Targeting Anti-Inflammatory Drugs Directly to Atherosclerotic Lesions in Blood Vessel Walls

Precision targeting makes all medicine better: delivering smaller total doses to precise locations in the body opens many doors. Types of therapeutic compound that would otherwise be impractical to use become practical. Localized dosage levels that would otherwise be impossible can be obtained. Many examples of targeted medicine under development in recently involve the delivery entirely new types of drug or therapy, but there is also a strong incentive to generalize that delivery platform and walk back through the existing library of potential therapeutics to find those that can now be made much more useful.

Most of the targeting mechanisms reported in the media are associated with cancer research: a matter of finding ways to kill specific cells with certain characteristics with minimal collateral damage. Killing cells is easy. The hard part is doing it while leaving their neighbors - and the patient - alive and healthy. So it is the targeting mechanism that is the important part of this line of development, not the method for cell destruction, of which there are many. The next generation of cancer treatments aims to leave behind the fine line between harming the cancer and harming the patient that shapes chemotherapy and radiation therapy, building a basis for treatments that cause no discomfort while seeking out and destroying tumor cells wherever they may be. This is an important line of research, as it turns out that there are numerous types of cell in the aged body that we'd like to be able to safely and effectively destroy: senescent cells, fat cells, cells with damaged mitochondria, dysregulated immune cells, and so forth.

There are also other uses for targeting beyond cell destruction. Let us say, for example, that you can target therapeutics to the precise areas in blood vessel walls in which the characteristic fatty lesions of atherosclerosis are in a late stge of development, and either slow down or reverse that process. The type of approach demonstrated below may also be useful in the early stages of the condition, long before any noteworthy damage develops, but of course that is never going to be the goal in initial proof of concept studies. In the present regulatory environment researchers must work towards a therapy for the late stages of age-related disease if they want their work to progress towards clinical application:

Keeping Atherosclerosis in-check with Novel Targeted Inflammation-Resolving Nanomedicines

Targeted biodegradable nano 'drones' that delivered a special type of drug that promotes healing ('resolution') successfully restructured atherosclerotic plaques in mice to make them more stable. This remodeling of the plaque environment would be predicted in humans to block plaque rupture and thrombosis and thereby prevent heart attacks and strokes. 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.

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." 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."

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

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 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, suppression of oxidative stress, and a decrease in plaque necrosis. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.

Comments

I can tell you what would be even better to put inside those targeted nano particles than a small molecule drug - SENS' enzymes that can break down oxidized LDL.

Would they fit though??

Posted by: Jim at February 19th, 2015 5:07 AM

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