Five weeks of nanoparticle treatment reduced artery damage by up to 80% in mice

Very promising core-shell nanoparticle platform employs a hydrophobic interior comprising PLGA, a block copolymer of lactic and glycolic acids—both natural metabolic products—and diagnostic and therapeutic cargo molecules. Some PLGA molecules are linked to a fluorescent dye to track the disposition of the nanoparticles in animals. Encapsulated with the PLGA are molecules of a 25-amino acid peptide that acts to resolve inflammation through binding to important cell surface receptors. Some PLGA molecules are attached at one end to the hydrophilic polyethylene glycol (PEG), which forms the outer shell of the nanoparticle. Attachment of a peptide to the other end of PEG targets the nanoparticle to a collagen protein found in the vascular basement membrane that becomes exposed with vascular injury and inflammation.

(H/T Foresight Institute nanodot)

Nanoparticles seek out and repair sections of artery damage could signal the future of treatments for heart disease and strokes. Successful tests of the nanodrones have been carried out in mice – and researchers hope to conduct the first human trials soon. They are designed to latch on to atherosclerotic plaques – hard deposits made from accumulated fat, cholesterol and calcium that build up on the walls of arteries and are prone to rupture, producing dangerous clots.

Once they have attached, they release a drug derived from a natural protein which can repair damage in the body.

In the mice, scientists found that just five weeks of treatment resulted in significant repairs to artery damage while the plaques were shrunk and stabilised, making it less likely for fragments to break off and cause clots.

Nanoparticles for treating Atherosclerosis Credit: Harvard Medical School

Keeping Atherosclerosis in-check with Novel Targeted Inflammation-Resolving Nanomedicines [Brigham and Women’s Hospital at Harvard Medical School]

Science Translational Medicine – Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice

In this study, targeted nanomedicines made from polymeric building blocks that are utilized in numerous FDA approved products to date, were nanoengineered to carry an anti-inflammatory drug payload in the form of a biomimetic peptide. Furthermore, this peptide was derived from one of the body’s own natural inflammatory-resolving proteins called Annexin A1. The way the nanomedicines were designed enabled this biological therapeutic to be released at the target site, the atherosclerotic plaque, in a controlled manner.

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.”

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.”

Schematic of a targeted nanoparticle with a hydrophilic polymer shell containing targeting ligands and a hydrophobic polymer core containing therapeutic cargo. Credit: Harvard Medical School and Science Translational Medicine.

Abstract

Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2–26 (Ac2-26). Collagen IV (Col IV)–targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV–Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.

Other Work to use programmable nanoparticles to treat cancer and other diseases

At the British Friends of Bar-Ilan University’s event in Otto Uomo October 2014 Professor Ido Bachelet announced the beginning of the human treatment with nanomedicine. He indicates DNA nanobots can currently identify cells in humans with 12 different types of cancer tumors.

A human patient with late stage leukemia will be given DNA nanobot treatment. Without the DNA nanobot treatment the patient would be expected to die in the summer of 2015. Based upon animal trials they expect to remove the cancer within one month.

Within 1 or 2 years they hope to have spinal cord repair working in animals and then shortly thereafter in humans. This is working in tissue cultures.

SOURCES – Foresight nanodot, Brigham and Women’s Hospital at Harvard Medical School, Science Translational Medicine

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