A prerequisite for successful therapy is that the therapeutic agents reach their target cells in sufficient amount to inactivate the cells, and that the exposure of normal tissue is limited to reduce toxic side effects.
One of the major obstacles using conventional cancer therapies such as radiotherapy or chemotherapy is the lack of specificity for the cancer cells.
Novel nanomedicines are promising tumour selective agents
- Monoclonal antibodies binding to tumour specific antigens on the cell surface and carrying radionuclides, toxins or other drugs
- Capsules or liposomes carrying drugs
- Complexes of DNA and DNA vectors protecting and carrying DNA (figure 1)
However, nanomedicines are rather large molecules facing severe problems reaching the tumour cells. In solid tumours, blood-borne therapeutic molecules have to extravasate across the capillary wall into the extracellular matrix (ECM) or interstitium, and move through the ECM to reach the individual cancer cells (figure 2). If the target is intracellularly, the nanomedicine or the therapeutic agent has to be taken into the cell probably by endocytosis, and escape lysosomal degradation.
Identifying and understanding the physiological barriers posed by these compartments are of crucial importance to improve the delivery of nanomedicine.
The transport across the blood vessel wall as well as through the interstitium is governed by convection (driven by the hydrostatic pressure gradient) and diffusion (driven by the concentration gradient). A major obstacle to accumulation of therapeutic macromolecules in tumour tissue is the high interstitial fluid pressure. The interstitial fluid pressure is high due to the leaky tumour blood vessel and the lack of functional lymphatics. Excess water will thus stay in the interstitium.
This pressure is shown to be higher in tumour tissue than in normal tissue, and a step pressure gradient is reported at the periphery of the tumour. The transport across the capillaries might thus be more pronounced at the periphery than in the interior of the tumour. The high interstitial fluid pressure also impedes the penetration through the interstitium. Within the tumour the interstitial fluid pressure might be about equal to the pressure in the blood vessel, hence convection virtually ceases. The main mechanism to reach the tumour cells is thus by diffusion. Diffusion depends strongly on the size of the molecule, and for large molecules the process is extremely slow. The diffusion coefficient is proportional to the square of the distance, and to illustrate how slow the diffusion actually is: an antibody uses more than 10 days to diffuse 1 cm.