Vorinostat nanoformulation triggers cell cycle blockade and apoptosis for colorectal cancer therapy.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Histone deacetylase (HDAC) inhibitors such as vorinostat (VOR) eventuate cell cycle arrest and apoptosis by suppressing the HDAC activity, representing a promising class of anti-cancer agents. The clinical application of VOR in solid tumors (e.g., CRC) is hindered by rapid circulatory clearance, insufficient tumor distribution, and off-target cell delivery. To overcome these limitations, we constructed a targeted nanoformulation (T-NP.VOR) using the aminoethyl anisamide (AEAA)-functionalized, poly(ethylene glycol) (PEG)-decorated poly(lactic-co-glycolic acid) (PLGA) nano delivery carrier. In vitro, T‑NP.VOR significantly enhanced cellular uptake in CRC cells via Sigma‑1 receptor‑mediated uptake, leading to HDAC inhibition, cell cycle arrest, and apoptosis. In an orthotopic CRC mouse model, T‑NP.VOR markedly prolonged blood circulation and improved tumor distribution, resulting in significant tumor growth suppression and extended animal survival compared to free VOR and non‑targeted nanoformulation. Our findings confirm the PLGA-PEG-AEAA nanocarrier as a promising VOR delivery platform for CRC therapy.