Scientists have developed nanomedicines that can deliver drug packets directly to lesions in diseased arteries, acting like nano-sized 'drones' to target atherosclerosis, a major risk factor for deaths caused by heart attack or stroke, reports Medical News Today.
In their study, Dr Omid Farokhzad and colleagues successfully restructured atherosclerotic plaques in mice to make them more stable – by targeting them with biodegradable nanomedicines. "This is the first example of a targeted nanoparticle technology that reduces atherosclerosis in an animal model," says Farokhzad, associate professor and director of the laboratory of nanomedicine and biomaterials at Brigham and Women's Hospital and Harvard Medical School.
The targeted nanomedicines were nanoengineered to carry an anti-inflammatory drug payload in the form of a biomimetic peptide derived from one of the body's own natural anti-inflammatory proteins called Annexin A1. The design was such that this biological therapeutic could be released at the target atherosclerotic plaques in a controlled manner.
In mice with advanced atherosclerosis the nanomedicines were compared with controls, and after 5 weeks of treatment, artery damage "was significantly repaired and plaque was stabilised." The researchers observed that the nanomedicine-treated mice, compared with those given empty nanoparticles, showed a reduction in reactive oxygen species and increase in collagen, strengthening the fibrous cap of atherosclerotic plaques, which can otherwise rupture.
Reducing inflammation is an approach taken by many, say the researchers, but one that can mean drugs are taken "for years, even decades." If the anti-inflammatory drug is not targeted, but distributed throughout the body, it "will also impair the immune system's ability to fight infection," says co-senior author Dr Ira Tabas, the Richard J Stock professor of medicine (immunology) and professor of pathology and cell biology at Columbia University Medical Centre, New York. Taking drugs with side-effects for many years to prevent a heart attack that might not have happened anyway, "may not be worth the risk."
Reducing inflammation does not address any damage already done, either, whereas the nanoparticles in this study – being 1,000 times smaller than the tip of a single human hair – were able to get underneath atherosclerotic plaques to effect repair.
The nanomedicines "were shown to be capable of manoeuvering through the blood circulation, and traversing leaky regions through to the inside of the plaques, as was demonstrated by fluorescence microscopy imaging of the plaque lesions," say the researchers. "In addition to their specific 'sticky' surfaces, their small sub-100 nanometer size is also a key property that facilitates the retention and accumulation of these nanoparticles within the plaques."
HealthCanal writes that in mouse models with advanced atherosclerosis, researchers administered nanomedicines and relevant controls. Following five weeks of treatment with the nanomedicines, damage to the arteries was significantly repaired and plaque was stabilized.
Specifically, researchers observed a reduction of reactive oxygen species; increase in collagen, which strengthens the fibrous cap; and reduction of the plaque necrotic core, and these changes were not observed in comparison with the free peptide or empty nanoparticles.
“Many researchers are trying to develop drugs that prevent heart attacks by tamping down inflammation, but that approach has some downsides,” said co-senior author Ira Tabas, MD, Richard J. Stock professor of Medicine (Immunology) and professor of Pathology & Cell Biology at Columbia. “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.”
In addition, it’s not enough to deliver an anti-inflammatory drug to the plaques, said 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. If the damage isn’t repaired, you may not prevent heart attacks.”
The targeted nanomedicines used in this current study were engineered by researchers at BWH. Following preliminary proof-of-principle studies at Columbia University in models of inflammation, they were further tested in a clinically relevant disease model in mice and were shown to be capable of manoeuvering through the blood circulation, and traversing leaky regions through to the inside of the plaques, as was demonstrated by fluorescence microscopy imaging of the plaque lesions.
Researchers note that in addition to their specific ‘sticky’ surfaces, their small sub-100 nanometer size is also a key property that facilitates the retention and accumulation of these nanoparticles within the plaques. These nanoparticles are 1000 times smaller than the tip of a single human-hair strand.
“These nanomedicines are developed using biodegradable polymers that can break-up over time in the body using the bodies natural mechanisms, and can be nanoengineered using scale-able chemistries and nanotechnologies, which ultimately can facilitate their rapid translation to the clinic,” said co-lead author Nazila Kamaly, PhD, instructor in the Laboratory of Nanomedicine and Biomaterials at BWH and HMS.
Researchers caution that although 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,” said Tabas. To be ready for testing in humans, the team plans 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,” , he said.
Farokhzad and colleagues have considerable expertise with bench-to-bedside translation of nanotechnologies for medical applications, and foundational work done in part by his team has led to the development and first in human testing of a targeted nanoparticle capable of controlling drug release for treatment of cancers, and the first in human testing of a targeted nanoparticle vaccine capable of orchestrating an immune response to facilitate smoking cessation and relapse prevention.
“The inflammation resolving targeted nanoparticles have shown exciting potential not only for the potential treatment of atherosclerosis as described here, but also other therapeutic areas including wound repair, for example, as described in the Feb. 9 online issue of Journal of Clinical Investigation, in addition to other applications currently underway with our collaborators,” Farokhzad said. “I’m optimistic that with additional animal validation we will also consider the human testing of the inflammation resolving targeted nanoparticles for a myriad of unmet medical needs—these are exciting times in medicine and the future of nanomedicine is incredibly bright.”
[link url="http://www.medicalnewstoday.com/articles/289545.php"]Full Medical News Today report[/link]
[link url="http://stm.sciencemag.org/content/7/275/275ra20"]Science Translational Medicine abstract[/link]
[link url="http://www.healthcanal.com/blood-heart-circulation/heart-disease/60374-keeping-atherosclerosis-in-check-with-novel-targeted-inflammation-resolving-nanomedicines.html"]Full Healthcanal report[/link]