Promising drug delivery system
Nature reviews Rheumatology Researchers have developed a new chondrocytetargeting drug delivery system to overcome the biological barrier of dense, anionic cartilage tissue. Conjugating insulin like growth factor 1 (IGF1) an anabolic growth factor with diseasemodifying potential, to cationic nanocarriers improved the pharmacokinetics and efficacy of IGF1 intra articular therapy in a rat model of knee osteoarthritis (OA) "Poor drug delivery has been a cause of failure of a number of clinical candidates in OA, which is part of the reason that treatment is so limited for patients," reports Brett Geiger, first author of the new study. To develop an improved means of drug delivery, they used highly branched spherical molecules, called dendrimers, that were modified with polyethylene glycol (PEG) chains. This modification not only shielded the surface charge of the molecule, but also provided versatile branches for conjugation of other molecules, such as IGF1. "Positively charged nanoparticles can bind to negatively charged cartilage, which keeps them concentrated in the cartilage rather than getting swept away through the venules and lymphatics," explains Geiger. "Not only does this approach enable the delivery of a wide variety of drugs of interest, but we've also shown that we can exert tight control over the dendrimer's degree of cartilage binding based on the amount of PEG we add to its surface." The chosen PEGylated dendrimer IGF1 formulation was nontoxic and could bind to cartilage for long periods, increasing the halflife of IGF1 within rat knee cartilage by a factor of 10. Furthermore, therapeutic levels of the growth factor were maintained in the cartilage for 30 days. In a surgical rat model of OA, a single injection of dendrimer IGF1 (2 days after surgery) rescued cartilage from degeneration more effectively than free IGF1. Treatment considerably reduced the width of cartilage degeneration and the volumetric osteophyte burden at 4 weeks compared with no treatment. "We're very interested in studying this technology further in large animal preclinical models," says corresponding author Paula Hammond. "We intend to test our PEGylated dendrimer system in additional avascular tissues similar to cartilage and test additional diseasemodifying drugs of interest." Interestingly, in this study, the PEGylated dendrimer could fully penetrate 1 mmthick bovine cartilage (a good representation of human cartilage in terms of thickness and structure) after ex vivo incubation, whereas the penetration of free IGF1 was limited. "This preclinical research presents exciting signs that improving drug delivery directly to cartilage can improve efficacy of therapeutics and potentially lead to the approval of the first diseasemodifying OA drug in the near future," concludes Hammond. Jessica McHugh O S T E OA RT H R I T I S
Nature Reviews Rheumatology