Aphios Corporation

Taxotere® Prodrug

Although paclitaxel is an effective anticancer drug, its solubility is low (~ 0.4 µg/ml) limiting its medical utility to intravenous applications. Docetaxel (Taxotere®) was developed as a paclitaxel derivative having improved water solubility; its solubility, however, is only ~ 14 µg/ml. Several encapsulation techniques have been utilized to reformulate paclitaxel in more biocompatible solvents. These include liposomes, dextran, PEG and albumin, the latter of which have been approved by the FDA under the name Abraxane®. While these formulations may reduce/eliminate toxicity and side effects associated with Cremophor EL®, they are still administered intravenously.

We have developed Taxotere prodrugs with improved water solubility by utilizing sugars as hydrophilic appendages to docetaxel. Since taxoids are susceptible to Lewis acids often utilized in glycosylation protocols, sugars are tethered to the C-10 hydroxyl group in a taxoid through an ester linkage. Compared with paclitaxel and docetaxel, the solubilities of the taxoid derivatives show strikingly high values. Solubilities of the docetaxel derivatives were increased 630 to 2600 times compared with paclitaxel and 20 to 75 times compared with docetaxel (United States and Japanese Patents).

The in vitro antitumor activities of the various Taxotere derivatives were examined using P-388 leukemia cells. All docetaxel prodrug derivatives, with the exception of the most water-soluble derivative 10--MAG-DT, were more active than docetaxel in a dose-dependent manner.

The in vivo antitumor activities of the docetaxel prodrugs versus paclitaxel and controls were also tested. Again, all docetaxel prodrug derivatives, with the exception of the most water-soluble derivative 10--MAG-DT, were more active than paclitaxel in the constant dose-in vivo studies.

The effects of 10--GAG-DT and docetaxel on body weight (side effect) were evaluated. Interestingly, at a dosing level of 20 mg/Kg, the decrease in body weight as an index of side effects is suppressed for the prodrug 10--GAG-DT compared to docetaxel.

Research results suggest that these docetaxel derivatives act as prodrugs without the use of a toxic solvent, and for the most part are superior to paclitaxel in terms of both in vitro and in vivo bioactivities and equivalent to docetaxel in therapeutic efficacy.

We are seeking strategic corporate partners/licensors to develop an orally-bioavailable water-soluble Taxotere prodrug. The prodrug is a combination of a docetaxel molecule, the potent anticancer drug, and a sugar molecule that enhances solubility. This molecular combination is not bioactive prior to treatment and is significantly more water-soluble than docetaxel. The water-soluble nature of this novel therapeutic allows for oral digestion rather than by intravenous infusion. After ingestion and adsorption in the gut, serum enzymes break the combined molecule down into the bioactive docetaxel and a sugar molecule. We will utilize patented drug delivery nanotechnologies to enhance the oral bioavailability of this Taxotere prodrug (US Patents).