Dendrimer Drug Conjugates for Sustained Intra-Articular Delivery

Technology

This technology is an amine terminated polyamidoamine dendrimer (PAMAM) that is conjugated at its terminal groups with an optimal number of polyethylene glycol (PEG) polymer chains to govern effective surface charge.  At the selected surface charge, the PEGylated dendrimers are nontoxic and reversibly bind to anionic cartilage tissue in such a way to enable penetration.  A small fraction of the PEG groups have a reactive linker domain that can be used to conjugate a therapeutic protein or small molecule drug to the dendrimer. As a proof of principle, the inventors synthesized optimally PEGylated dendrimers bound to insulin-like growth factor IGF1, a chondrocyte stimulating growth factor previously shown to stimulate cartilage extracellular matrix deposition.  Dendrimer-IGF-1 retains bioactivity equivalent to free IGF-1.  Dendrimer-IGF-1 conjugates display penetration of human thickness cartilage at much greater concentrations than IGF-1 alone. Additionally, the half-life of intra-articular injected dendrimer-IGF-1 is >4 days in an in vivo rat model.  In contrast, free IGF-1 has a half-life of less than 0.4 days in the joint. Based on the concentrations injected and these half-lives, dendrimer-IGF-1 provides about 30 days of IGF-1 at therapeutic concentration, whereas free IGF-1 provides about 3 days.  In summary, these inventors have developed a revolutionary drug delivery system that allows sustained, targeted delivery of therapeutics to cartilage cells.

Problem Addressed

For patients with osteoarthritis, there are no disease modifying drugs capable of slowing degeneration or promoting regeneration of cartilage. Current treatment is focused on managing pain for as long as possible until surgery is necessary.  Disease modifying drug candidates have been under clinical development for decades but have repeatedly encountered failure largely due to rapid clearance from the joint.  The dense, avascular cartilage tissue between the joint space and cartilage cells provides another barrier that further compounds this drug delivery challenge in osteoarthritis.  An Amgen sponsored trial of Anakinra, an interleukin 1 receptor antagonist (IL1-RA), provides clinical evidence of the delivery problem (NCT00110916, X. Chevalier et al, Arthritis & Rheumatism, 2009). These inventors have engineered nanoparticle-drug conjugates that can penetrate cartilage to avoid joint clearance and target cartilage cells, extending time at a therapeutic concentration of drug by tenfold.  The improved joint pharmacokinetics offered by this technology could enhance efficacy of disease modifying drugs, thereby improving the chances of clinical success.

Advantages

• Penetration of dendrimer-drug conjugate through human thickness (~ 1 mm) cartilage
• Retention of dendrimer in cartilage for up to one month
• Sustained delivery of dendrimer-drug conjugate directly to chondrocytes
• Capable of accommodating biologic drugs