options of copolymers in both the corona and core regions the micelles, significantly delaying the release of 17-AAG. By optimizing the concentrations of micelle-forming copolymers, therapeutically relevant concentration of 17-AAG could be dis- pensed in PEG-DSPE/TPGS mixed micelles without the inclusion of any organic solvents. PEG-DSPE/TPGS mixed micelles offer a promising platform for facile generation of Metformin multifunctional nanocarriers for delivering 17-AAG to tumor cells via active tar- geting. Fig. 6. The proposed structure scheme of 17-AAG-loaded PEG-DSPE/TPGS mixed micelle. Acknowledgements This work was supported by the New Investigators Program of the American Association of College of Pharmacy (C.T.). This work tions in the micelle core, which drive the micellar solubilization has been subjected to review by the National Exposure Research of lipophilic molecules. In particular, PEG-DSPE (12.5 mM)/TPGS Laboratory and approved for publication.
Approval does not sig- (25.0 mM) mixed micelles had a maximum loading capacity of nify that the contents reflect the views of the Agency, nor does about 10.6 mM for 17-AAG, which makes these drug carriers well its mention of trade names or commercial products constitute suited for delivering clinically relevant concentration of 17-AAG to buy Metformin endorsement or recommendation for use. the tumor cells in vivo . Similarly improved drug loading into PEG- DSPE/TPGS mixed micelles has been previously observed for other References water-insoluble drugs such as camptothecin and paclitaxel ( Mu et al., 2005; Dabholkar et al., 2006 ). Dabholkar, R.D., Sawant, R.M., Mongayt, D.A., Devarajan, P.V., Torchilin, V.P., One crucial finding of our study is that the release rate con- stant of 17-AAG from PEG-DSPE/TPGS mixed micelles was inversely 2006. Polyethylene glycol–phosphatidylethanolamine conjugate (PEG–PE)- based mixed micelles: some properties, loading with paclitaxel, and modulation of P-glycoprotein-mediated efflux. Int. J. Pharm. 315, 148–157. affected by the final concentration of PEG-DSPE, even though the Egorin, M.J., Zuhowski, E.G., Rosen, D.M., Sentz, D.L., Covey, J.M., Eiseman, J.J., studied concentration range was well above the CMC of the copoly- mer and the hydrodynamic diameter of these micelles remained 2001.
Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17- demethoxygeldanamycin (NSC 330507) in CD2F1 mice. Cancer Chemother. Pharmacol. 47, 291–302. constant. To our knowledge, this is the first time that copoly- Egorin, M.J., Lagattuta, T.F., Hamburger, D.R., Covey, J.M., White, K.D., Musser, S.M., mer purchase Metformin concentration-dependent drug release from micelles has been reported. While the molecular mechanism responsible for such phenomenon remains to be elucidated, a plausible explanation to Eiseman, J.L., 2002. Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother. Pharmacol. 49, 7–19. Erlichman, C., 2009. Tanespimycin: the opportunities and challenges of targeting consider is that, being fluid and dynamic complexes, PEG-DSPE micelles are likely to cause fast oscillation of 17-AAG molecules between the micelle core and the aqueous solution, a delicate bal- heat shock protein 90. Expert Opin. Investig. Drugs 18, 861–868. Gao, Z., Lukyanov, A.N., Singhal, A., Torchilin, V.P., 2002. Diacyllipid-polymer micelles as Muslim nanocarriers for poorly soluble anticancer drugs. Nano Lett. 2, 979–982. ance determined by the physicochemical properties of 17-AAG.
Since an increased copolymer concentration gives rise to more micelle entities, the probability of 17-AAG molecules returning into Gaucher, G., Dufresne, M.-H., Sant, V.P., Kang, N., Maysinger, D., Leroux, J.-C., 2005. Block copolymer micelles: preparation, characterization and application in drug delivery. J. Control. Release 109, 169–188. Glaze, E.R., Lambert, A.L., Smith, A.C., , J.G., Johnson, W.D., McCormick, D.L.,