Multiple myeloma (MM) is an incurable plasma cell dyscrasia that progresses through stages to overt, symptomatic myeloma that remains a devastating public health problem. The bone marrow (BM) niche is known to contribute to the growth of tumours such as multiple myeloma (MM) in many ways. Designing better methods of bone-specific delivery for direct and indirect treatment, through the modulation of bone cells, may produce a potent, two-pronged anti-cancer strategy that both heals osteolytic lesions and directly inhibits tumour cells. Nanoparticles (NPs) made from PEGPLGA coupled to alendronate (bone-targeted) or alone were formulated and loaded with bortezomib or empty. NPs were characterised for physiochemical properties, bone affinity, drug release profile, and anti-myeloma effects on MM1S myeloma cells in vitro. In vivo, anti-myeloma effects, were assessed using bioluminescence imaging (BLI) and effects on bone were done using uCT and IHC. The biodegradable NPs had a uniform size distribution (100-200 nm), with a zeta potential of ±5mV. Bone-targeted NPs showed high affinity towards bone mineral and better bone accumulation in vivo. Drug release kinetics showed a burst followed by a sustained-release pattern over 60 hrs. Treatment with bone-targeted bortezomib NPs, non-targeted NPs and free drug worked comparably. In another mouse model, pre-treatment with bortezomib-bone-targeted NPs decreased tumour growth, compared to free drug or non-targeted NPs. Treatment with bortezomib in non-cancer mice increased bone formation in long bones, measured by μCT and histology. Approval of these studies was obtained from our Institution. Bone-targeted nanoparticles hold potential for clinical applications in delivering chemotherapies to bone marrow niches, reducing off-target effects, increasing local drug concentrations, and lengthening the therapeutic window. Future research into how bortezomib modifies the local bone marrow milieu to make it less inhabitable for tumour cells should be explored. Bortezomib-bone-targeted NPs may have potential future clinical utility.
Disclosure: The authors declared no competing interests. This work was supported by Department of Defense Grant W81XWH-05-1-0390; National Institutes of Health Grants R00 CA160350, R01 FD003743, R01 CA154648, and CA151884.