To enhance oral bioavailability for chronic chemotherapy or as a chemopreventive
Poor Solubility and Associated Formulation and Bioavailability Difficulties
Although paclitaxel is an effective anticancer drug, its solubility is low (~ 0.4 µg/mL), which limits 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 has been approved by the FDA under the name Abraxane®.
While these formulations may reduce or eliminate toxicity and side effects associated with Cremophor EL®, they are still administered intravenously.
Taxoid Sugar Pills (Prodrugs)
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 to paclitaxel and 20 to 75 times compared with docetaxel.
In Vitro Efficacy of Taxoid Sugar Pills (Prodrugs)
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-α-MAG-DT, were more active than docetaxel in a dose-dependent manner.
In Vivo Efficacy of Taxoid Prodrugs
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-α-MAG-DT, were more active than paclitaxel in the constant dose in vivo studies.
The effects of 10-α-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-α-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.
APH-0911 - Nanoformulation of Taxoid Prodrug
APH-0911 is a nanotechnology formulation of the taxoid prodrug10-α-GAG-DT, designed to improve the oral bioavailability of water-soluble nanoTaxotere™ prodrug. The nanotechnology formulation utilizes polymer nanospheres made of biodegradable PLGA biopolymers and manufactured with Aphios SuperFluids™ PNS technologies [US Patents].
After ingestion and absorption in the small intestines, serum enzymes break the combined molecule down into the bioactive docetaxel and a sugar molecule. Oral delivery of low dosage docetaxel allows for the acute rather than chronic treatment of breast, ovarian and other cancers.
This paradigm change in cancer therapy will reduce hospitalization stays and side effects of high doses of cytotoxic agents and will lead to chemoprevention regimens very similar to “aspirin” regimens for cardiovascular health.