Spatiotemporally controlled calcitonin delivery: Long-term and targeted therapy of skeletal diseases.

Bone is a connective tissue that support the entire body and protect the internal organs. However, there are great challenges on curing intractable skeletal diseases such as hypercalcemia, osteoporosis and osteoarthritis. To address these issues, calcitonin (CT) therapy is an effective treatment alternative to regulate calcium metabolism and suppress inflammation response, which are closely related to skeletal diseases. Traditional calcitonin formulation requires frequent administration due to the low bioavailability resulting from the short half-life and abundant calcitonin receptors distributed through the whole body. Therefore, long-term and targeted calcitonin delivery systems (LCDS and TCDS) have been widely explored as the popular strategies to overcome the intrinsic limitations of calcitonin and improve the functions of calcium management and inflammation inhibition in recent years. In this review, we first explain the physiological effects of calcitonin on bone remodeling: (i) inhibitory effects on osteoclasts and (ii) facilitated effects on osteoblasts. Then we summarized four strategies for spatiotemporally controlled delivery of calcitonin: micro-/nanomedicine (e.g. inorganic micro-/nanomedicine, polymeric micro-/nanomedicine and supramolecular assemblies), hydrogels (especially thermosensitive hydrogels), prodrug (PEGylation and targeting design) and hybrid biomaterials. Subsequently, we discussed the application of LCDS and TCDS in treating hypercalcemia, osteoporosis, and arthritis. Understanding and analyzing these advanced calcitonin delivery applications are essential for future development of calcitonin therapies toward skeletal diseases with superior efficacy in clinic.