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.

Branched and Dendritic Polymer Architectures: Functional Nanomaterials for Therapeutic Delivery

“…The size and surface charge of the nanocarrier was pivotal in achieving cartilage penetration and drug therapeutic lifetime. 189 In 2016, the group of Siegwart, reported modular and degradable dendrimers that had low toxicities and high antitumor efficiencies, and gave a significant survival benefit in the in vivo cancer model studied (Figure 8). 190 The ester based dendrimers were synthesised using sequential thiol or amine Michael additions, which allowed a large library of dendrimers to be produced with differing functionalities and generations.…”

Transcription Factors in Cartilage Homeostasis and Osteoarthritis

“…Drug delivery into the cartilage is very ineffective, and, therefore, nanodrugs may offer a solution. In a recent study, the growth factor insulin-like growth factor 1 (IGF-1) was conjugated to a nanocarrier designed to better infiltrate cartilage, and treatment of a surgical OA rat model with this IGF-1 nanodrug resulted in significantly less cartilage degeneration compared to treatment with free IGF-1 [203]. Together, these recent developments in both TF-targeting drugs and better local delivery systems are promising for the development of disease-modifying drugs for OA.…”

Leveraging Electrostatic Interactions for Drug Delivery to the Joint

“…The collagen network has a mesh size of *50-60 nm 15,16 and is primarily filled with sulfated glycosaminoglycan-containing proteoglycans, with *20 nm spacing between side chains, which give the cartilage an anionic charge. 17,18 Targeting strategies for cartilage have leveraged these unique ECM characteristics, including passive targeting of nanomaterials to cartilage via electrostatic attraction to the anionic cartilage matrix 19,20 and active targeting strategies using binding moieties or agents specific to collagen type II. [21][22][23] Synovial fluid, the viscous non-Newtonian fluid within the joint space, is essential not only for shock absorption and lubrication but also for modulating the transport of various molecules to different tissues of the joint.…”