Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis.

ABSTRACT: Osteoarthritis is a debilitating joint disease affecting nearly 30 million people for which there are no disease-modifying therapies. Several drugs that have failed clinical trials have shown 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, we conjugated a growth factor to a cationic nanocarrier for targeted delivery to chondrocytes and retention within joint cartilage after direct intra-articular injection. The nanocarrier uses reversible electrostatic interactions with anionic cartilage tissue to improve tissue binding, penetration, and residence time. Amine terminal polyamidoamine (PAMAM) dendrimers were end functionalized with variable molar ratios of poly(ethylene glycol) (PEG) to control surface charge. From this small family of variably PEGylated dendrimers, an optimal formulation showing 70% uptake into cartilage tissue and 100% cell viability was selected. When conjugated to insulin-like growth factor 1 (IGF-1), the dendrimer penetrated bovine cartilage of human thickness within 2 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. Dendrimer-IGF-1 reduced width of cartilage degeneration by 60% and volumetric osteophyte burden by 80% relative to untreated rats at 4 weeks after surgery. These results suggest that PEGylated PAMAM dendrimer nanocarriers could improve pharmacokinetics and efficacy of disease-modifying osteoarthritis drugs in the clinic.

SUBMITTER: Geiger BC 

PROVIDER: S-EPMC8103617 | biostudies-literature |

REPOSITORIES: biostudies-literature