Total Award: 799,960 PLN, 100 % contribution from the European Regional Development Fund. Awarded to Soumyananda Chakraborti (pictured)
Background
Typically drugs, including anti-cancer drugs are small “dumb” molecules, inflexible and with a single target. Cancer cells have three strategies to outwit them; Firstly cancer cells divide ant a tremendous rate, and each time they divide they can make errors, making the new cells slightly different from the parent, over billions and billions of divisions this can lead to a whole library of slightly different cancer cells. By chance some of these cells may have changes, which make them resistant to drugs. Secondly, cancer cells, unlike invading bacteria, are your own cells. This can make it very difficult to affect cancer cells without destroying or damaging healthy cells; one of the reasons why anti-cancer drugs can lead to very bad side effects, sometimes even strong enough to force treatment to stop. Traditional drugs are too dumb to overcome these problems; they cannot adapt to changing circumstances and are too small to have the complicated structures necessary to encode many different alternative or cooperating functions.
The answer lies in trying to make the drugs as sophisticated as the cancer – to design and construct biocompatible “nanorobots”. Our design firstly uses a protein called ferritin, which is a hollow sphere made from from 24 identical proteins found in our own cells where it is used to store iron. Other researchers have already shown that the iron inside of ferritin can be replaced with numerous molecules of toxic drugs, protecting them from the outside world. This includes the anti-cancer agent cisplatin, which we will use. The next challenge is how to deliver the drugs to the cancer cells. To do this we harnesss a special DNA structure called DNA origami. DNA origami has been developed in recent years and is a way whereby DNA can be programmed to from almost any shape. Together we can build the nanorobot will attach only to cancer cells, Once attached the robot will be internalised by the cell where the ferritin will release its cargo of toxic drug, killing the cells.
Aims
We have seen phenomenal development of bio-nanoscience in last few years, however the number of functional biological “nanorobots” is limited. In this HOMING project we are trying to build sophisticated hybrid nanorobots by fusing the protein cage and DNA origami fields together (we are building a system in which DNA origami is used to target and deliver ferritin to cancer cells . Apart from this we develop the ferritin “ball” protein further for use as a modular container for encapsulation of enzyme. Interestingly we have found that enzyme encapsulated inside ferritin has increased activity, likely due to protein crowding effects. Furthermore, we have succeeded in arranging filled ferritins into superlattices that retain the enzymatically active cargo. These results were published in a leading nanoscience journal (Nano Letters, IF: 12)1 where the project leader is the first and co-corresponding author. The project leader has also been involved in other protein cage research, making an important contribution to work published in Nature2.
FNP HOMING funding (FNP website)
1. A three-dimensional protein cage array capable of active enzyme capture and artificial chaperone activity. Soumyananda Chakraborti et al. Nano Letters, 2019, 19, (6): 3918-3924. DOI: 10.1021/acs.nanolett.9b01148.
2. An ultra-stable gold-coordinated protein cage displaying reversible assembly. A. D. Malay et al. Nature, 2019, 569(7756): 438-442. DOI: 10.1038/s41586-019-1185-4.
