About the Project
Targeting established tumour vasculature is a very attractive therapeutic strategy since as the tumour endothelium is readily accessible, shutdown as well as loss of vasculature would have the knock-on effect of starving the nutrient supply, ultimately killing the tumour cells supported. Among the different types of vascular disrupting agents (VDAs), to date, small molecule VDAs have progressed the furthest in terms of clinical development. These can be sub grouped as agents which bind to tubulin and result in the depolymerisation of microtubules, leading to the disruption of the endothelial cytoskeleton with the ultimate shutdown of blood flow, and the flavonoids, whose mechanism of action is still unclear. Agents which have progressed to early clinical trials include the tubulin-binders combretastatin A4 phosphate, combretastatin A1 diphosphate, ZD6126, ABT-751, and the flavone-like DMXAA.
A problem with administering VDAs alone, is that they do not act on normal functional vasculature supporting viable tumour at the periphery of the tumour following treatment. This is a problem as once the VDA effect is removed, the tumour is capable of regrowth. One of the strategies to remove this peripheral tumour is to combine VDA therapy with a standard cytotoxic agent such as cisplatin, doxorubicin or BCNU. The challenge then comes in the dose ratio of the administered agents and it has recently been demonstrated that ratiometric dosing is crucial for the efficacy of combination therapies, and this will be investigated at the in vitro level to optimise the therapeutic opportunity. If successful, then further funding will be sought to progress to in vivo proof-of-principle studies.
Another major issue with several of the therapeutic VDAs and cytotoxics used in cancer therapy is off-target toxicological effects due to the lack of specificity of these agents. Ideally the majority of an administered drug would be delivered to the primary and metastatic tumour sites with minimal exposure of normal tissues to the drugs.
Several drug carrier systems have been evaluated which focus delivery of the drug payload to the tumour, the majority based around liposomes. Packaged in liposomes, due to the colloidal nature of the liposomal carrier system, drugs are protected from enzymatic degradation and can be delivered specifically to tumour sites via the well-explored Enhanced Permeability and Retention (EPR) effect.
Liposomes have been used for about 40 years as carrier systems for the treatment of life-threatening diseases including cancer, and in the case of Doxil & AmBisome have proved very successful. However in a large number of cases, very often liposomes have been used without the basic physico-chemical knowledge of the interaction between drug and liposomal carrier systems and have failed.
Whilst recently there has been a trend to develop highly elaborate targeting systems associated with the liposomes, it is our belief that a complicated targeting systems based on biologics (e.g. antibodies) is not the ideal approach to take in order to achieve considerable therapeutic improvement in comparison to classical formulations. For example these carrier systems are often rapidly inactivated in the body due to promoting an immune response.
As mentioned above, liposomes of an ideal size and physico-chemical properties to pass through the compromised tumour blood vessel walls will passively accumulate in the tumour via the EPR-effect. If the drug is tightly bound to the liposome, the entire liposome-drug complex is taken up by the cells and the drug released intracellularly. In this project a simpler approach to drug carrier design, which is less susceptible to unwanted and often unknown biological responses, will be adopted. Using passively targeted liposomes the focus will be on optimising drug loading capacity and liposome composition in order to allow a slow but steady release of the drug only at the tumour site. While it is recognised that drug release also takes place in circulating liposomes, the circulation time is short compared to residence time in the tumour, and circulating liposomes will in any case be removed by standard lipid clearance routes. The application of heat can accelerate drug release form the liposomes and this project will also investigate the effects of local application of ultrasound to improving efficacy.
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