Enhancing Drug Penetration of Tumours

Image: Flickr - elektroholunder
One problem associated with the treatment of solid tumours is that chemotherapeutic agents have difficulty in penetrating more than a few cell diameters from the vasculature. Higher doses of drug are required and, because some tumour cells are not reached, the risk of recurrence is high. To address this issue, researchers at Sanford-Burnham Medical Research Institute have now described a peptide able to enhance the ability of drugs to access tumour tissue.

Some years ago it was shown that peptides containing the RGD (Arg-Gly-Asp) sequence recognise a family of cell-surface receptors, integrins, which mediate the interaction of cells with the extracellular matrix (ECM) components fibronectin and type I collagen and are important for the migration and invasion of tumour cells. RGD peptides have been used for homing to malignant tissue and the Sanford-Burnham team have taken this a step further. The new agent is a cyclic nona-peptide (CRGDK/RGPD/EC), referred to as iRGD. The contained RGD sequence targets the agent to tumour tissue where it is cleaved to reveal a ‘CendR’ sequence that binds to neuropilin-1, mediating an active transport system.

In a paper published in Cancer Cell late last year, the research team showed that coupling iRGD to anti-cancer drugs allowed them to penetrate deep into tumours, effectively increasing the activity of the drugs. In their latest study, published in Science, the team have shown that the chemotherapeutic agents do not need to be conjugated to the peptide. Co-administration of iRGD with a variety of drugs, including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab), improved their therapeutic index.

The team hope that iRGD may be a valuable adjunct to enhance efficacy of anti-cancer agents, whilst reducing side-effects.

Oral Delivery of Short Interfering RNA Molecules

trojan horseAlthough many studies have shown the potential for gene silencing using short interfering RNA (siRNA), a major hurdle to the therapeutic use of the technique has been the lack of effective delivery systems. Writing in the journal Nature, researchers at the University of Massachusetts Medical School now report a method of delivering siRNA to specific cell types following oral administration. The researchers exploited a characteristic of macrophages – the ability to engulf yeast particles – to deliver the siRNA. Macrophages are attractive targets for RNA interference therapy since they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes. Yeast particles were treated to remove components that would elicit an immune response to give β-1,3-D glucan, a polysaccharide formed from D-glucose, as the delivery vehicle. Oral delivery of β-1,3-D glucan-encapsulated siRNA particles containing as little as 20 µg kg-1 siRNA directed against tumour necrosis factor α (TNF-α) depleted messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum TNF-α levels. The technique was also used to identify the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) as a previously unknown mediator of cytokine expression. Silencing Map4k4 in macrophages protected mice from lipopolysaccharide-induced lethality by inhibiting TNF-α and interleukin-1β production. The siRNA-carrying particles were engulfed by macrophages in the gut and, over time, a large proportion of macrophages exhibited gene silencing, resulting in systemic immune suppression.

Crossing the Blood-Brain Barrier

brainPaclitaxel is highly effective for the treatment of cancers of the lung, ovary, breast, and head and neck. The efficacy of paclitaxel in treating malignant gliomas (cancers of the brain and spine) and brain metastases, however, is severely compromised by the relative inability of the drug to cross the blood-brain barrier. Cancers of the brain are very difficult to treat, and the prognosis for patients is generally poor. A new drug delivery system has been developed to increase the effectiveness of paclitaxel in treating brain tumours. Three paclitaxel molecules were joined by a cleavable succinyl ester linkage to a brain peptide vector, Angiopep, to provide a paclitaxel-Angiopep conjugate named ANG1005. ANG1005 enters the brain to a much greater extent than paclitaxel, and leads to a significant increase in survival of mice with intracerebral implantation of U87 MG glioblastoma cells.

Preliminary data have recently been released showing that initial doses of ANG1005 are safe and well tolerated in brain cancer patients. Two parallel phase I/II studies are being carried out, one in patients with recurrent glioblastoma and the other in patients with brain metastases. ANG1005 is administered by intravenous infusion for 1 hour every 21 days. The studies aim to determine safety, tolerability and maximum tolerated dose, as well as giving preliminary pharmacokinetic and efficacy data. Both studies involve around 30 patients and top-line data are expected by the end of 2008.

The Angiopep vector system may provide a way of effectively transporting other drugs, including antibodies, siRNA, peptides and small molecules, across the blood-brain barrier to improve the treatment of a variety of CNS disorders.