micelles may therefore increase, leading to an apparent decline in Brown, A.P., Levine, B.S., Covey, J.M., Egorin, M.J., Eiseman, J.L., Holleran, J.L., the release rate constant. This finding has important implication when devising PEG-DSPE micellar nanocarriers for tumor-targeted Sausville, E.A., Tomaszewski, J.E., 2005. Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino) Diabex demethoxygeldanamycin (17- DMAG), in rats and dogs: potential clinical relevance. Cancer Chemother. delivery of 17-AAG in vivo . It suggests that the plasma concentra- Pharmacol. 56, 637–647. tion of PEG-DSPE needs to substantially exceed its CMC, in order to minimize premature drug release from micellar carriers to the Goetz, M.P., Toft, D., Reid, J., Ames, M., Stensgard, B., Safgren, S., Adjei, A.A., Sloan, J., Atherton, P., Vasile, V., Salazaar, S., Adjei, A., Croghan, G., Erlichman, C., 2005. Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with systemic circulation. advanced cancer. J. Clin. Oncol. 23, 1078–1087.

Compared to the extremely slow release of some chemothera- peutic agents ( Mu et al., 2005; Dabholkar et al., 2006 ), the release of 17-AAG from PEG-DSPE/TPGS mixed micelles appears to be rel- Grem, J.L., Morrison, G., Guo, X.-D., Agnew, E., Takimoto, C.H., Thomas, R., Szabo, E., Grochow, L., Grollman, F., Hamilton, J.M., Neckers, L., Wilson, R.H., 2005. Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J. Clin. Oncol. 23, 1885–1893. atively fast. This may be rationalized by the compatibility between the incorporated drug and the micelle core, which is determined by the physicochemical properties intrinsic to the drug molecules. Guo, W., Reigan, P., Siegel, D., Ross, D., 2008. Enzymatic reduction and glutathione conjugation of benzoquinone ansamycin heat shock protein 90 inhibitors: rele- vance for toxicity and mechanism of action. Drug Metab. Dispos. 36, 2050–2057. Heath, E.I., Hilman, D.W., Vaishampayan, U., Sheng, S., Sarkar, F., Harperet, F., Gaskins, When administered in vivo , albeit some loaded 17-AAG molecules will inevitably be Diabex 1115-70-4 prematurely released from these micellar carriers, it is conceivable that a significant proportion of 17-AAG- M., Pitot, H.C., Tan, W., Ivy, S.P., Pili, R., Carducci, M.A., Erlichman, C., Liu, G., 2008. A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin.

Cancer Res. 14, 7940–7946. Hollingshead, M., Alley, M., Burger, A.M., Borgel, S., Pacula-Cox, C., Fiebig, loaded PEG-DSPE/TPGS micelles may still be able to preferentially H.-H., Sausville, E.A., 2005. In vivo antitumor efficacy of 17-DMAG (17- accumulate at the tumor site via the EPR effect, improving the pharmacokinetic characteristics of free 17-AAG. This is because dimethylaminoethylamino buy Diabex 17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother. Pharmacol. 56, 115–125. the extravasation of PEG-DSPE micelles to the tumor tissue occurs Isaacs, J.S., Xu, W., Neckers, L., 2003. Heat shock protein 90 as a molecular target for rapidly following intravenous administration and reaches a plateau by 4–5 h. The prolongation of the release half-life of 17-AAG from cancer therapeutics. Cancer Cell 3, 213–217. Kastantin, M., Ananthanarayanan,

B., Karmali, P., Ruoslahti, E., Tirrell, M., 2009. Effect of the lipid chain melting transition on the stability of DSPE-PEG(2000) micelles. micelles beyond this time frame will therefore be of critical conse- Langmuir 25, 7279–7286. 7 S716 I. J. Radiation Oncology d Biology d Physics Volume 81, Number 2, Supplement, 2011 Results: The V79 and MCF7 cell lines roundworm  showed split-dose recovery indicating SLD repair for 2×6 Gy or 2×4 Gy (yielding surviving fractions, SF 0.004 – 0.006 for single total-dose irradiation). The SLD repair halftime for split-dose intervals up to 40 min increased from 15 to 25 min for V79, but wa