Pyrano[2,3-c]pyrazole derivatives have been reported as exerting various biological activities. One compound with potential anti-tumor activity was screened out by MTT assay from series of dihydropyrazopyrazole derivatives we had synthesized before using a one-pot, four-component reaction, and was named as 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (hereinafter abbreviated as AMDPC). The IC50 of AMDPC against Bcap-37 breast cancer cells was 46.52 μg/mL. Then the hydrophobic AMDPC was encapsulated in PEG-PLGA block copolymers, and then self-assembled as polymeric micelle (mPEG-PLGA/AMDPC) to improve both physiochemical and release profiles. The effect of mPEG-PLGA/AMDPC on BCAP-37 cancer cells showed similar anti-tumor effects as AMDPC. Furthermore, the anti-tumor mechanism of mPEG-PLGA/AMDPC was investigated, which can probably be attributed to stimulating the expression of P21 gene and therefore protein production on BCAP-37 cells, and then blocked the cell cycle through the P53-independent pathway both in S phase and G2 phase. Thus, mPEG-PLGA/AMDPC is a promising therapeutic agent for cancer treatment, and further in vivo studies will be developed.
The purpose of this study was to overcome the clinical defects of 7-ethyl-10-hydroxycamptothecin (SN-38) and explore its characteristics and antitumor effects. Materials and methods: An amorphous solid dispersion of SN-38 with disodium glycyrrhizin (Na 2 GA) was prepared by mechanical ball milling (Na 2 GA/SN-38-BM). Moreover, an untreated mixture of Na 2 GA and SN-38 (Na 2 GA/SN-38-UM), a pure drug SN-38, was prepared for comparison with Na 2 GA/SN-38-BM. The samples were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), dynamic light scattering, and transmission electron microscopy. Then, further in vitro and in vivo studies were performed including cell uptake, cytotoxicity, antitumor efficacy, tissue distribution, and histopathological evaluation (H&E staining). Results: SN-38 loaded in Na 2 GA was self-formed as nano-micelles in water. The particle size of nano-micelle was 69.41 nm and ζ-potential was-42.01 mV. XRD and SEM analyses showed that the ball milling transformed SN-38 crystals into amorphous form and that solubility increased by 189 times. Compared with SN-38 and Na 2 GA/SN-38-UM, Na 2 GA/SN-38-BM has a stronger cytotoxicity to tumor cells and exhibited a significant inhibition of tumor growth. Then, pharmacokinetic studies showed that the bioavailability of Na 2 GA/SN-38-BM was about four times that of SN-38 suspension. Conclusion: Na 2 GA/SN-38-BM (69 nm,-42 mV) nanoparticles which had excellent pharmacokinetic and distribution properties can dramatically enhance the anticancer efficacy of SN-38 in vitro and in vivo, suggesting a promising formulation for efficient anticancer therapy.
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