Breaking down the wall of protein delivery

When I decided to start my PhD I asked myself: How can I make a difference in cancer research? The answer came along within the almost four years I spent reading, learning and developing nanoparticles for the intracellular delivery of monoclonal antibodies (mAbs). Because when what you want to target is inside the cell you need to think differently and… break down the wall of protein delivery!

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Ana Cadete

It is not by causality that cancer is considered the emperor of all maladies. In 2015 only, 15.2 million new cases of cancer were diagnosed, which resulted in almost 9 million deaths. Although those numbers are expected to grow in 2016, progress in the fight against cancer has been pushing the availability of new anticancer treatments further and, thanks to it, we can face an improvement in patient survival.

Among the new research areas, nanotechnology has proved to be essential in the development of new therapies. These nanometric particles, commonly called nanoparticles, can be designed to incorporate diverse anticancer drugs and specifically target cancer cells. With the use of nanoparticles, old cytotoxic drugs can have a better effect and complex biomolecules can be applied in new ways to improve cancer treatment.

This is the case for mAbs. Targeting cancer cells receptors with mAbs is one of the best strategies to improve drug efficacy and decrease the undesirable side effects of conventional chemotherapy. However, cancer receptors are not only present on the surface of cells, but they can be exclusively located inside the cells. In fact, hundreds of intracellular proteins have been associated to cancer progression and they are considered a very promising target to fight cancer. The actual strategy to target these proteins is to use cytotoxic molecules, silenced therapy or protein kinase inhibitors which, up to now, haven’t led to an effective treatment. In this sense, the use of mAbs against intracellular proteins would seem a logical therapeutic strategy. However, this approach has not been achieved yet, mainly due to the difficulties associated to the delivery of these large and hydrophilic molecules inside the cell.

To overcome these barriers, we have designed nanocapsules (nanoparticles composed of an oil core surrounded by a polymeric shell) able to carry the mAb to the intracellular compartment. This nanocapsules were prepared using a new environmentally friendly method, without any organic solvents, heat and high energy input. This technology was considered very advantageous from two main perspectives: for the pharmaceutical industry it is a green methodology which has environmental and economic advantages for the production of a new nanocarrier, and for its successful application in the delivery of sensitive proteins.

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Once packed into the nanocapsules, the mAb was able to cross the cell membrane barrier and to be released inside the cytosol. Different in vitro experiments were done in order to prove that the mAb maintained its original conformation and was able to target and block the intracellular cancer protein, leading to a decrease in cell migration and invasion. In vivo assays are ongoing to understand how powerful this therapy could be in the treatment of tumors that lack a surface receptor.

So far, we have been able to create a pathway where no one else went before. We are still at the beginning, but the results are promising and make us believe that this can be a new and effective way to fight cancer by targeting intracellular oncoproteins. Due to the lack of treatment and alternatives, these oncoproteins are frequently called the “undruggable targets”. With our work we hope that, from now on, they won’t be undrugabble anymore.

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Ana is Portuguese, she has a Master’s degree in pharmaceutical sciences and a PhD in nanomedicine and pharmaceutical innovation. Currently, she is a postdoc at Novobiotic Pharmaceuticals where she is developing new formulations for the delivery of antimicrobial peptides. This project described above is funded by Bill and Melinda Gates Foundation and is a collaboration with the Langer Lab at MIT. She was a Finalist at the Falling Walls Lab 2015.

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