generation-cationic-nanoliposomes-for-efficient-delivery-vitro

Generation of Cationic Nanoliposomes for the Efficient Delivery of <em>In Vitro</em> Transcribed Messenger RNA

The development of messenger RNA (mRNA)-based therapeutics for the treatment of various diseases becomes more and more important because of the positive ...

Baker Heart & Diabetes Institute

Monash University

Mesoscale Nanoparticles: An Unexpected Means for Selective Therapeutic Targeting of Kidney Diseases!

Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.

A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense.

Abdominal aortic aneurysm (AAA) is an often deadly disease without medical, non-invasive treatment options. The upregulation of vascular cell adhesion molecule-1 (VCAM-1) on aortic endothelium provides an early target epitope for a novel biotechnological theranostic approach. MicroRNA-126 was used as a therapeutic agent, based on its capability to downregulate VCAM-1 expression in endothelial cells and thereby reduces leukocyte adhesion and exerts anti-inflammatory effects. Ultrasound microbubbles were chosen as carriers, allowing both molecular imaging as well as targeted therapy of AAA. Microbubbles were coupled with a VCAM-1-targeted single-chain antibody (scFv) and a microRNA-126 mimic (M) constituting theranostic microbubbles (Targ-M). Targ-M downregulates VCAM-1 expression in vitro and in an in vivo acute inflammatory murine model. Most importantly, using Targ-M and ultrasound-guided burst delivery of M, the development of AAA in an angiotensin-II-induced mouse model can be prevented. Overall, we describe a unique biotechnological theranostic approach with the potential for early diagnosis and long-sought-after medical therapy of AAA.

Article	Year
Mesoscale Nanoparticles: An Unexpected Means for Selective Therapeutic Targeting of Kidney Diseases! Hypertension (Dallas, Tex. : 1979)\| PubMed ID: 29133359	2018
A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense. Nature communications\| PubMed ID: 29410422	2018
Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development. Molecular therapy : the journal of the American Society of Gene Therapy\| PubMed ID: 29525742	2018

Karlheinz Peter

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