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.