Let the Trojan vesicles in

By Paulo Szwarc, Federal University of Paraná, Brazil

Cancer sure is tricky. We try to starve it, cut it, stress it out of our bodies. We even bombard it with radiation until it dies. And yet, not due to lack of trying, many times we lose the fight. It escapes, evades our resistance. Its overly mutational nature leads it to adapt, dodging the deadly effects of chemotherapeutics. Not only that, but the lack of selectivity in many treatments means that while we harm the tumour, we also wreak havoc to our own healthy cells. It makes the battle much harder.

Improving the ‘targeting’ efficacy of therapeutics is an interesting way to lessen this significant drawback. An ideal anti-cancer agent would be able to tip-toe around our body, ignore healthy cells and selectively destroy the cancerous tissue. Extracellular vesicles (EVs) of distinct origins are being explored as cell-free chemotherapy agents who can possess these features.

These tiny biological particles are secreted naturally by every cell, as they respond to external stimuli and communicate with neighbouring tissues. Their cargo can vary widely, and as many things in nature, can be bioengineered. Their surface antigens, what coats and guides them, are also variable. This makes EVs versatile as a drug biodelivery method. Since they can withstand traveling through our fluids, compounds added inside of EVs would be protected from the extracellular environment until some cells uptakes the vesicles.

Now imagine this is a cancer cell, and the surface antigens of the vesicle were bioengineered in a way that facilitates attachment to this cell specifically. The vesicle will be internalized, and its cargo can be freed inside the cytoplasm. If we also built the vesicle as to carry a powerful anti-cancer drug, then the now-liberated drug would damage the cell (and only this diseased cell) profusely. Like a ‘Molecular Trojan Horse’, secretly bringing warriors inside of the enemy territory.

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‘The Trojans Bring the Wooden Horse into Their City’ by Luca Penni

The principal areas of research surrounding this EV biodelivery method consist of selecting the right type of cargo (small molecule, enzyme, microRNA) and the right type of EV. Speaking of cargo, this will be very dependant on the type of cancer being treated. For example, RNAi is seen as a possibility for treatment or adjuvant therapy. There is growing interest in how to better deliver the ribonucleic components to cells. One option is to associate RNAi to EVs, so they can be successfully transported without the risk of degradation by RNAses.

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RNA interference mechanism. By meddling with the expression of key mRNAs, a cancer cell can be crippled or even self-destruct. Knowledge of which pathways to interfere with is a must, and increasingly being explored for each type of cancer.

The EVs can be obtained through a variety of ways, for example, parental cell modification. By bioengineering the original cells who secrete EVs, one can alter the EV cargo and surface antigens, building them in a way as to attach them to a specific cancer cell type. Additionally, EVs can be modified directly post-secretion by adding compounds through electroporation, sonication and other permeability-altering techniques.

But the vesicles don’t have to necessarily be of biological origin. Synthetic polymer-based vesicles can be built from scratch, with a variety of advantages: greater stability, compositional variety, and a diverse set of sizes. The possibilities are endless, and certain to grow in the future due to massive efforts in nanotechnology.

A growing number of studies have excitingly used EVs as the main therapeutic carriers, not only in cancer but in diabetes, cardiovascular diseases and neurological disorders. This technology looks extremely promising, and treatments of the future may very well include an EV component. Cancer sure is tricky, but we can trick it too.

Further reading

For those interested in the therapeutic uses for vesicles, I really recommend the recent review by Mentkowski et al. (see below), where they delve deep into the bioengineering strategies currently being explored. This including recent pre-clinical and clinical trials involving vesicles as the main therapeutic agent carrier.

The ‘Molecular Trojan Horse’ idea is not new. Check out the work by Pardridge involving Blood Brain Barrier crossing.

References

About me:

myphotoI am an undergraduate in Biomedical Sciences from the Federal University of Paraná, stationed in lovely southern Brazil. My main interests are microbiology, molecular biology, translational biology and innovation in the biomedical field. I work at the Carlos Chagas Institute, one of the biggest biomedical research organizations in my country. You can find me on Twitter and LinkedIn.

This post is the fourth in our biomaterials series. The first – Plant-based biomaterials: engineering the future by Emily May Armstrong; second – Your scales look awfully fishy also by Paulo Szwarc; and third – Better biodegradables: taking ‘going green’ to a whole new level by Michelle Dookwah were published in March. If you are interested in reading more on this topic, you can also check out the February issue of The Biochemist magazine on the theme of biomaterials.

 

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