Title : 15,16-dihydrotanshinone-I-laden PLGA-co-PEG nanoparticles are potential therapeutic agents for the treatment of colorectal cancer by targeting the β-catenin/CD36 axis
15,16-dihydrotanshinone I (DHTS) is tanshinones, a class of lipophilic abietane diterpenes rich in Salvia miltiorrhiza Bunge. It has many pharmacological activities. However, the poor solubility and biocompatibility of DHTS have hindered its clinical application. To enhance the solubility of DHTS in aqueous solutions and the bioavailability, an amphiphilic co-polymer polylactic-co-glycolic acid-block-polyethylene glycol (PLGA-co-PEG) was utilized to form polymeric micelles for the encapsulation of DHTS. The DHTS-laden PLGA-co-PEG nanoparticles were prepared via the emulsion-solvent evaporation method. In the aqueous solution, the PLGA-co-PEG copolymer was self-assembled into a micellar structure, with PLGA block as the hydrophobic core to provide the encapsulation capacity for DHTS. The hydrophilic PEG block formed the outer shell and stabilized the micelles. With the encapsulation by PLGA-co-PEG nanoparticles, DHTS was stability dispersed to facilitate the in vivo administration. Our in vivo data showed that DHTS-laden PLGA-co-PEG nanoparticles significantly reduced the tumor weight and the percentage increase in tumor size in colorectal cancer (CRC)-bearing xenograft mouse model when compared to free DHTS. Subsequent studies showed that DHTS physically bound to β-catenin, and significantly reduced the nuclear expressions and transcriptional activity of β-catenin. Our data also demonstrated that CD36, an integral membrane protein on the cell surface for fatty acid entry, was a downstream target of β-catenin. In parallel with the reduction of beta-catenin, DHTS also reduced CD36 expression which was reversed by β-catenin overexpression. The reduction of β-catenin and CD36 levels significantly reduced cellular ATP levels and inhibited CRC growth. Our study strongly suggests the translational potential of DHTS-laden PLGA-co-PEG nanoparticles as therapeutic agents for the treatment of CRC.
Audience Take Away Notes:
- Our study has demonstrated how to modify DHTS to DHTS-laden PLGA-co-PEG nanoparticles that can be used to treat CRC.
- Since DHTS is an herbal compound that possesses many pharmacological properties, we believe this therapeutic design can be applied in many other disease treatments.
- Our study may have drawn people’s attention to this herbal compound and broadened the usage of DHTS for disease treatments.