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Oil‐Filled Lipid Nanoparticles Containing 2′‐(2‐Bromohexadecanoyl)‐Docetaxel for the Treatment of Breast Cancer
Author(s) -
Feng Lan,
Benhabbour Soumya R.,
Mumper Russell J.
Publication year - 2013
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201300017
Subject(s) - conjugate , docetaxel , prodrug , chemistry , in vivo , in vitro , cytotoxicity , nanoparticle , pharmacology , hydrolysis , nuclear chemistry , materials science , cancer , biochemistry , nanotechnology , medicine , mathematical analysis , mathematics , microbiology and biotechnology , biology
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 AUC 0‐∞ 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.