Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with chemotherapeutic agents for the treatment of colorectal cancer (CRC) are a promising therapeutic strategy. NSAIDs can effectively boost the antitumor efficacy of chemotherapeutic agents by inhibiting the synthesis of COX-2. However, hazardous side effects and barriers to oral drug absorption are the main challenges for combination therapy with chemotherapeutics and NSAIDs. To address these issues, a safe and effective lysine-polydopamine@abemaciclib-flurbiprofen (Flu) codrug nanocrystal (Lys-PDA@AF NCs) was designed. Abemaciclib (Abe), a novel and effective inhibitor of the CDK4/6 enzyme, and Flu were joined to prepare Abemaciclib-Flu codrug (AF) by amide bonds, and then the AF was made into nanocrystals. Lysine-modified polydopamine was selected as a shell to encapsulate nanocrystals to enhance intestinal adhesion and penetration and lengthen the duration time of drugs in vivo. Nuclear magnetic resonance, Fourier transform infrared, Massspectrometry, X-ray photoelectron spectroscopy, Transmission electron microscopy, and drug loading were used to evaluate the physicochemical characteristics of the nanocrystals. In our study, Abe and Flu were released to exert their synergistic effect when the amide bond of AF was broken and the amide bond was sensitive to cathepsin B which is overexpressed in most tumor tissues, thus increasing the selectivity of the drug to the tumor. The results showed that Lys-PDA@AF NCs had higher cytotoxicity for CRC cell with an IC(50) of 4.86 μg/mL. Additionally, pharmacokinetics showed that Abe and Flu had similar absorption rates in the Lys-PDA@AF NCs group, improving the safety of combination therapy. Meanwhile, in vivo experiments showed that Lys-PDA@AF NCs had excellent antitumor effects and safety. Overall, it was anticipated that the created Lys-PDA@AF NCs would be a potential method for treating cancer.