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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 21, 2006

Gold and Lasers

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Posted by Derek

There's been a lot of work in the last four or five years using nanoparticles of gold in biological systems. When they're are brought down to this size their electronic properties get quite unusual - in gold's case, the particles become huge absorbers and scatterers of certain wavelengths of light. They're thousands of times better then the kinds of dyes that organic chemists like me can crank out, which gives you potentially huge signal-to-noise in microscopy applications and assays.

Another exotic property these things have is that they convert the energy they absorb very efficiently into heat, and it didn't take long for people to have the idea of using this effect for cancer therapy. Heating cells, after all, kills them. Of course, you'd want to have some way to get the metal particles to stick only on to cancerous cells, and this has been realized by linking antibodies to the surfaces of both hollow and solid gold nanospheres.

The latest advance in this area has come from changing shapes. Rods are predicted to absorb more efficiently and at much different wavelengths than other shapes, and a joint Georgia Tech/UCSF team (who had worked earlier on the solid gold nanospheres) has verified these effects. They were able to grow rods of various sizes and aspect ratios and to conjugate them to anti-EGFR antibodies. EGFR, of course, is a well-known cancer target (via inhibition of angiogenesis), which is hit by several small molecules as well as antibodies like Imclone's Erbitux.

Each of these types of particle has its advantages. The gold nanosphere/antibody conjugates actually absorb at slightly different wavelengths when they interact with EGFR-expressing cancerous cells compared to noncancerous ones, which could make for a useful diagnostic assay. This can really only be done ex vivo, though, in thin preparations, because the wavelengths of light needed are also absorbed by the tissue itself.

The rods don't manage to show the differences between cells, although (as with the spheres) you can see the differences (scroll down on that page) qualitatively in how many particles are bound to the cell surfaces. But they do have a property that's potentially even more useful: their absorbing wavelengths are shifted to the near-infrared, which penetrates tissue much better (up to four inches)! You need green 520nm light for the spheres (with a convenient argon laser wavelength nearby at 514nm), but the rods need red 800nm light from a titanium/sapphire laser. When cell cultures are hit with that wavelength, the heating of the gold nanorods kills them off - and the EGFR-expressing cancerous cells can be killed by laser light of only half the strength needed for normal cells.

That's probably just barely enough of a gap to be therapeutically useful, for several reasons, not least because for tumors inside the body, I think that you'd be dosing the outer skin layers with too much wattage in order to hit the deeper tissues. No doubt work is already underway on widening the window between the two effects. I can certainly imagine some possible next steps as well: simultaneous treatment with conjugates of different antibodies, for example. Since many cancerous cell lines overexpress more than one type of cell surface protein, you might be able to hit them in several ways at the same time.

As much as I love small molecules (and the organic chemistry used to make them) I have to admit: they may not be able to hold their position against ideas like this. We can try to target things like EGFR that are overexpressed in many cancers, but we don't have much of a guarantee of success, because overexpression doesn't make a pathway crucial enough by itself. But overexpression alone is all you need with this technique, and the cellular pathways downstream don't matter a bit. It's a liberating thought. . .

Comments (13) + TrackBacks (0) | Category: Cancer


COMMENTS

1. Dlib on February 22, 2006 1:12 AM writes...

The idea isn't that new. nanoparticles of magnetic minerals have been conjugated to Antibodies too. The advantage there is that the heat is generated by magnetic fields.

To my knwoledge it never went anywhere though. The idea is plucky.

Cheers,

Dlib

Permalink to Comment

2. Dlib on February 22, 2006 1:18 AM writes...

Guess I was wrong, People are actually selling the stuff.

http://www.tritonbiosystems.com/Products.htm

Still don't know the efficacy.

Cheers,
Dlib

Permalink to Comment

3. RKN on February 22, 2006 8:29 AM writes...

That's probably just barely enough of a gap to be therapeutically useful, for several reasons, not least because for tumors inside the body, I think that you'd be dosing the outer skin layers with too much wattage in order to hit the deeper tissues.

How about an extension of the endoscopic technique as a light source? This would put the laser light specifically where you want it. I'm wondering if the biggest practical challenge wouldn't be getting the conjugated anti-bodies in vivo to stick precisely where you want them.

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4. jeet on February 22, 2006 3:57 PM writes...

you could use something like the gamma knife system to target high energy delivery at a specific point within the body while minimizing delivery to the non-diseased areas. But you would need to conjugate a molecule that responds to wavelengths that generally pass through the body.

Permalink to Comment

5. Derek Lowe on February 22, 2006 5:04 PM writes...

RKN, I think that endoscopy could be a good idea for localized tumors. But for poorly defined or metastatic tumors, a whole-body treatment would be just the thing.

As for targeting the antibodies, that's (in theory) taken care of for you by the overexpression profile of the cancer cells. If you can find something (like EGFR) that's much more heavily expressed in the tumor line, then you can just dose the whole body and let the antibodies sort themselves out statistically.

That's why I think doing this simultaneously with more than one protein target/antibody would work ever better. By the time you mix in three or four overexpressed targets, the malignant cells are really going to be loaded down with gold-bearing antibodies compared to any other cell population.

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6. srp on February 22, 2006 8:20 PM writes...

I'm a little puzzled by this. I always thought it was really hard to distinguish cancer cells from normal cells. If this antibody technique is so selective, what else besides gold could you attach to the antibody? Maybe something (chemical or mechanical) that kills the cell without needing a laser at all?

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7. zak on February 22, 2006 9:58 PM writes...

Tangentially, here in Japan they think ingesting gold is good for you. They sell sake with gold flakes floating around in it, for example, which is traditionally drunk at new year's.

I wonder if there is anything to back this up, or if it was just invented by the gold dealers...

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8. Richard Holliday on February 23, 2006 3:49 AM writes...

Hi there, just came across this blog from a 'Google' alert. Actually, there is tonnes of research currently underway looking to harness gold nanoparticles's potential in this area. The basic advantages of gold are 1) it's bio-compatable 2) it's surface chemistry allows a whole host of molecules to be attached 3)it's easy to prepare in colloidal/nanoparticulate form. A good example of the type of development underway is the following company http://www.cytimmune.com/go.cfm?do=Page.View&pid=14

For loads of other stuff on the developing use of gold see www.utilisegold.com ...this funded by the gold mining companies to expand the practical uses of gold

Permalink to Comment

9. RKN on February 23, 2006 8:58 AM writes...

RKN, I think that endoscopy could be a good idea for localized tumors. But for poorly defined or metastatic tumors, a whole-body treatment would be just the thing.

One of the things I learned when briefly looking into this was that current photodynamic cancer therapy is limited by the inability of the lasers used to penetrate cancer tissue very deeply, making it largely useless on big tumors. Given that, I doubt these lasers could penetrate adipose tissue and be effective on metastatic tumors without also harming the patient.

Then again, technology moves on...

Permalink to Comment

10. Derek Lowe on February 23, 2006 9:19 AM writes...

RKN, the current phototherapy options use wavelengths that don't penetrate well at all, making the near-IR frequencies used in this work much more desirable. But you raise an interesting point - how does it do through adipose tissue vs. muscle?

Permalink to Comment

11. David Bliss on February 23, 2006 10:25 PM writes...

This reminds me strongly of the Boron Neutron Capture Therapy being done by (among others) MIT, except that they use epithermal neutrons (which have excellent penetrating ability) instead of light and boron (which has a very high neutron-capture cross section) instead of gold. No nanoparticle formation required, only chemically binding a boron into your antibody. The mechanism is alpha emission instead of thermal, which I would think would also decrease the amount of collateral damage from any given molecule since alpha penetration is so tiny.

Permalink to Comment

12. John on March 1, 2006 3:14 PM writes...

Perhaps adjusting the geometry / particle composition to absborb the 1064 nm line from a YAG would help in tissue penetration?

Permalink to Comment

13. Groko on May 7, 2006 12:14 PM writes...

Derek,

Nice you love small molecules. So do I. They can work well in combination with nano tech for combating cancer too. Here is short about what a team from MIT have come up with:

http://tinyurl.com/d6ax8

"The article “MIT engineers an anti-cancer smart bomb” summarizes work done [Sengupta 2005] as a collaborative effort by researchers in the Massachusetts Institute of Technology (MIT) Biological Engineering Division, Department of Chemistry, and Whitehead Institute for Biomedical Research. The research team, led by Prof. Ram Sasisekharan, developed a drug delivery system that uses dual chamber nanocells to kill cancer cells. Given the complex dual chamber structure of nanoparticles, they call them nanocells. They use two anti-cancer agents, one in each chamber, that are sequentially released within cancer cells.

Just as the Triche and Davis teams did, they coated their nanoparticles with a molecular tag that binds to cancer cell receptors. Once inside the cancer cells, the outer membrane of the nanocell dissolves and releases an anti-angiogenic agent from the outer chamber that collapses the blood vessels feeding the tumor and traps the nanocell within the cancerous cell. The nanoparticles then release a chemotherapeutic agent, from the inner chamber, slowly over time, killing the cancer cell.

The researchers tested the two chamber nanocell in mice having either B16/F20 melanomas or Lewis lung carcinoma. They used combretastatin-A4 as the anti-angiogenesis drug and doxorubicin as the chemotherapeutic agent. They noted that the combretastatin caused a rapid vascular shutdown inside a tumor by disrupting the cytoskeletal structures. The cytoskeleton forms the inner structure, or backbone, of a cell and consists of microtubules and various filaments that spread out through the cytoplasm. They also noted that doxorubicin induced apoptosis (cell death) by intercalating with the DNA. The researchers fabricated the nanoparticles using the biodegradable and non-bioactive copolymer, PLGA. They bind (conjugate) the doxorubicin to the PLGA to achieve a slow release profile that is distinct from the characteristic ‘burst’ release associated with many nanoparticles.

There are more detailed results in the paper, but I’ll summarize here by stating that untreated mice died within 20 days, but 80% percent of the mice treated with the nanocell survived beyond 65 days. The nanocell worked better against melanoma than lung cancer, indicating the need to modify the design for different cancers. Their approach allows them to systematically evaluate drug combinations and loading mechanisms"

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