Bone-Targeted Nanoparticle Containing Protein Therapeutics As An Effective Delivery System For Bone Metastasis

Background: Protein drugs are one of the most promising new areas in drug research and development, however, great challenges are still faced in the drug delivery in vivo. Previously, we constructed bone targeted micelles for bone metastases. In order to address the issues of protein delivery in vivo and enhanced cancer bone metastasis treatment, we engineered and evaluated a bone-targeting nanoparticles by using metal organic framework nanoparticles (MOFs), bone-targeting agents (Alendronate) and hyaluronic acid (HA) as materials and a protein toxin as therapeutic. Methods: Alendronate (ALN) were conjugated to HA through PEG as linker and ALN-PEG-HA were obtained. Cytochrome C, as modle proteins, were caged in the MOFs (ZIF-8) by selfassembly of Zn2+ and organic ligands (2-methylimidazole) to form protein-encapsulated nanoparticles (ZIF8-CC). And ALN-PEG-HA were further decorated on the surface of ZIF8-CC nanoparticles via the coordination effect between its carboxyls and metal ions in ZIF-8 to result in active-targeting ALN-HA@ZIF8-CC nanopartilces. The materials and nanoparticles were synthesized and characterized by NMR, FT-IR, TEM, DLS, XRD, TGA and N2 adsorption−desorption isotherms analysis. The in vitro release profiles, stability and cytocompatibility were also studied. Results: The synthesis of ALN-PEG-HA was confirmed by 1H-NMR and FT-IR. TEM, XRD and DLS showed that ALN-HA@ZIF8-CC nanopartilces had been prepared, and the experiment of washing nanoparticles with SDS confirmed that protein was encapsulated in ZIF-8 instead of adsorbed on its surface. TGA and N2 absorption-degradation isotherms analysis also confirmed the formation of the crystal structure and porous structure, respectively. HA coated nanoparticles have good stability while ZIF8-CC were easy to aggregate. The results of in vitro release showed that the nanoparticles have acid sensitive release properties and excellent cell compatibility. In addition, In vitro bone fragment targeting experiment confirmed that nanoparticles have strong bone affinity. Conclusions: Our data demonstrated that bone-targeted protein drug-encapsulated MOFs were constructed. Citation Format: Yimin Niu, Cuicui Gao, Hongbin Yang, Qiang Huo, Andrew Wang, Ming Xu, Yang Liu. Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6237.