Tumor-targeted hyaluronic acid-mPEG modified nanostructured lipid carriers for cantharidin delivery: An in vivo and in vitro study.

AIM: Cantharidin (CTD), the major component of the anti-cancer medicine obtained from Mylabris cichorii, exerts good inhibitory effects on several cancers, such as liver and breast cancer. However, owing to its toxicity, its oral administration can cause various adverse effects, limiting its clinical applications. Therefore, the development of a novel nano-drug delivery system for CTD would be highly beneficial. METHODS: A nanostructured lipid carrier (NLC) was designed to actively target CTD to tumor cells using a hyaluronic acid (HA)-decorated copolymer (mPEG-NH2); the NLCs were called HA-mPEG-CTD-NLC. HA-mPEG was synthesized using amidation, and HA-mPEG-CTD-NLC was generated through ultrasonic emulsification in water. The mean hydrodynamic diameter of the particles was approximately 119.3 nm. RESULTS: Pharmacokinetic studies revealed that the half-life of HA-mPEG-CTD-NLC and its area under the curve were higher than those of a CTD solution. Further, the plasma clearance rate of HA-mPEG-CTD-NLC was 0.41 times that of the CTD solution, implying a significantly prolonged drug retention time in vivo. Fluorescence in vivo endo-microscopy and optical in vivo imaging revealed that HA-mPEG-CTD-NLC had superior cytotoxicity and targeting efficacy against SMMC-7721 cells. An evaluation of the in vivo anti-tumor activity showed that HA-mPEG-CTD-NLC significantly inhibited tumor growth and prolonged survival in tumor-bearing mice, with a tumor inhibition rate of 65.96%. CONCLUSIONS: Our results indicate that HA-mPEG-CTD-NLC may have great potential in liver cancer-targeted therapy.

Pharmacokinetics and tissue distribution of cantharidin after oral administration of aqueous extracts from Mylabris in rats.

A sensitive gas chromatography-mass spectroscopy method was established for the determination of cantharidin (CTD) in rat plasma and liver homogenates. During the experiment, rats were randomly divided into two groups (low, high) and were administered aqueous extract of Mylabris compound for 7 days. Then, plasma and tissue samples were taken at different time points to study the pharmacokinetics and tissue distribution of CTD in rats. The selected reaction monitoring transitions for CTD and clofibrate (internal standard) were m/z 128 → 85 and m/z 169 → 141, respectively. The calibration curve ranged from 10.26 to 3,078 ng/ml for plasma and from 10.26 to 246.24 ng/ml for liver homogenates. The lower limits of quantification were 10.26 ng/ml for both plasma and liver. The intra- and inter-day precision and accuracy were <20% for both plasma and liver homogenates. Extraction recovery ranged from 89.21 to 103.61% for CTD in rat plasma and liver and from 83.79 to 102.74% for IS in rat plasma and liver. Matrix effects ranged from 93.06 to 110.44% for CTD and from 91.65 to 110.80% for IS.

[Pharmacokinetics and bioavailability of cantharidin in beagle dogs].

OBJECTIVE: To study the pharmacokinetics and bioavailability of cantharidin in beagle dogs to evaluate the pharmacokinetic parameters and bioavailability of cantharidin in beagle dogs by determining dose-time curve and by comparing with the pharmacokinetics of cantharidin injection. METHOD: Six beagle dogs, after protein precipitation by hydrochloric acid, ethyl acetate was applied to extract cantharidin from plasma The plasma concentration of cantharidin in beagle dogs was determined by GC-MS. The WinNonLin program was used to calculate the pharmacokinetic parameters and bioavailability. RESULT: The main pharmacokinetic parameters of cantharidin by iv in dogs (34 mL x h(-1) x kg(-1)) were AUC (203.5 +/- 23.8) h x microg x L(-1), CL (168.8 +/- 18.6) mL x h(-1) x kg(-1), t1/2 (0.69 +/- 0.03) h. The main pharmacokinetic parameters of cantharidin by op (102 microg x kg(-1)) were: AUC (160.4 +/- 26.9) h x microg x L(-1), CL (649.1 +/- 97.7) mL x h(-1) x kg(-1), t1/2 (0.38 +/- 0.1) h., F (bioavailability) = 26.7% comparing to injection. CONCLUSION: As compared with cantharidin injection, the absorption of catharidin by op is poor and the bioavailability is also low, indicating that enhancement of the bioavailability will be beneficial to the clinical application.

Determination of trace cantharidin in plasma and pharmacokinetic study in beagle dogs using gas chromatography-mass spectrometry.

The blister beetle is traditional Chinese medicine that was first discovered and used as anticancer drug in China, and cantharidin proved to be its principal active ingredient. Cantharidin-based pharmaceutical preparations are now widely used in clinics in China with good therapeutic efficacy. As a toxic anticancer drug, the therapeutic dose of cantharidin is low, and no method to determine the blood cantharidin concentration under the therapeutic dose has so far been reported. Here, we present a simple, sensitive, and reliable gas chromatography-mass spectrometry (GC-MS) method to monitor the plasma cantharidin and perform the pharmacokinetic study of cantharidin in beagle dogs. After protein precipitation by hydrochloric acid, a liquid-liquid extraction procedure using ethyl acetate was applied to extract cantharidin from plasma. An elastic quartz capillary GC column DB-5MS was used in GC-MS, the temperature was kept at 60 degrees C for 1 min, then increased to 220 degrees C at the rate of 6 degrees C/min, held there for 1 min, and then to 280 degrees C at the rate of 20 degrees C/min, held for 3 min. The extraction recovery was over 80% for all the tested specimens. The linearity ranged from 2.14 to 314.2 ng/mL, the intra- and interday precisions were both below 20%, the limit of detection was 0.5 ng/mL, and the limit of quantification was 2.14 ng/mL. Cantharidin in plasma proved to be stable during the whole period of storage, treatment, and analysis. Cantharidin demonstrated as one-compartment model after i.v. administration with an elimination half-life of 0.69 +/- 0.03 h and area under curve of 204 +/- 24 h.ng/mL. This GC-MS assay proved to have high precision, accuracy, reliability, and sensitivity, and it was suitable for determination of trace cantharidin in plasma.

Determination of the release of hydrolyzed demethylcantharidin from novel traditional chinese medicine-platinum compounds with anticancer activity by gas chromatography.

The present paper describes the development of a simple, accurate and reproducible gas chromatographic method for the determination of hydrolyzed demethylcantharidin release from a novel series of traditional Chinese medicine (TCM)-platinum compounds possessing potent anticancer and protein phosphatase 2A (PP2A)-inhibition properties. The salient features of the validated assay were a limit of detection (LOD) of 2 microg/mL, a limit of quantitation (LOQ) of 6 microg/mL, an intra- and inter-day precision of less than 11%, and an accuracy of more than 92%. The developed GC-flame ionization detection (FID) method was successfully utilized for the analysis of hydrolyzed demethylcantharidin, the TCM component that is slowly released from the novel compounds over 24 h, leading to PP2A inhibition. Further structural confirmation was achieved by GC-MS. The GC method is suitable for further mechanistic, pharmacokinetic and metabolic studies of the TCM-Pt compounds that might prove to be new anticancer agents with novel mechanisms of cytotoxic action.