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Unpicking two locks to selectively deliver cancer therapy
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Intense research efforts are ongoing on methods for effectively targeting therapies to disease sites, such as delivery of cancer medication selectively to tumours. One method which is receiving a lot of attention is use of adeno-associated virus (AAV), which are relatively benign, as a delivery vehicle for gene therapy. An innovative adaptation of this method has been developed by researchers in Rice University in Texas and in the University of Florida to improve specificity of delivery of AAVs containing tumour therapeutic agents. The paper appears online this week in the American Chemical Society journal ACS Nano.

The method involves incorporating peptides in the capsid of the AAV that can only be degraded in the presence of two proteases, whose activity is increased in the tumour microenvironment. Only then can the AAV release its therapeutic contents. Tumours themselves over-secrete proteases and infiltrating immune cells such as neutrophils also release a high level of proteases in the region of the tumour. In the absence of these correct proteases the AAV is effectively locked so that the contents are unlikely to be released ‘accidentally’ at sites distant from the tumour.

Senior author Dr Junghae Suh further explains the ‘double lock’ strategy: “So that’s what we’re going after to do targeted delivery. Our basic idea is to create viruses that, in the locked configuration, can’t do anything. They’re inert”. However, when programmed AAVs encounter the correct proteases at sites of disease, “these viruses unlock, bind to the cells and deliver payloads that will either kill the cells for cancer therapy or deliver genes that can fix them for other disease applications.” She goes on to further explain the specificity of the method in targeting therapy to the correct site: “If we were just looking for one protease, it might be at the cancer site, but it could also be somewhere else in your body where you have inflammation. This could lead to undesirable side effects…By requiring two different proteases – let’s say protease A and protease B – to open the locked virus, we may achieve higher delivery specificity since the chance of having both proteases elevated at a site becomes smaller.”

Dr Suh is confident that the applicability of this method could extend beyond tumours to neurological and cardiovascular diseases. Also, advances in molecular-imaging techniques should help in identification of and assessment of concentration of elevated proteases. Ultimately, it is hoped that targeting can be even more sensitive so that viruses can be designed to carry out a combination of steps for targeting. Dr Suh concludes: “To increase the specificity of virus unlocking, you can imagine creating viruses that require many more keys to open…For example, you may need both proteases A and B as well as a cellular receptor to unlock the virus. The work reported here is a good first step toward this goal.”

Sources:

Judd, J. et al. (2014). Tunable Protease-Activatable Virus Nanonodes. ACS Nano, Article ASAP; DOI: 10.1021/nn500550q (May 5, 2014)

Press release: ACS Nano; Rice University; available at http://news.rice.edu/2014/05/06/two-lock...r-therapy/ [Accessed 7 May 2014]
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Unpicking two locks to selectively deliver cancer therapy00