Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel.

Certain natural fatty acids are taken up avidly by tumors for use as biochemical precursors and energy sources. We tested in mice the hypothesis that the conjugation of docosahexaenoic acid (DHA), a natural fatty acid, and an anticancer drug would create a new chemical entity that would target tumors and reduce toxicity to normal tissues. We synthesized DHA-paclitaxel, a 2'-O-acyl conjugate of the natural fatty acid DHA and paclitaxel. The data show that the conjugate possesses increased antitumor activity in mice when compared with paclitaxel. For example, paclitaxel at its optimum dose (20 mg/kg) caused neither complete nor partial regressions in any of 10 mice in a Madison 109 (M109) s.c. lung tumor model, whereas DHA-paclitaxel caused complete regressions that were sustained for 60 days in 4 of 10 mice at 60 mg/kg, 9 of 10 mice at 90 mg/kg, and 10 of 10 mice at the optimum dose of 120 mg/kg. The drug seems to be inactive as a cytotoxic agent until metabolized by cells to an active form. The conjugate is less toxic than paclitaxel, so that 4.4-fold higher molar doses can be delivered to mice. DHA-paclitaxel in rats has a 74-fold lower volume of distribution and a 94-fold lower clearance rate than paclitaxel, suggesting that the drug is primarily confined to the plasma compartment. DHA-paclitaxel is stable in plasma, and high concentrations are maintained in mouse plasma for long times. Tumor targeting of the conjugate was demonstrated by pharmacokinetic studies in M109 tumor-bearing mice, indicating an area under the drug concentration-time curve of DHA-paclitaxel in tumors that is 8-fold higher than paclitaxel at equimolar doses and 57-fold higher at equitoxic doses. At equimolar doses, the tumor area under the drug concentration-time curve of paclitaxel derived from i.v. DHA-paclitaxel is 6-fold higher than for paclitaxel derived from i.v. paclitaxel. Even at 2 weeks after treatment, 700 nM paclitaxel remains in the tumors after DHA-paclitaxel treatment. Low concentrations of DHA-paclitaxel or paclitaxel derived from DHA-paclitaxel accumulate in gastrocnemius muscle; which may be related to the finding that paclitaxel at 20 mg/kg caused hind limb paralysis in nude mice, whereas DHA-paclitaxel caused none, even at doses of 90 or 120 mg/kg. The dose-limiting toxicity in rats is myelosuppression, and, as in the mouse, little DHA-paclitaxel is converted to paclitaxel in plasma. Because DHA-paclitaxel remains in tumors for long times at high concentrations and is slowly converted to cytotoxic paclitaxel, DHA-paclitaxel may kill those slowly cycling or residual tumor cells that eventually come into cycle.

Fatty acid derivatives of clozapine: prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat.

Stable amides of clozapine derived from fatty acids prominent in cerebral tissue might enhance the central activity of clozapine and reduce its exposure to peripheral tissues. Such derivatives might enhance the safety of this unique drug, which is the only agent with securely established superior antipsychotic effectiveness, but with a risk of potentially lethal systemic toxicity. Amide derivatives of clozapine were prepared from structurally varied fatty acid chlorides and evaluated for ability to inhibit behavioral arousal in rat induced by dopamine agonist apomorphine and to induce catalepsy. Their duration-of-action and potency were compared to free clozapine, and concentrations of clozapine were assayed in brain and blood. Selected agents were also evaluated for affinity at dopamine receptors and other potential drug-target sites. Clozapine-N-amides of linoleic, myristic, oleic, and palmitic acids had moderate initial central depressant activity but by 6 h, failed to inhibit arousal induced by apomorphine. However, the docosahexaenoic acid (DHA) derivative was orally bioavailable, 10-times more potent (ED(50) 5.0 micromol/kg) than clozapine itself, and very long-acting (>/= 24 h) against apomorphine, and did not induce catalepsy. DHA itself was inactive behaviorally. Clozapine showed expected dopamine receptor affinities, but DHA-clozapine was inactive at these and other potential target sites. After systemic administration of DHA-clozapine, serum levels of free clozapine were very low, and brain concentrations somewhat lower than after administering clozapine. DHA-clozapine is a long-acting central depressant with powerful and prolonged antidopaminergic activity after oral administration or injection without inducing catalepsy, and it markedly reduced peripheral exposure to free clozapine. It lacked the receptor-affinities shown by clozapine, suggesting that DHA-clozapine may be a precursor of free, pharmacologically active clozapine. Such agents may represent potential antipsychotic drugs with improved central/peripheral distribution, and possibly enhanced safety.