Supporting Literature

M. N. Khalid, P. Simard, D. Hoarau, A. Dragomir, J. Leroux, Long Circulating Poly(Ethylene Glycol)Decorated Lipid Nanocapsules Deliver Docetaxel to Solid Tumors, Pharmaceutical Research, 23(4), 2006.

In this regard, the authors want to:

  • Modify or remove the current vehicle for standard docetaxel
  • Alter the pharmacokinetics of standard docetaxel
  • Improve the tumor uptake of docetaxel

The studies reported within describe the process for making a lipid nanocapsule docetaxel, pharmacokinetics of the lipid product, and tumor uptake of docetaxel.

It appears that the authors intend to perform MTD studies, toxicity studies, and tumor xenograft studies, but no efficacy results were reported in this publication even thought they treated animals with a colorectal tumor.

The Process:
The researchers describe a multi-step process representative of a traditional method for the preparation of a liposomal product. Vesicle sizes ranged form 90–120 nm and were dependant on the formulation receipt. The method that is used is an inversion-based process typical used for small scale preparation of liposomes and is extremely difficult to scale-up. Also, it should be noted their final product is a liposomal solution that has to be used immediately. Their preparation protocol differs substantially from the method developed by Azaya Therapeutics where the liposomal product is prepared in a 1 step process, yielding a freeze dried powder ready for use after being reconstituted with 0.9% saline. Azaya Therapeutics manufacturing process consistently yields uniform particles with an average particle size of 60–80 nm.

Study Results:
The process described results in 98% encapsulation with 57% of the active drug being released from the PEG-lipid nanocapsule within 2 hours. The pharmacokinetic data clearly suggests that the lipid nanocapsule does alter the pharmacokinetics of docetaxel with a prolonged exposure (i.e. increased T ½) and much greater tumor uptake compared to standard docetaxel. These attributes would be expected with a &lodquo;liposomal” preparation. In addition, the change in PK parameters was reasonable (T ½ of 0.3hr for standard docetaxel and 1.4hr for PEG-lipid nanocapsule docetaxel), tumor uptake of docetaxel increased substantial when incorporated into the lipid nanocapsules. It should be noted that the particle size (80 versus 120 nm) and PEG density did effect removal from the blood (i.e. pharmacokinetics) of docetaxel when incorporated into the lipid nanocapsule. One question that did come to mind was the fact they measured only total radioactivity, which may not reflect only the fate docetaxel, since it would also measure any metabolites of docetaxel that also contained the C14 label. They also report their data as a % of injected dose versus the actual amounts of docetaxel.

Overall they are observing a markedly improve profile compared to taxotere with the liposome encapsulated docetaxel; 4 fold enhanced tumor uptake, longer half life, and a 5 fold increase of area under the curve. This paper demonstrates that the liposomal formulation of docetaxel does improve the drug profile of the known drug taxotere. As such, this paper supports and conclusively verifies previous experiments carried out by Azaya Therapeutics.

  1. Yoshio Nakano, Phospholipids, Drug Delivery Technologies, 6(6), 2006, 60-63.
  2. Jason McKinnie, Nanobiotechnology, Drug Delivery Technologies, 6(6), 2006, 40-44.
  3. Cindy H. Dubin, Formulation Strategies for Poorly Soluble Drugs, Drug Delivery Technologies, 6(6), 2006, 34-38.