RNAi delivery system tackles brain cancer
of diseases, but delivering the RNAi compounds to the right
location has been a major obstacle to their development. Now, US
researchers have succeeded in getting the drugs into the brain, one
of the hardest areas of the body to target.
The researchers, from the University of California, Los Angeles, have combined a number of molecular targeting technologies to deliver gene-silencing therapy specifically to tumour cells shielded by a normally impermeable obstacle, the blood brain barrier.
The UCLA team designed a liposome carrier for a plasmid coding for the RNAi compound equipped with two specific antibodies that first recognises the transferrin receptor, a key protein portal in the blood brain barrier, and then gains entry into brain cancer cells with the second antibody targeting the human insulin receptor, used to gain access to the tumour cells. They report their work in the 1 June issue of the journal Clinical Cancer Research.
Using the antibody keys to traverse both the blood brain barrier and the tumour cell membrane, the liposomes deposit the plasmid into the brain cancer cells. The plasmid encodes a short hairpin RNA (shRNA) designed to interfere with the expression of the epidermal growth factor receptor (EGFR), a potent stimulator of tumour cell proliferation.
When the tumour cell divides, the RNAi molecule is produced and binds to the message from the tumour cells' pool of EGFR RNA. Binding of the RNAi therapeutic molecule to the cells' innate RNA results in the silencing of the EGFR message. No EGFR protein is produced, and the gene is effectively inactivated.
Without its normal workload of EGFR proteins to encourage cell proliferation, the tumour growth is held in check.
In the Clinical Cancer Research article, the researchers described how they treated mice with brain tumours with a weekly intravenous dose of the therapeutic. They found that treated mice survived almost twice as long as untreated mice.
EGFR has emerged as a new drug target for cancer, and the first products targeting the protein are already on the market. Leading the way was AstraZeneca's Iressa (gefitinib), first launched in 2002, and this is being followed by ImClone Systems' antibody Erbitux (cetuximab; launched in Switzerland in December 2003) and Roche, Genentech and OSI Pharmaceuticals' small molecule drug Tarceva (erlotinib).
