DOTAM Derivatives as Active Cartilage-Targeting Drug Carriers for the Treatment of Osteoarthritis

Abstract

Targeted drug-delivery methods are crucial for effective treatment of degenerative joint diseases such as osteoarthritis (OA). Toward this goal, we developed a small multivalent structure as a model drug for the attenuation of cartilage degradation. The DOTAM (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide)-based model structure is equipped with the cathepsin D protease inhibitor pepstatin A, a fluorophore, and peptide moieties targeting collagen II. In vivo injection of these soluble probes into the knee joints of mice resulted in 7-day-long local retention, while the drug carrier equipped with a scrambled peptide sequence was washed away within 6-8 h. The model drug conjugate successfully reduced the cathepsin D protease activity as measured by release of GAG peptide. Therefore, these conjugates represent a promising first drug conjugate for the targeted treatment of degenerative joint diseases.

The Scope of Application of Macrocyclic Polyamines Beyond Metal Chelation

“…To further exploit the unique opportunity offered by MPA‐based multimerization, Schultz, Nazare and co‐workers described an elegant chemical strategy in which they insert on a DOTA platform up to three active biomolecules (collagen targeting peptides) along with a fluorescent reporter (i.e., the near‐infrared fluorescent Cy5.5 dye) . The use of DOTA mono‐, di‐ or tri‐ tert ‐butyl ester in combination with Fmoc/Boc protecting group strategy enables a facile and effective synthesis of these fluorescently‐labeled multi‐peptide conjugates through sequential peptide coupling‐type reactions performed in solution (i.e., with DMF as solvent).…”

Targeting the extracellular matrix for delivery of bioactive molecules to sites of arthritis

“…Cathepsin D ‐mediated aggrecan damage and glycosaminoglycan (GAG) release could be inhibited by DOTAM when covalently linked to pepstatin A with either one or three copies of WYRGRL. Trivalent molecules were retained more strongly than monovalent versions (Hu et al, ). Theoretically, loading DOTAM with other targeting technologies and payloads could achieve multiple additional novel therapeutic effects in the cartilage.…”

Targeting collagen for diagnostic imaging and therapeutic delivery

“…A peptide WYRGRL that binds to α1 chain of type II collagen was discovered via phage-display and found to target articular cartilage [23–25]. Using this collagen binding sequence, Schultz and coworkers achieved targeted drug delivery of the cathepsin D inhibitor for the treatment of OA [24]. Three WYRGRL peptides and one cathepsin D inhibitor were tethered via a tetrapodal DOTAM [26] template, and the drug conjugate was administered intra-articularly to not only allow lipophilic drug molecules to penetrate joint compartments, but also to enhance the retention of inhibitor within cartilage through its multi-valent binding.…”