NEW YORK, NY (February 18, 2015) - 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 a recent study in mice by scientists at Columbia and Harvard universities is a guide. Full findings appear in the February 18 online issue of Science Translational Medicine.
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.
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 our arteries act like splinters in our 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.
Many researchers are trying to develop drugs that prevent heart attacks by tamping down inflammation, but that approach has some downsides, says Columbia atherosclerosis researcher Ira Tabas, MD, Richard J. Stock Professor of Medicine (Immunology) and professor of pathology & cell biology, one of the study's two senior leaders.
"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," he says. 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." [Tabas & Glass, Science 2013]
In addition, it's not enough to deliver an anti-inflammatory drug to the plaques, says Columbia associate research scientist Gabrielle Fredman, PhD, one of the study's lead co-authors. "Atherosclerosis is not only inflammation; there's also damage to the arterial wall," she says. "If the damage isn't repaired, you 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, Dr. Tabas's and Dr. Farokzhad's team packed them with pieces of a resolving protein called annexin A1.
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--created by biotechnologists Omid Farokhzad and Nazila Kamaly of Harvard--are 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 this study, we've 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," says Dr. Tabas.
To be ready for testing in humans, Dr. Tabas and Dr. Farokzhad plan to fine-tune the nanoparticles to optimize drug delivery and to package them with more potent resolution-inducing drugs. "We think that we can obtain even better delivery to plaques and improve healing more than with the current peptides," Dr. Tabas says.
The nanoparticles themselves are now being used in clinical trials for cancer (see 1, 2, 3, and 4),but their longer-term safety still needs to be addressed. Research into modifying the particles so they can be taken by pill, instead of injection, is also under way.
The best way to prevent hearts attacks, however, remains maintaining low levels of LDL (aka bad cholesterol) through diet, exercise, weight control, and if necessary, medications. "Atherosclerosis is driven by non-resolving inflammation," Dr. Tabas says, "but we often forget that the lipoprotein that collects in our arteries is the single most important factor driving that atherosclerosis."
This work was supported by a Program of Excellence in Nanotechnology (PEN) Award, HHSN268201000045C, from the NIH (O.C.F., I.T.); NIH Pathway to Independence K99 grant HL119587 (G.F.); the Welcome Trust Programme Grant (086867/Z/08); NIH grants CA151884 and the David Koch-Prostate Cancer Foundation Award in Nanotherapeutics (O.C.F.); and NIH grants HL106019, HL075662, and HL054591 (I.T.).
O.C.F. discloses his financial interest in BIND Biosciences, Selecta Biosciences, and Blend Therapeutics, three biotechnology companies developing nanoparticle technologies for medical applications. BIND, Selecta, and Blend did not support the research in this study, and currently these companies have no rights to any technology or intellectual property developed as part of this research.
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