How to Get Smaller…

A group from Harvard Medical School and MIT, whose work is published this week in Proceedings of the National Academy of Sciences, has designed a spiropyran-based nanoparticle cancer drug that gets smaller when irradiated. When the drug is hit with ultraviolet light (at a wavelength of 365 nm, to be specific), its chemical structure alters causing it to shrink from 103 nm to 49 nm, which subsequently allows the drug to penetrate farther into tumors.

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Cancerous cells (Source: http://www.osbcng.org)

Researchers attached photosensitive nanoparticles to a cytotoxic compound, docetaxel, which triggers cell death (or apoptosis if you prefer) in cancerous cells. Using mouse tumors, they tested the ability of the nanoparticle to deliver docetaxel when it was triggered with ultraviolet light after being injected. Mice injected with the nanoparticle and drug combination and hit with the light after injection survived better than mice given only the drug, only the nanoparticle, or a pre-activated combination of the two. Those mice injected with the drug alone saw much more severe levels of weight loss and more frequent deaths stemming from the drug’s toxic effects, whereas those mice given the nanoparticle hybrid experienced lowered overall toxicity, but increased effects on the tumors.

When activated, the nanoparticle both releases docetaxel and shrinks. Since they can be triggered multiple times, with each subsequent trigger releasing more of the drug, these nanoparticles could allow for more nuanced approaches to cancer treatments, where drugs are released in waves as the nanoparticles penetrate deeper into cancerous tissue.

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A general, basic structure of a nanoparticle (Source: http://www.sciencedaily.com)

Tumors are notoriously difficult to infiltrate thanks to the weak and shoddily constructed blood vessels that surround them (a product of the tumor’s rushed attempts at angiogenesis), which make efficient drug delivery tough. At the same time, the tumor tissue itself is typically very dense as a result of the very intricate collagen matrix tumors often build around themselves, and so getting drugs to effectively penetrate malignant tissue once they do arrive becomes its own obstacle. This is where nanoparticles come in.

A nanoparticle is defined as any particle that has at least one dimension between 1 and 100 nanometers. They’re interesting for cancer research in that they are one of a variety of molecules whose size is just right to be retained in tumors, a phenomenon called the “enhanced permeability and retention effect.” It is thought that this effect arises as a result of that same shoddy angiogenesis that makes drug delivery so tough. The blood vessels built around tumors are not very permeable, meaning that molecules of a certain size can’t pass through and tend to accumulate (like our lucky nanoparticles). Tumors really only focus on building blood vessels, leaving lymphatic tissue out of the equation, meaning there isn’t an effective system in place to filter all those quickly accumulating bits of chemical detritus out of the bloodstream.

As a result, nanoparticles present a unique possibility in drug delivery, since they are just the right size to preferentially accumulate around tumors. If you attach a drug to those nanoparticles, you’ve got a quick and relatively direct means for targeted treatments. So now mix in this new finding that you can design a nanoparticle to shrink when it releases its drug, which means it can carry its load deeper into those tumors and provide a more complete attack.  That’s a hell of an ingenious tactic if you ask me.

Original article:

http://www.pnas.org/content/110/47/19048.full

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