The Pharmaceutical Journal
Vol 273 No 7320 p532
9 October 2004

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Nanomedicines: now in clinical use

The 2004 British Pharmaceutical Conference and Exhibition “Medicines: from cell to society” took place at Manchester International Convention Centre from 27–29 September

BPC 2004 summary

Products relying on nanotechnology — known as nanomedicines — are now in routine clinical use, delegates heard. These include medicines incorporating polyethylene glycol (ie, pegfilgrastim), stealth liposomes (ie, Doxil), polyglutamation (ie, polyglutamated paclitaxel, Xyotax) and antibodies (ie, gemtuzumab, Mylotarg).

Pegfilgrastim

Attaching polyethylene glycol (PEG) to filgrastim avoids the need for the product to be injected daily, according to Graham Molineux, from the Department of Hematology at Amgen, California. Filgrastim is used to avoid febrile neutropenia in patients undergoing bone marrow transplantation.

The hypothesis behind the development of pegfilgrastim was that if renal clearance of filgrastim could be eliminated, the only remaining route of removal would be neutrophil-mediated clearance. Neutrophils are actually the product of filgrastim action, so the clearance of the drug could be linked to the drug’s effectiveness — the faster the recovery, the quicker the drug is cleared, and the slower the patient’s response, the longer the drug persists.

Dr Molineux explained that filgrastim has five potential sites for linkage of PEG (via free amine groups on lysine or methionine moieties). In the process of developing the final product more than 40 different pegylated filgrastim molecules were synthesised, using linear and branched chain PEGs, PEGs of different molecular weights and with PEGs of different sizes at different sites. The product that was finally selected has a linear PEG attached to the N-terminal methionine of granulocyte-colony stimulating factor, so that the bulky PEG component does not interfere with the rest of the molecule or its ability to interact with its cognate receptor.

Turning to the clinical use of pegfilgrastim, Dr Molineux described how a daily injection of filgrastim enhances the diurnal variation of neutrophil levels. However, pegfilgrastim produces a relentless increase in neutrophil levels. Normal filgrastim is associated with a 48-hour response as it steadily leaks out via the kidneys, but this is not the case with pegfilgrastim. Moreover, the half-life of pegfilgrastim increases with increasing dose, suggesting that there is a saturable element to its clearance. Had a form been developed that was not sensitive to neutrophil-mediated destruction it was possible the drug could have lasted an inordinate length of time in the body, raising concerns about the possibility of excessive exposure to the drug, Dr Molineux said.

Phase 3 studies have been conducted in breast cancer, one trial dosed by weight and the other using a fixed dose. A curious feature of pegfilgrastim is that as body mass increases the bioavailability of the drug increases, with the result that heavy patients are effectively exposed to larger doses. “This is one instance where one size really does fit all,” Dr Molineux noted. Further studies have shown that the dose effect holds over a wide range of body weights, although there is still uncertainty about the correct dose for children, he said.

Stealth liposomal doxorubicin

Stealth liposomes differ from conventional liposomes in that they are coated with polyethylene glycol (PEG), explained Alberto Gabizon from Shaare Zedek Medical Centre, Jerusalem. This enhances their hydrophilicity, and enables them to “evade” the reticulo-endothelial system, thereby slowing their clearance from the body. They have been used to develop “stealth liposomal doxorubicin” (Doxil), Professor Glabizon explained.

There can be 10,000 to 15,000 drug molecules inside a single stealth liposome making the concentration so high that the substance is gelified. Once the liposomes reach permeable (eg, tumour) tissue, they leak into the interstitial fluid and release their drug cargo. The drug can then diffuse into the tumour cells. Higher concentrations of doxorubicin are therefore achieved in tumour tissue after administration of Doxil than after free doxorubicin and the inhibition of tumour growth is correspondingly greater. Doxil is four times more effective than the equivalent dose of free doxorubicin and a small increase in the dose results in a large increase in the dose delivered to tumour tissue. One critical parameter that affects drug delivery is the diameter of the liposome — particles greater than 400nm in diameter are hardly extravasated at all and therefore deliver little of the drug, explained Professor Gabizon.

Stealth liposomes that contain other drugs for cancer treatment are being developed, said Professor Gabizon. They include cisplatin, a mitomicin prodrug and a targeted form of Doxil.

Polyglutamated paclitaxel

A polyglutamated form of paclitaxel (Xyotax) has made it possible to deliver large doses of the drug without the need for extensive premedication and without the risk of alopecia, Jack Singer from Cell Therapeutics Inc, Seattle, Washington, told delegates.

Conventional paclitaxel injection is formulated in “toxic solubilising agents” because of its poor aqueous solubility. It is given by injection over a three-hour period, preceded by a battery of premedication. Xyotax, however, is water-soluble and can be given over 10 minutes. It achieves plasma levels that are 12 times higher than the conventional form with little or no free drug in the plasma. The absence of free drug in the plasma is thought to account for the low systemic toxicity of Xyotax, Dr Singer explained.

Experiments suggest that Xyotax is taken into tumour cells by a process of active endocytosis and that the drug is released as a result of intracellular enzyme action. This might form the basis of its ability to overcome the effects of the multi-drug resistance pump, unlike conventional paclitaxel, Dr Singer postulated. In addition, Xyotax is synergistic with other cancer treatments. In particular, it increases radio-curability of animal model tumours. The results of trials of Xyotax in non-small cell lung cancer are expected early in 2005, Dr Singer told delegates.

Gemtuzumab

Gemtuzumab (Mylotarg) is a humanised antibody linked with the anti-tumour antibiotic calicheamycin. It is licensed in the US (but not yet in Europe) for the treatment of certain patients with CD33-positive acute myeloid leukaemia, according to Michael Eaton, from Celltech R&D.

Calicheamicin is too toxic for human use on its own, Professor Eaton explained, but when linked to an antibody, its toxic effects can be targeted. The antibody portion of the molecule binds to the CD33 antigen, which is commonly expressed by myeloid leukaemic cells. The drug binds to the minor groove of the DNA molecule and causes irreparable double-stranded breaks to occur.