Lentinan as a natural stabilizer with bioactivities for preparation of drug-drug nanosuspensions.

Lentinan is a natural ß-glucan with various bioactivities and is combined with chemotherapy drugs for cancer treatment. Regorafenib is an oral multi-kinase inhibitor approved by FDA for treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors. Regorafenib has poor water solubility and multiple toxicities. We report drug-drug nanosuspensions of regorafenib and lentinan. Results of dynamic light scattering and scanning electron microscopy showed that the mean particle size of the regorafenib-lentinan nanosuspensions was approximately 200 nm and was uniformly distributed. Transmission electron microscopy findings indicated that lentinan stabilized the nanosuspensions by steric manner. Hydrogen bonds and hydrophobic interactions were found between regorafenib and lentinan by molecular dynamics simulation. The results of cytotoxicity assay and pharmacokinetics study in rats showed that the regorafenib-lentinan nanosuspensions reduced the toxicity and enhanced the in vitro anticancer activity and oral bioavailability of regorafenib. Lentinan as a natural stabilizer has the potential using for drug nanosuspensions. Drug-drug nanosuspensions are a new form of combination therapies that can reduce the number of drugs taken by patients and improve their compliance.

[Change of blood lentinan level in patients with advanced cancers].

A conventional limulus test can detect not only endotoxin but also beta(1----3) glucan. Therefore, with a quantitative limulus test, the limulus colorimetric test, we studied the pharmacokinetics of lentinan, an antitumor beta(1----3) glucan preparation, in the blood of 10 healthy volunteers and 20 patients with advanced cancers. The calibration curve of lentinan in the human plasma was linear in the range of 0 to 100 ng/ml. Two mg of lentinan was administered once a week and blood samplings for the measurement were done immediately before the next lentinan administration to document trough-levels serially at a week interval. Trough-levels tended to rise gradually and showed a rapid elevation between 4 and 8 weeks after beginning of administration. This phenomenon may correlate closely with the antitumor effect of lentinan and, therefore, deserves further investigations.

Quantitative assay of lentinan in human blood with the limulus colorimetric test.

A conventional limulus test detects not only endotoxin but also beta (1----3) glucan. Therefore, using a quantitative limulus test (the limulus colorimetric test) we studied the pharmacokinetics of lentinan, an antitumor beta (1----3) glucan, in the blood of 10 health volunteers and three patients with advanced gastric cancer. The calibration curve of lentinan in the human plasma was linear in the range of 0 to 100 ng/ml. When incubated with human plasma at 37 degrees C in vitro, lentinan had the recovery of almost 100% as compared to the initial concentration even after 60-min incubation, indicating the stability of lentinan in human plasma. When 1 mg of lentinan was intravenously administered over a 2 hr period, lentinan concentration reached the maximum levels (50-80 ng/ml) at the end of the drip infusion and decreased gradually thereafter. In the near future, the more appropriate modes of lentinan administration will be determined by further investigation of its kinetics in the human body.