Abemaciclib

CDK4/6 phosphorylate and inhibit the retinoblastoma (Rb) oncosuppressor protein, leading to cell cycle progression (G1 to S phase) which ultimately stimulates cell proliferation. Abemaciclib (ABE) has antineoplastic activity due to an ATP-competitive reversible inhibition of CDK4 and 6. ABE has multiple secondary targets that have been identified, such as CDK1-cyclin B and CDK2-cyclin A/E complexes. This helps to explain how ABE can also cause G2 cell-cycle arrest as well as a pan-CDK transcriptional signature. CDK9 is another secondary target of ABE. This kinase is crucial for intestinal cell proliferation in experimental models. ABE also inhibits glycogen synthase kinase-3 beta (GSK3β), which is a member of a protein complex that phosphorylates β-catenin, which otherwise would translocate to the nucleus and function as a transcriptional coactivator. GSK3β also complexes with other transcription factors (TFs) to form TF transcriptional activators of many genes including MYC, CCND1 and AXIN2. The inhibition of GSK3β leads to Wnt pathway/β-catenin activation, which would promote cellular proliferation. ABE also profoundly inhibits Ca2+/calmodulin-dependent protein kinase, which plays a role in intestinal motility and has been connected to bowel movements.

Fig. 1 Pharmacodynamic of abemaciclib. (Martorana F, et al. 2024)

Abemaciclib (Abm) is a new fourth-generation CDK4/6 inhibitor with a well-established efficacy for the treatment of hormone-positive breast cancer; its poor water solubility and low oral bioavailability has limited its full clinical potential. The polymer-based drug delivery system was developed with the aim of improving its solubility by loading Abm on chitosan (CS) nanoparticles, in which tripolyphosphate (TPP) was used as cross-linking agent.
To optimize the developed drug delivery system using Abm, the Minitab 18 software package and Response Surface Methodology (RSM) was utilized to study 18 experimental runs. The various independent variables, namely CS concentration, TPP concentration, and pH of the medium, were chosen to study their effect on the selected dependent variables i.e., particle size and %LE. The Pareto chart, ANOVA, and statistical analysis suggested that the independent variables and their interactions have a significant effect on the nanocomposite. The optimized values were found to be 100 mg CS, 91 mg TPP (approx), and a pH of 5.1 which led to a particle size of 189 nm and %LE of 67.9%. The successful loading of the drug on CS and the change to the amorphous state which was evident in the improved dissolution profile was supported by the FTIR, XRD, and SEM studies. The in vitro release studies indicated a prolonged drug release up to 1,400 minutes which shows the potential of the Abm-CSNPs nanocomposite as an alternate drug delivery system for improving the solubility and PK profile of Abm.

Fig. 2 The SEM image of Abm-CSNPs nanocomposite. (Ali M M, et al. 2025)