 85.73 ± 2.41% and 26.07 ± 0.76%, respectively. The in vitro drug release demonstrated that only about 55% of CZ48 was released for CZ48-loaded PLA microbubbles in 48 h. In contrast, over 90% of CZ48 was released for free CZ48 crystals sample in only 5 h. Besides, in vivo pharmacokinetic studies further revealed that the availability of both CZ48 and its metabolite CPT were obviously enhanced after the incorporation of CZ48 into PLA microbubbles. To be noted, the value of AUC_0-∞ of the CZ48-loaded microbubbles was about 5-fold higher than that of free CZ48 suspension, implying a much higher anticancer effect of the CZ48-loaded microbubbles. The half-life time (T_1/2) of both CZ48 and CPT of the CZ48-loaded microbubbles were also significantly longer than that of the free CZ48, indicating a delayed release time for the microbubbles. Hence, this work promotes a promising drug carrier system for the controlled release of CZ48 as well as other drugs with poor water-solubility.