Self-assembled natural small molecule diterpene acids with favorable anticancer activity and biosafety for synergistically enhanced antitumor chemotherapy

Natural biocompatible materials such as self-assembled natural small molecule products (NSMP) with anticancer activity are of increasing interest for synergistic biomedical applications. Herein, we discovered and developed four new self-assembled tricyclic diterpene acids NSMP with favorable anticancer activity for synergistic and safe antitumor chemotherapy, including dehydroabietic acid, 15-hydroxy-dehydroabietic acid, abietic acid, and 12-hydroxyabietic acid. The self-assembled performance and mechanism of these four compounds with different morphologies were explored in detail by molecular dynamics simulation, and revealed the coplanarity and orderliness of molecular arrangements which are speculated to be responsible for the self-assembly into spheres or rods. The screened and optimized abietic acid (AA) was chosen to prepare the synergistic antitumor drug AA-PTX NPs by co-administration with paclitaxel through multiple hydrogen bonds. The resulting nanodrugs were internalized into cells through a lysosome acidification uptake pathway. The improved water-solubility, significantly enhanced in vitro cytotoxicity, and excellent biosafety, lead to a highly efficient and safe in vivo anticancer efficacy of 81.2% inhibition rate with only three doses. This work provides new insights to explore the self-assembly behavior of small molecules and broadens the types of self-assembled active NSMP, providing a promising perspective for the fabrication of active NSMP mediated medical agents for multiple synergistic therapies.