Self-assembled supramolecular nanomicelles from a bile acid-docetaxel conjugate are highly tolerable with improved therapeutic efficacy.

Herein, we present the engineering of a supramolecular nanomicellar system that is composed of self-assembled units of the PEGylated lithocholic acid (LCA)-docetaxel (DTX) conjugate (LCA-DTX-PEG). We tethered a short polyethylene glycol unit to LCA and used an esterase-sensitive ester linkage between DTX and LCA. The LCA-DTX-PEG conjugate formed nanomicelles (LCA-DTX-PEG NMs) with ∼160 nm hydrodynamic diameter that are sensitive to cellular esterases and maximized the release of DTX under high esterase exposure. LCA-DTX-PEG NMs were found to be effective as the parent drug in breast cancer cells by stabilizing tubulin and arresting the cells in the G2/M phase. We determined the maximum tolerated dose (MTD) and systemic and vital organ toxicity of LCA-DTX-PEG NMs in mice, rats, and rabbits. LCA-DTX-PEG NMs showed a MTD of >160 mg kg-1 and are found to be safe in comparison with their parent FDA-approved drug formulation (Taxotere® or DTX-TS) that is highly toxic. LCA-DTX-PEG NMs effectively reduced the tumor volume and increased the survival of 4T1 tumor-bearing mice with improved blood circulation time of the drug and its higher accumulation in tumor tissues. Therefore, this study highlights the potential of PEGylated bile acid-drug conjugate based nanomicelles for the development of next generation cancer therapeutics.