Nanobot ‘drones’ successfully target atherosclerosis in animal model.


Nanometer-sized drones that deliver a special type of healing molecule to fat deposits in arteries could become a new way to prevent heart attacks caused by atherosclerosis, if an animal model developed by scientists at Columbia and Harvard universities is a guide.  In the study, biodegradable nanoparticles, loaded with a molecule that promotes healing, were injected into mice with advanced atherosclerosis. The nanoparticles were designed to home in on the hot spots of atherosclerosis in the arteries.  The opensource study is published in the journal Science Translational Medicine.

About 70 percent of the nanoparticles implanted themselves into atherosclerotic plaques and slowly released the drug. In these mice, the damage to the arteries was repaired, leading to a plaque that, in humans, would be less likely to cause heart attacks.

Atherosclerosis is driven by inflammation that is uncoupled from the body’s normal repair response. In essence, the fat-containing particles (called low-density lipoproteins, or LDL) that stick to arteries act like splinters in human skin. But whereas skin is repaired once splinters are removed, LDL deposits can last indefinitely and healing never starts.

These inflamed and damaged hot spots are the reason why atherosclerosis causes heart attacks. The spots are prone to rupture, and when they do, blood clots form around the break and obstruct blood flow to the heart.

The team state that many researchers are trying to develop drugs that prevent heart attacks by tamping down inflammation, but that approach has some downsides.  One is that atherosclerosis is a chronic disease, so drugs are taken for years, even decades. An anti-inflammatory drug that is distributed throughout the entire body will also impair the immune system’s ability to fight infection. That might be acceptable for conditions that severely affect quality of life, like rheumatoid arthritis, but using this approach to prevent a heart attack that may never happen may not be worth the risk as has been observed in past studies by the team.

In addition, it’s not enough to deliver an anti-inflammatory drug to the plaques as it has been seen that atherosclerosis is not only inflammation; there’s also damage to the arterial walls.  If the damage isn’t repaired, the medical team may not prevent heart attacks.  Nature’s way of starting repairs is with a suite of resolving molecules that extinguish inflammation and then initiate healing. Instead of packing the nanoparticles with anti-inflammatory drugs the team packed them with pieces of a resolving protein called annexin A1.

The team state that with this combination of annexin peptides and precision-guided nanoparticles, therapy is delivered only to the areas that need them, and potentially dangerous side effects can be avoided.  The nanoparticles used in the current study were designed to latch onto areas of the arteries that are damaged by atherosclerotic plaques. They are also cloaked in polymers that hide the particles from the immune system.

In mice that received the nanoparticles loaded with annexin peptides, marked improvements were seen in the plaques, including a thickening of the collagen layer that prevents rupture and a reduction of inflammation. No improvements were seen in mice that received only nanoparticles or only injections of the peptides.

Though plaques in mice look a lot like human plaques, mice do not have heart attacks, so the real test of the nanoparticles will not come until they are tested in humans.  In the current study the team have shown, for the first time, that a drug that promotes resolution of inflammation and repair is a viable option, when the drug is delivered directly to plaques via nanoparticles.

To be ready for testing in humans the researchers plan to fine-tune the nanoparticles to optimize drug delivery and to package them with more potent resolution-inducing drugs. The team theorise that they can obtain even better delivery to plaques and improve healing more than with the current peptides.

The nanodrones themselves are now being used in clinical trials for cancer. Research into modifying the particles so they can be taken by pill, instead of injection, is also under way.

The team stress that the best way to prevent hearts attacks remains maintaining low levels of LDL (aka bad cholesterol) through diet, exercise, weight control before to avoid having to use medications.

Source:  Columbia University

Engineered NPs with Col IV targeting peptide.  (A) The synthesized polymers and Ac2-26 or scrambled (Scrm) peptide were dissolved in acetonitrile, and NPs were formed by nanoprecipitation in water via a single self-assembly process. (B) TEM image of targeted ColIV-Ac2-26 NPs. Scale bar, 100 nm. (C) Structures of synthesized diblock PLGA-PEG, PLGA-Alexa 647, and PLGA-PEG-Col IV polymers, as well as the peptide sequence for Ac2-26. (D) Hydrodynamic size, as measured by DLS (nm) and zeta potential (mV), of the Ac2-26 NPs and controls.  Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice.  Tabas et al 2015.

Engineered NPs with Col IV targeting peptide. (A) The synthesized polymers and Ac2-26 or scrambled (Scrm) peptide were dissolved in acetonitrile, and NPs were formed by nanoprecipitation in water via a single self-assembly process. (B) TEM image of targeted ColIV-Ac2-26 NPs. Scale bar, 100 nm. (C) Structures of synthesized diblock PLGA-PEG, PLGA-Alexa 647, and PLGA-PEG-Col IV polymers, as well as the peptide sequence for Ac2-26. (D) Hydrodynamic size, as measured by DLS (nm) and zeta potential (mV), of the Ac2-26 NPs and controls. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Tabas et al 2015.

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