A docetaxel (DX) lipid conjugate 2′-(2-bromohexadecanoyl)-docetaxel (2-Br-C16-DX) is synthesized to enhance the drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The conjugate is successfully entrapped in the previously optimized NPs with an entrapment efficiency of 56.8%. In-vitro release studies in 100% mouse plasma show an initial 45% burst release with no additional release within 8 h. The conjugate is able to be hydrolyzed to release DX by esterases in-vitro. The conjugate is less potent than unmodified DX in DU-145 and 4T1 cells. However, NPs containing the conjugate show significantly higher cytotoxicity compared to its free form especially in 4T1 cells. In-vivo, the AUC0-∞ value of NP-formulated 2-Br-C16-DX is about 100-fold higher than DX formulated in Taxotere. Furthermore, 2-Br-C16-DX NPs improve DX AUC 4.3-fold compared to Taxotere. The high concentration and prolonged exposure of both 2-Br-C16-DX and DX from 2-Br-C16-DX NPs in circulation result in a 10-fold and 1.5-fold higher accumulation of 2-Br-C16-DX and DX, respectively, in tumors compared to Taxotere. In mice bearing syngeneic 4T1 tumors, 2-Br-C16-DX NPs show markedly greater anticancer efficacy, as well as survival benefit over all controls. The results of these studies support that the oil-filled NPs containing hydrolyzable lipophilic DX prodrug 2-Br-C16-DX improve the therapeutic index of DX and are more efficacious in the treatment of breast cancer.