Oil-filled Lipid Nanoparticles Containing Docetaxel Conjugates for Controlled Drug Release

It has always been challenging to deliver anticancer agents effectively, safely and selectively to solid tumors. Taxotere, as the only marketed dosage form of docetaxel (DX), has various drawbacks. The overall objective of this dissertation was to develop oil-filled nanoparticles (NPs) as novel alternative formulation to deliver DX. Novel oil-filled NPs were developed by sequential simplex optimization. Miglyol 808 was selected as the oil phase due to its high solvation ability for DX. Despite the desirable formulation properties, DX was found to be very quickly released in mouse plasma in-vitro. To overcome the poor retention of DX in the NPs, three DX lipid conjugates: 2'-lauroyl-docetaxel (C12-DX), 2'-stearoyl-docetaxel (C18-DX) and 2'-behenoyl-docetaxel (C22-DX) were synthesized. The three conjugates showed 10-fold higher solubility in Miglyol 808 than DX. Consequently, the conjugates were entrapped in NPs prepared with reduced surfactant and showed 50-60% entrapment efficiencies. All three conjugates had good retention in mouse plasma. In-vivo, NP-formulated DX conjugates showed 8-450-fold higher AUC0-[infinity] values than that of Taxotere. More importantly, C12-DX and C18-DX improved DX AUC0-[infinity] over that of Taxotere. In addition, these conjugates were significantly less toxic than DX in-vitro. To further improve the hydrolysis kinetics, a bromoacyl DX-lipid conjugate 2'-(2-bromohexadecanoyl)-docetaxel (2-Br-C16-DX) was synthesized. The conjugate exhibited similar entrapment efficiency and in-vitro release profile in mouse plasma with the other three conjugates without bromine. The NP-formulated 2-Br-C16-DX was slowly hydrolyzed to DX to an extent of 45% in 48 hr by esterases in-vitro. The superior hydrolysis kinetics led to improved cytotoxicity in-vitro with 2-Br-C16-DX NPs. In-vivo, the AUC0-[infinity] value of NP-formulated 2-Br-C16-DX was about 100-fold higher than Taxotere in mice. Furthermore, 2-Br-C16-DX NP improved DX AUC by 4.3-fold compared to Taxotere. The 2-Br-C16-DX NPs extensively accumulated in solid tumors compared to Taxotere. The 2-Br-C16-DX NPs were well tolerated in mice. In mice bearing metastatic 4T1 tumor, 2-Br-C16-DX NPs showed marked 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 improved the therapeutic index of DX and were efficacious in the treatment of breast cancer in animal models