The removal of senescent cells using therapeutic agents

As discussed in the previous blog, one of the strategies for overcoming the detrimental effects of senescent cells is to remove them as they appear through the use of therapeutic agents. At present, no drug-based system exists which can specifically identify senescent cells and remove them. However, there is currently great interest in the development of drugs which specifically target and remove cancer cells. The problem with current cancer treatments (such as drugs used in chemotherapy) is that they are non-specific and as such can cause damage and undesirable changes to non-cancerous cells, causing side-effects. The development of cell-specific drug targeting is greatly needed and such research could be adapted to target senescent cells. Cell-specific drug targeting requires a carrier molecule containing a targeting agent which specifically recognises and binds to a specific receptor or binding site on the surface membrane of target cells and a therapeutic agent which could trigger programmed cell death, apoptosis. The following are crucial factors in determining the success of drug-targeting systems (Beljaars et al, 2001, Petrak 2005).

(1) Cellular specificity: For a drug to exert its desired effect it needs to be in physical contact with its physiological target, such as a receptor.

(2) Rate of elimination of the drug-carrier conjugate: It is essential that the drug-carrier conjugate is not removed too rapidly from the circulation. If it is eliminated from systemic circulation more rapidly than it is delivered to the target site, the amount of conjugate at the target site might never be enough to provide the required concentration of free (unbound) drug.

(3) Rate of release of free drug at the non-target site: Depending on the amount of drug, the release of drug away from the target site could nullify any benefits that might potentially come from delivering the drug to the target site.

(4) Rate of delivery of drug-carrier conjugate to the target site: If the drug conjugate reaches the target site too slowly, the supply of free drug might never be sufficient to generate the concentration required to elicit the desired therapeutic effect at the site of action.

(5) Rate of release of free drug at target site: The capacity of the system selected for the release of free drug from the conjugate should be considered. It needs to be suitable for processing the entirety of the drug-carrier conjugate arriving at the target site, doing so at a rate that also ensures drug accumulation at this site.

(6) Rate of removal of free drug from the target site: Drugs that benefit most from target-selective delivery are those that are retained at the site while acting on their target of action.

(7) Rate of elimination of the drug-carrier conjugate and free drug from the body: For optimal targeting, elimination of the complete drug-carrier system should be minimal.

One promising area of research in the development of drug delivery systems incorporates the use of nanotechnology (http://nano.cancer.gov/). Such technology has been used to create dendrimers, spheroid or globular nanostructures which are highly branched (Alexis et al, 2008). The branched regions of these dendrimers can be used to attach molecules such as targeting and therapeutic agents (Gillies and Frechet 2005). To test this nano-delivery system, invesitgators at the University of Michigan attached a targeting agent, a therapeutic agent and an imaging agent to the surface of dendrimers (Majoros et al, 2006, Shi et al 2007). The investigators chose folic acid as the tumour-targeting agent (a molecule which binds to a high-affinity receptor found on many types of tumour cells), paclitaxel as the therapeutic agent (a drug which triggers programmed cell death, apoptosis) and the fluorescent dye known as fluorescein isothiocyanate as the imaging agent. This nano-dilivery system was then tested on two sets of cancer cells in vitro: one that expresses the folic acid receptor and one that does not. Only the cells containing the folic acid receptor took up the dendrimer, visualised by the presence of the imaging agent. The dendrimer construct was highly toxic to these cells but had no effect on cells without the folic acid receptor. When both of these cells were exposed to dendrimers containing the targeting and imaging agent but no paclitaxel, no detrimental effects were observed.

These promising initial results thus call for tests to be carried out on animals with tumours that overexpress folic acid receptors. It is research like this that could one day be adapted to specifically target senescent cells. For this to be the case, a target agent is required that specifically recognises senescent cells. For this to be achieved, a deeper understanding of the changes which occur when a cell becomes senescent is required. Ideally a universally expressed senescent membrane receptor would be ideal, but at present no such receptor is known. If it did, it would also make a useful biomarker for detecting senescent cells in tissues.