Tumor targeting by conjugation of DHA to paclitaxel

Targeting an anti-cancer drug to tumors should increase the Area Under the drug concentration-time Curve (AUC) in tumors while decreasing the AUC in n ormal cells and should therefore increase the therapeutic index of that dru g. Anti-tumor drugs typically have half-lives far shorter than the cell cyc le transit times of most tumor cells. Tumor targeting, with concomitant lon g tumor exposure times. will increase the proportion of cells that move int o cycle when the drug concentration is high, which should result in more tu mor cell killing. In an effort to test that hypothesis, we conjugated a nat ural fatty acid, docosahexaenoic acid (DHA), through an ester bond to the p aclitaxel 2 ' -oxygen. The resulting paclitaxel fatty acid conjugate (DHA-p aclitaxel) does not assemble microtubules and is non-toxic. In the M109 mou se tumor model, DHA-paclitaxel is less toxic than paclitaxel and cures 10/1 0 tumored animals, whereas paclitaxel cures 0/10. One explanation for the c onjugate's greater therapeutic index is that the fatty acid alters the phar macokinetics of the drug to increase its AUC in tumors and decrease its AUC in normal cells. To test that possibility, we compared the pharmacokinetic s of DHA-paclitaxel with paclitaxel in CD2F1 mice bearing similar to 125 mg sc M109 tumors, The mice were injected at zero time with a bolus of either DHA-paclitaxel or paclitaxel formulated in 10% cremophor/10% ethanol/80% s aline. Animals were sacrificed as a function of time out to 14 days. Tumors and plasma were frozen and stored. The concentrations of paclitaxel and DH A-paclitaxel were analyzed by LC/MS/MS. The results show that DHA targets p aclitaxel to tumors: tumor AUCs are 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eight-fold higher at equimolar doses. Likewise, at equi-toxic doses, the tumor AUCs of paclitaxel derived from i .v. DHA-paclitaxel are 6.1-fold higher than for paclitaxel derived from i.v . paclitaxel. The tumor concentration of paclitaxel derived from i.v. pacli taxel drops rapidly, so that by 16 h it has fallen to the same concentratio n (2.8 muM) as after an equi-toxic concentration of DHA-paclitaxel. In plas ma, paclitaxel AUC after an MTD dose of DHA-paclitaxel is approximately 0.5 % of DHA-paclitaxel AUC. Thus, the increase in tumor AUC and the limited pl asma AUC of paclitaxel following DHA-paclitaxel administration are consiste nt with the increase in therapeutic index of DHA-paclitaxel relative to pac litaxel in the M109 mouse tumor model. A phase I clinical study has been co mpleted at The Johns Hopkins Hospital to evaluate the safety of DHA-paclita xel in patients with a variety of solid tumors. Twenty-one patients have be en treated to date. The recommended phase II dose is 1100 mg/m(2), which is equivalent to 4.6 times the maximum approved paclitaxel dose on a molar ba sis. No alopecia or significant peripheral neuropathy, nausea, or vomiting have been observed. Asymptomatic, transient neutropenia has been the primar y side effect. Eleven of 22 evaluable phase I patients transitioned from pr ogressive to stable disease. as assessed by follow-up CT. Significant quali ty of life improvements have been observed. Thus. DHA-paclitaxel is well to lerated in patients and cures tumors in mice by targeting drug to tumors. ( C) 2001 Published by Elsevier Science B.V.