Improving regorafenib's organ target precision via nano-assembly to change its delivery mode abolishes chemoresistance and liver metastasis of colorectal cancer

A regorafenib nanodrug is prepared by self-assembly using regorafenib and clinically approved indocyanine green, which sufficiently delivers regorafenib into colorectal tumor and liver metastasis, markedly enhances regorafenib’s therapeutic efficacy. [Display omitted] •A regorafenib nanodrug (nanoRF) was fabricated by self-assembly.•NanoRF encapsulated regorafenib with a high loading content of 96%.•NanoRF exhibited excellent reproducibility and colloidal stability.•NanoRF effectively delivered regorafenib into tumor local and liver.•NanoRF enhanced regorafenib’s antitumor efficacy in advanced colorectal cancers. Distant metastases and chemotherapy repellency are the key causes of colorectal cancer (CRC)-related mortality. Regorafenib, an oral multi-kinase inhibitor approved for treating advanced CRC with distant metastases and/or chemo-resistance, however only improves median overall survival by 1.4 months. Such limited therapeutic effect is likely due to the low bioavailability of orally administered hydrophobic regorafenib. A regorafenib nanodrug is fabricated by one-step self-assembly with a clinically often-used fluorescent agent (indocyanine green) for overcoming regorafenib’s limitations, towards improving regorafenib’s therapeutic efficacy in advanced CRC. This nanodrug (nanoRF) was characterized, and its antitumor effects were assessed in three preclinical CRC models. NanoRF converts regorafenib’s delivery approach from oral to intravenous with a significantly high encapsulation efficacy of regorafenib (96%) and a long-time colloidal stability. Nanodrug (nanoRF) markedly prolongs regorafenib’s blood circulation by halving clearance rate, and enhances regorafenib’s tumor accumulation. Across three preclinical CRC models (xenografted tumor, chemodrug-resistant xenografted tumor, and liver metastasis), nanoRF drastically enhances regorafenib’s tumor inhibiting efficacy by 0.5–4 folds and effectively extends survival by 0.5–5 folds. This regorafenib nanodrug is a simple, safe, and efficient therapeutic nanodrug for treating advanced CRC with a ready-to-be-clinically-translated potential.