Tehran University of Medical Sciences Acta Medica Iranica 0044-6025 59 6 2021 08 14 333 345 Parichehr Hassanzadeh 1 Nanotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran .AND Sasan Hospital, Tehran, Iran Elham Arbabi ReResearch Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran Fatemeh Rostami Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2020 09 11 2021 04 16 Breast cancer therapy has remained one of the major healthcare challenges. Based on the critical role of cyclin-dependent kinase 4/6 (CDK 4/6) in cell cycle progression, targeting this signaling appears promising for cancer therapy. Palbociclib, a selective CDKs 4/6 inhibitor, is the first-line treatment for estrogen receptor-positive breast cancer. However, poor absorption or side effects may negatively affect its efficiency. This prompted us to incorporate palbociclib into the nanostructured lipid carriers (NLCs) and evaluate the anticancer effect of the nanoformulation (Pa-NLCs) in in vitro and in vivo models of breast cancer. Pa-NLCs were developed by high-pressure homogenization followed by assessment of the physicochemical characteristics and bioactivities in MCF-7 breast cancer cells and female Wistar rats exposed to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). The prepared Pa-NLCs demonstrated suitable physicochemical characteristics, including the controlled release pattern, efficient cellular uptake, and cytotoxicity, while free palbociclib failed to show significant effects. Rats treated with Pa-NLCs exhibited significantly reduced tumor volumes, increased survival rates, and histopathological improvement. Free palbociclib was significantly less efficient than Pa-NLCs. Pa-NLCs, by improving the pharmacological profile of palbociclib and providing longer-lasting effects, can be considered as a promising nanoformulation against breast cancer. https://acta.tums.ac.ir/index.php/acta/article/view/8793