Cancer is one of the world’s most life threatening diseases, with millions of new cases every year. The war against this disease is going on strong. Some battles have been won and others lost, but the weapons that this disease uses are really powerful. They are heterogenity, adaption and resistance. The scientific community has been actively researching on the development of new and improved weapons to overcome and finally win the battle against cancer. Here we will talk about the current approaches against this life threatening disease.
It is widely known that current cancer treatments include:
1. Surgical intervention
2. Radiation
3. Chemotherapeutic drugs, which often also kill healthy cells and cause toxicity to the patient.
Unfortunately the effectiveness of current cancer treatments depends on the early diagnosis and the type of cancer. It is therefore needed to develop chemotherapeutics that can either passively or actively target cancerous cells and eliminate them effectively.
In summary 'passive targeting' investigates the characteristic features of tumur biology that allows nanocarriers to accumulate in the tumor site by the Enhanced Permeability and Retention (EPR) effect.
The EPR effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from healthy tissues. Angiogenesis, which is a physiological process involving the growth of new blood vessels from pre-existing vessels, leads to high vascular density in solid tumors. Large gaps exist between endothelial cells in tumor blood vessels, and tumor tissues show selective extravasation and retention of macromolecular drugs, which is the desired effect in order to see the therapeutic efficacy and the shrinkage or elimination of tumors.
Impaired reticuloendothelial/ lymphatic clearance of macromolecules from tumor, or lack of such clearance, is another unique characteristic of tumors, resulting in intratumor retention of macromolecular drugs thus delivered.
It has been found that the effective pore size in the endothelial lining of blood vessels in most peripheral human tumors ranges from 200 to 600 nm in diameter, and the EPR effect allows for passive targeting to tumors based on the cut-off size of leaky vasculature.
But on the other hand there are a lot of limitations to the passive targeting, and one way to overcome these limitations is to program the nanocarriers so that they actively bind to specific cells after extravasation.
This binding may be achieved by attaching targeting agents such as ligands, which are molecules that bind to specific receptors on the cell surface, to the surface of the nanocarrier by a variety of conjugation chemistries.
Nanocarriers will recognize and bind to target cells through ligand–receptor interactions, and bound carriers are internalized before the drug is released inside the cell. In general, when using a targeting agent to deliver nanocarriers to cancer cells, it is imperative that the agent binds with high selectivity to molecules that are uniquely expressed on the cell surface, so that it minimizes the undesired and strong side effects of the cancer therapy. This is otherwise known as active targeting.
But what are nanocarriers? Why are they important in cancer diagnosis and therapy? Why not just use the traditional chemotherapeutic drugs? What are their advantages over the current approved cancer treatments? How many types of nanocarriers have been discovered and what is the future perspective? If you want to know more specifics on nanocarriers you can read my other post on this topic entitled 'Nanocarriers for cancer therapy'.
To simply define, a nanocarrier is nanomaterial composite, used as a transport mean for another substance, such as a drug or an imaging agent, which can be monitored by a specific machine. Such carriers should be targeted to the pathological area to provide maximum therapeutic efficacy while also providing diagnostic imaging.
The family of nanocarriers includes polymer conjugates, polymeric nanoparticles, lipid-based carriers such as liposomes and micelles, dendrimers, carbon nanotubes, and gold nanoparticles, including nanoshells and nanocages.
Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. Cancer has been the most often investigated among the many potential targets for these nanocarriers.
Integration of diagnostic imaging capability with therapy may be key to overcoming the challenges of cancer heterogeneity and adaption. In addition, codelievery of imaging contrast agent and chemotherapeutic drugs can provide real-time validation of the targeting strategy, resulting in an another step forward for individual-based therapy.
If molecular targets became unavailable, imaging can be used to map out alternative targets. The advantage of this approach is that it can provide early feedback of therapeutic efficacy before detection by means of traditional diagnosis, such as tumor shrinkage.
That is why “theranostic” was originally used as a term to describe a treatment platform that combines a diagnostic test with targeted therapy and which monitors response to therapy. We will talk more in deep about 'theranostics' in another post, because it is a fascinating and a very promising topic.
In theranostic treatments imaging can be used to track nanoparticles systemically, prevalidate appropriate targeting, and track the expression pattern of surface markers for adaptive targeting, as well as provide real-time information on tumor response. It is very important to see how the therapy is going, because the canccer therapy has pretty strong side effects, that may be lethal and if it is controlled that the chemotherapeutic drug is not arriving at its tumore target, the treatment regime can be urgently changed, before the damage happens and shows the symptoms in the organism. The surface properties of the polymeric nanoparticulate drug delivery systems play a key role on the biological behavior that is shown in the organism by the drug delivery system.
Surface modification can be defined as the improvement and replacement of the surface properties of nano-sized drug delivery systems. In the field of pharmaceutical technology, surface modification provides several advantages to improve the physicochemical properties and pharmaceutical activities of many nanosized carriers particularly polymeric nanoparticles.
By the modification circulation times are prolonged, especially the accumulation in the tumor tissues is improved to higher levels.
On the other hand lipid-based carriers pose several challenges, which represent general issues in the use of other targeted nanocarriers such as polymeric nanoparticles. For example, upon intravenous injection, particles are rapidly cleared from the bloodstream by the reticuloendothelial defence mechanism, regardless of particle composition.
Moreover, instability of the carrier and burst drug release, as well as non-specific uptake by the mononuclear phagocytic system (MPS), provides additional challenges for translating these carriers to the clinic.
Several anticancer drugs enter the cells in our body through diffusion method. But there are some integral proteins in the cell membrane that are known as MDR transporters, which transport a variety of anticancer drugs out of the cancer cell and produce resistance against chemotherapy. As a solution to this challenge the delivery of drugs through targeted nanocarriers that are internalized by cells, can provide an alternative route to diffusion of drugs into cells.
It is very important not to forget that cancer drug resistance is very complex and has been linked to elevated levels of enzymes that can neutralize chemotherapeutic drugs. However, it is more frequently due to the overexpression of MDR transporters that actively pump chemotherapeutic drugs out of the cell and reduce the intracellular drug doses below lethal threshold levels.
Since fortunately not all cancer cells express the MDR transporters, chemotherapy will kill only drug-sensitive cells that do not or only mildly express MDR transporters, while leaving behind a small population of drug resistant cells that highly express MDR transporters. But with new forming tumors, chemotherapy may fail because residual drug-resistant cells can dominate over the normal cells, resulting in a more aggressive tumor mass.
Among the MDR transporters, the most widely investigated proteins are: P-glycoprotein, the multidrug resistance associated proteins and the breast cancer resistance protein. These proteins have different structures, but they share a similar function of expelling chemotherapy drugs from the cells.
Combination treatments with targeted nanocarriers for selective delivery of drugs and MDR pump inhibitors will likely address some of the problems posed by resistant tumors in the future.
Do not forget that it is always better to prevent than to cure, so do not neglect the regular check ups at the doctor and if you have familiar history with the cancer disease double them up to twice a year.
Stay well!
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