DNA nanoRobot — the next-generation of targeted drug delivery systems?

Targeted drug delivery is a highly sought after technology. Not only does it increase the efficiency of the drugs, but it may also reduce the side effects by localizing the drug only where it’s needed. Shawn Douglas and co-researchers at the Harvard Hansjorg Wyss Institute for Biologically Inspired Engineering have created a nano-robot made of DNA strands that is designed to only release its payload at desired sites.

DNA

The double helix structure of DNA

The double helix structure of DNA with the base- pairs labeled. Picture from U.S. National Library of Medicine.

We are all used to seeing DNA with the double helix structure. The double helix actually consist of two molecules (or strands) of DNA bonded by the struts of this twisted ladder called bases [1]. There are 4 bases in DNA: adenine (A), cytosine (C), guanine (G) and thymine (T) [1]. A can only bond to G and vice versa, and C can only bond to T and vice versa [1]. The pair A-G, and C-T are known as complimentry base pairs. The sequence of the base pairs along the double helix determines our genetics makeup [1].

DNA Origami
Both 2-D and 3-D DNA structures can be created using a technique first invented by Paul Rothemund at the California Institute of Technology called DNA origami, [2,3]. This technique involves using one long strand of DNA to build the shape or scaffold, and have hundreds of shorter DNA strands acting as staples [2]. Instead of separating the two strands of DNA in the relatively stable double helix, DNA origami is often done with the naturally single stranded DNA of the M13 virus [2]. The M13 virus is actually a bacteriophage — a virus that only infects bacteria, E. Coli in this case, and not us [3].

DNA origami begins by designing how to fold the long strand of DNA to form the desired shape [2]. Next, the shorter staples strands are placed to hold together the desired shape [2]. The long strand folds as the staples search for the right genetic coding to fill all of its bonding sites with the bases of the long strand [2]. This is just like when it is necessary to fold or bend a long strip of paper in order to glue the ends of the strip together.

Finally, the genetic sequencing of the long strand DNA and the folding sequence designed in the first step are put into a computer software–like caDNAno  created by Shawn Douglas and his team–to determined the genetic sequences of the hundreds of staple strands [2]. The genetic sequence of the staple strands is determined so that the entire structure can really only form and fold in the desired way (at least very high probability of doing so)  by taking advantage of the complimentary pairs (A-G and C-T) [2].

I imagine the design process for DNA origami is like designing a jigsaw puzzle with DNA pieces in which they can really only fit and be solved in one way.

A design schematic for DNA origami from ref. 2. The black strand represents the long strand of DNA and the color strands represent "staple" strands with different genetic coding.

A bunch of the long DNA strands and a bunch of the staple strands are put into a solution and heated up to 95oC and slowly cooled down [2]. As if by magic, the DNA strands self assemble into the many copies of the designed structure. Well not by magic, but harnessing the nature of all matter to reach a lower energy state so the long DNA and the staple strands form the proper bonds of the double helix structure.

Dr. Rothemund among others have created many different shapes using this techniques, including happy faces, a map of North America, a hexagon, etc. shown in [2,3]. Dr. Rothemund has also shown DNA artwork of others and explained his DNA origami technique and its uses in his TED talk, which is attached to the bottom of this post if you are interested.

DNA nanoRobot
Shawn Douglas and his team at the Wyss Institute at Harvard used the DNA origami technique to create their DNA robot. The DNA robot consists of two vessels, each in the shape of half a hexagon. The two vessels form a regular hexagon when they are combined.  

Schematic of DNA nanoRobot created by Campbell Strong, Shawn Douglas, and Gaël McGill originating from the official press release of Harvard's Wyss Institute. *note: they also have a video explaining their robot in the official press release

One of most interesting designs is the way the two halves of the hexagon are latched together to form the vessel where the payload (i.e. the drugs) will be placed. Douglas et al. [4] have used aptamers to latch the two halves together on one end, and a DNA hinge on the other end. Aptamers are artificial nucleic acid strands that only bond to specific molecules (includes proteins, drugs, amino acids, etc.) [5]. By using aptamers as latches, Douglas et al. [4] have essentially created a lock for the vessel which will only unlock, and release the payload, when it comes into contact with the “keys”; in their case the “keys” were specific antigens.

The aptamer locks can have even better identification abilities when used in combination — having several different aptamer locks on the latch. Douglas et al. [4] demonstrate the robot’s ability to release the payload only when all the aptamer locks are released using various combinations of aptamer lock pairs targeted at different types of leukemia.

Although their current design has difficulty identifying between two of the leukemia types, namely T-cell leukemia and Acute lymphoblastic leukemia, because of the similar antigen keys found. The results successfully show  with the logical operation of the aptamer lock pairs as they were intended. I think if one puts 3 or 4 different aptamer locks on these vessels, then the identification ability can be improved significantly.

Targeted Drug Delivery System
These DNA robots with aptamer locks can make a great targeted drug delivery system (DDS), allowing drugs to be delivered only where it is needed and more importantly reduce side effects.

The use of targeted DDS can improve medical treatments for patients, such as the case of cancer and chemotherapy. Although there are many chemotherapy drugs, many of them are design to indiscriminately kill fast dividing cells [6]. Of course, fast dividing cells include cancer cells, but they also includes stomach lining, hair follicles, blood cells, etc. Because chemotherapy drugs attack all of these fast dividing cells, they usually lead to various side effect like nausea & vomitting, hair loss, low blood cell counts, and so on [6]. If a targeted DDS, like the DNA nanoRobot, can be used to deliver the chemotherapy drugs only to the cancerous cells, it should relieve many of the painful side effects of chemotherapy.

Cancer and chemotherapy are only two examples of where a DNA nanoRobot is useful. They will surely benefit many patients with other medical conditions. The invention of the DNA robot likely represents a large step towards the  development of an ideal targeted drug delivery system that brings medicine only to where it’s needed in our bodies. 

References

[1] Strachan, T., Read, A.P. Human Molecular Genetics 2nd edition; Wiley-Liss; New York, 1999. 

[2] Rothemund, P. (2006). Folding DNA to create nanoscale shapes and patterns Nature, 440 (7082), 297-302 DOI: 10.1038/nature04586

[3] Website of Paul W.K. Rothemund. Available: http://www.dna.caltech.edu/~pwkr/ 

[4] Douglas, S., Bachelet, I., & Church, G. (2012). A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads Science, 335 (6070), 831-834 DOI: 10.1126/science.1214081

[5] James, W. Aptamers. In Encyclopedia of Analytical Chemistry; Meyers, R.A., Ed. ; John Wiley and Sons: Chichester, UK, 2000; pp. 4848-4871.

[6] Chemotherapy – What It Is, How It Helps from Amercian Cancer Society . Available: http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Chemotherapy/WhatItIsHowItHelps/index.htm

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