Drug-loaded biomorphic scaffolds for tissue regeneration and targeted antitumor therapy in bone metastasis models

Renal cell (RCC) and breast carcinoma (BC) frequently develop lytic bone metastases (BM) that are usually treated with systemic and locoregional therapies. Surgery plays a crucial role when pathological fractures or lesions involve a load-bearing bone and consists in the removal of tumor area followed by replacement with implant or prosthesis. In the present study, a proof of concept of novel locoregional therapies for BM patients was evaluated, consisting in the functionalization of biomorphic apatitic scaffolds with proved intrinsic regenerative properties with Everolimus and an anti-RANKL antibody, selected as relevant anticancer and anti-resorptive biomolecules, respectively. Upon confirmation of the biocompatibility of unloaded scaffolds with healthy bone cells, the effective antitumoral activity of released EVE on BC cell lines (MCF-7 and MDA-MB-231) and RCC cell line (Caki-2) was demonstrated. The inhibitory effects of drugs on osteoclast differentiation were validated using peripheral blood mononuclear cells (PBMCs). Preclinical validation was performed on monocultures and cocultures of cancer and bone cells sharing the same culture medium. In silico analyses were exploited to predict cancer cell behavior on medicated scaffolds providing complementary insights while reducing the need for extensive wet-lab experimentation. Finally, as a preliminary proof of translational relevance, the medicated scaffolds were tested with RCC patient-derived explants.