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Deeply Penetrating Nanoparticles Designed to Treat Osteoarthritis

By BiotechDaily International staff writers
Posted on 12 Dec 2018
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Image: Six days after treatment with IGF-1 carried by dendrimer nanoparticles (blue), the particles have penetrated through the cartilage of the knee joint (Photo courtesy of Brett Geiger and Jeff Wyckoff, Massachusetts Institute of Technology).
Image: Six days after treatment with IGF-1 carried by dendrimer nanoparticles (blue), the particles have penetrated through the cartilage of the knee joint (Photo courtesy of Brett Geiger and Jeff Wyckoff, Massachusetts Institute of Technology).
A novel nanoparticle-based drug transport system designed to treat osteoarthritis delivers the anabolic growth factor IGF-1 (insulin-like growth factor 1) directly to injured chondrocytes, which are located deep within a dense layer of cartilage tissue.

Osteoarthritis is a debilitating joint disease for which there are no disease-modifying therapies. Several drugs have failed clinical trials due to inefficient and inadequate delivery to target cells. Anabolic growth factors are one class of such drugs that could be disease-modifying if delivered directly to chondrocytes, which reside deep within dense, anionic cartilage tissue.

To overcome this biological barrier, investigators at the Massachusetts Institute of Technology (Cambridge, USA) conjugated IGF-1 to a cationic nanocarrier for targeted delivery to chondrocytes and retention within joint cartilage after direct intra-articular injection. IGF-1 is an anabolic growth factor that promotes chondrocyte survival, proliferation, and biosynthesis of cartilage matrix macromolecules. It also shows anti-inflammatory effects in cytokine-challenged cartilage tissue. Because of these properties, IGF-1 has garnered considerable interest as a potential disease-modifying drug.

The nanocarriers were prepared from repetitively branched molecules known as dendrimers. Poly(amidoamide), or PAMAM, dendrimers were utilized for their tertiary amine groups at the branching points within the dendrimer. Metal ions were introduced to an aqueous dendrimer solution and the metal ions formed a complex with the lone pair of electrons present at the tertiary amines.

The nanocarriers were end functionalized with variable molar ratios of poly(ethylene glycol) (PEG) to control surface charge. PEG provided reversible electrostatic interactions with anionic cartilage tissue to improve tissue binding, penetration, and residence time. From a small family of variably PEGylated dendrimers, an optimal formulation showing 70% uptake into cartilage tissue and 100% cell viability was selected.

The investigators reported in the November 28, 2018, online edition of the journal Science Translational Medicine that when conjugated to IGF-1, the dendrimer nanocarriers penetrated bovine cartilage of human thickness within two days and enhanced therapeutic IGF-1 joint residence time in rat knees by 10-fold for up to 30 days. In a surgical model of rat osteoarthritis, a single injection of dendrimer–IGF-1 rescued cartilage and bone more effectively than free IGF-1. Cartilage in injured joints treated with the nanoparticle-drug combination was far less damaged than cartilage in untreated joints or joints treated with IGF-1 alone. The joints also showed reductions in joint inflammation and bone spur formation.

"This is a way to get directly to the cells that are experiencing the damage, and introduce different kinds of therapeutics that might change their behavior," said senior author Dr. Paula Hammond, professor of chemical engineering at the Massachusetts Institute of Technology.

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Massachusetts Institute of Technology


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