Utilization of bisphosphonate drugs in fluorescent imaging and targeted drug delivery

Bisphosphonates are a commonly prescribed class of medications currently used to treat postmenopausal osteoporosis, Paget’s disease, bone metastatic cancers, and other bone-related diseases. They are stable analogues of pyrophosphates and belong to a class of compounds that contains a P-C-P backbone. The presence of the two phosphonate groups enables the compounds to chelate calcium, which is found in bone mineral. This chelating ability of bisphosphonates to calcium is responsible for their specific uptake by the bone, where the drugs inhibit osteoclast mediated bone resorption. ❧ The unique high bone binding affinity of bisphosphonates is an attractive feature that could be exploited for targeted delivery of other drugs to bone. This idea was further explored in the work presented in this thesis for various applications, including targeted delivery of therapeutics to the bone and bone imaging. Two categories of projects are covered in this thesis: 1) non-ear related studies and 2) ear-related studies. ❧ The first chapter briefly summarizes history of the development of bisphosphonate drugs, their mechanism of action, clinical applications, and side effects. The three subsequent chapters focus on work related to the synthesis and characterization of various nitrogen-containing bisphosphonate analogues used in targeted drug delivery and bone imaging. Topics covered in these chapters are 1) the synthesis of a novel N-containing bisphosphonate drug possessing an activated carboxyl moiety for targeted delivery of peptide-coated gold nanoparticles to bone metastatic niches; 2) the development of a novel series of near infrared dye-bisphosphonate conjugates to explore the effect of different linker lengths on their anti-resorptive activities on osteoclasts; and 3) the establishment of a new analytical method to determine the bone binding affinity of these newly synthesized conjugates. ❧ The latter half of this thesis centers on the utilization of bisphosphonates for targeted drug delivery to the ear. This part of the thesis starts with a brief overview of the anatomy of the human ear and describes the challenges of drug delivery to the ear. This is followed by discussion of studies on drug delivery to the cochlea using bisphosphonates and imaging of cochlear drug distribution in murine models using fluorescently labeled bisphosphonates in search for effective treatments of ear disorders, such as otosclerosis and hearing loss.