Open AccessDesign and Synthesis of Cathepsin-K-Activated Osteoadsorptive Fluorogenic Sentinel (OFS) Probes for Detecting Early Osteoclastic Bone Resorption in a Multiple Myeloma Mouse Model
Author(s) -
Eric Richard,
Kenzo Morinaga,
Yiying Zheng,
Oskar Sundberg,
Akishige Hokugo,
Kimberly Hui,
Yvonne Peijun Zhou,
Hodaka Sasaki,
B. A. Kashemirov,
Ichiro Nishimura,
Charles E. McKenna
Publication year - 2021
Publication title -
bioconjugate chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.279
H-Index - 172
eISSN - 1520-4812
pISSN - 1043-1802
DOI - 10.1021/acs.bioconjchem.1c00036
Subject(s) - cathepsin k , chemistry , osteoclast , osteolysis , bone resorption , resorption , fluorescence , cathepsin , förster resonance energy transfer , diphosphonates , rankl , biophysics , microbiology and biotechnology , cancer research , biochemistry , pathology , medicine , in vitro , enzyme , dentistry , biology , physics , quantum mechanics , activator (genetics) , gene
We describe the design and synthesis of OFS-1, an Osteoadsorptive Fluorogenic Sentinel imaging probe that is adsorbed by hydroxyapatite (HAp) and bone mineral surfaces, where it generates an external fluorescent signal in response to osteoclast-secreted cathepsin K (Ctsk). The probe consists of a bone-anchoring bisphosphonate moiety connected to a Förster resonance energy transfer (FRET) internally quenched fluorescent (IQF) dye pair, linked by a Ctsk peptide substrate, GHPGGPQG. Key structural features contributing to the effectiveness of OFS-1 were defined by structure-activity relationship (SAR) and modeling studies comparing OFS-1 with two cognates, OFS-2 and OFS-3. In solution or when preadsorbed on HAp, OFS-1 exhibited strong fluorescence when exposed to Ctsk (2.5-20 nM). Time-lapse photomicrographs obtained after seeding human osteoclasts onto HAp-coated well plates containing preadsorbed OFS-1 revealed bright fluorescence at the periphery of resorbing cells. OFS-1 administered systemically detected early osteolysis colocalized with orthotopic engraftment of RPMI-8226-Luc human multiple myeloma cells at a metastatic skeletal site in a humanized mouse model. OFS-1 is thus a promising new imaging tool for detecting abnormal bone resorption.