Bacterially derived nanocells offer direct route for cancer therapy
drugs directly to cancer cells without the shortcomings of
liposomal or viral carriers could be in clinical trials by the end
of this year, an Australian biotechnology company says.
The company, EnGeneIC, has tested the delivery system successfully in animal models with minute but therapeutically significant doses of a range of anticancer chemotherapeutics. The "highly significant" tumour growth inhibition and regression observed in these studies suggests the nanocells could be used as carriers for highly toxic anticancers and/or complex combination/sequential therapy, write researchers led by Jennifer MacDiarmid of EnGeneIC in the May issue of the journal Cancer Cell. The so-called 'minicells' are generated through chromosomal mutations that force the parent bacteria to divide at the cell poles as well as at the centre, producing what MacDiarmid describes as "little empty sacs of cytoplasm". As these stable 'buds', each about 400 nanometres in diameter, do not carry any chromosomal material, they are non-reproductive and avoid the disease-making potential of viral vectors. The minicells also have solid membranes, allowing them to be "packed" with a drug payload and without the leakage problems that have hampered liposomal carriers, MacDiarmid noted. The targeting mechanism is achieved by attaching bispecific antibodies to the surface of the minicells via the O-polysaccharide component of the lipopolysaccharide in the cell membrane. One portion of this antibody can be engineered to recognise a specific receptor on the surface of a cancer cell, such as HER2 or EGFR (epidermal growth factor receptor). The minicell/antibody complex could be used to target "pretty much any solid tumour," MacDiarmid commented. Once the minicell locks onto the receptor, it is quickly endocytosed and broken down within the cancer cell, releasing the drug "like the Trojan horse," she explained. In their report in Cancer Cell, the EnGeneIC researchers and their colleagues said targeted minicell-mediated drug delivery, using chemotherapeutics such as doxorubicin and paclitaxel, resulted in "highly significant inhibition and even regression" of tumour growth in vivo in mice with human breast, ovarian, leukaemia or lung cancer xenografts. Rapid tumour regression was also observed in two dogs diagnosed with non-Hodgkin's lymphoma and treated with minicells. Moreover, safety tests with intravenously-administered minicells in healthy pigs showed the carriers were well tolerated, with no adverse effects in any of the actively treated animals despite repeat dosing. The most important feature of minicell drug delivery, the researchers noted, is its ability to achieve inhibition or regression of tumour growth with volumes of chemotherapeutics substantially lower than those required with systemic delivery of free drug. For example, with delivery of minicells carrying doxorubicin or paclitaxel, tumour growth inhibition was significantly more marked in the xenograft models than with administration of around 1,875-fold and 8,000-fold higher amounts of the respective free drugs. According to MacDiarmid, EnGeneIC is looking to take the minicells into first-in-man trials at the end of this year or the beginning of 2008. The initial target will probably be metastatic breast cancer and ovarian cancer, although it will depend on the specificities of the available antibodies. EnGeneIC was set up around the minicell technology in 2001. MacDiarmid said the company was "at a bit of a crossroads" now as far as development partnerships were concerned but was beginning to see some interest from Big Pharma. One incentive to find a larger partner, she added, was that EnGeneIC did not have cGMP manufacturing facilities. At the same time, it wanted to steer the minicells through development as quickly as possible while cancer still had priority with drug regulators.
