Development of novel bone targeting peptide–drug conjugate of 13-aminomethyl-15-thiomatrine for osteoporosis therapy

13-Aminomethyl-15-thiomatrine (M19) previously developed by our research group was a promising candidate for novel anti-osteoporosis drug development. However, the application of M19 was limited by its unsatisfactory druggability including poor chemical stability, excessively broad pharmacological activity and some degree of cytotoxicity. To solve these problems, M19-based bone targeting and cathepsin K sensitive peptide–drug conjugates (BTM19-1, BTM19-2 and BTM19-3) were developed to realize precise drug release in the bone tissue. Subsequent studies showed a rapid drug release process via cathepsin K digestion but sufficient stability over several hours in chymotrypsin. Besides, greatly improved chemical stability and strong hydroxyapatite binding affinity were also demonstrated. In biological evaluation studies, these PDCs showed less cytotoxicity and similar osteoclast inhibitory activity compared with the prototype drug. The optimal BTM19-2 could serve as a suitable candidate for further osteoporosis therapy research.