Dual targeted zeolitic imidazolate framework nanoparticles for treating metastatic breast cancer and inhibiting bone destruction

Abstract

Tumor bone metastasis is still difficult to cure despite the development of various treatment strategies. Drug delivery systems can improve the poor biological distribution of anticancer drugs in tumors. But only a very small number of nanoparticles can cross the physiological barrier to reach the tumor. In addition, the progression of bone metastasis is influenced by tumor cells, osteoclasts and bone matrix. To address these problems, a bone and tumor dual targeted nanocarrier was developed by utilizing NF-κB inhibitor loaded into zeolitic imidazolate framework-8 (ZIF-8) (CZ), which was then coated with hyaluronic acid/alendronate (HA/ALN). The CZ prepared by two-step method had high loading capacity, and the loading efficiency of Cur was to be 47.55 ± 4.03%. HA/ALN functionalization avoided explosive release of reagents and improved the stability of nanoparticles. The dual targeted ZIF-8 nanoparticle (CZ@HA/ALN) had a pH-triggered drug release performance, which effectively inhibited breast cancer cells growth and osteoclastogenesis in vitro. Uptake experiments showed that the conjugation of ALN with HA did not affect targeting ability of HA. Moreover, HA/ALN functionalized nanoparticles were more aggregated at bone metastasis sites than HA functionalized nanoparticles. CZ@HA/ALN could block the PD-1 immune check point, leading to Raw 264.7 cells differentiation into anti-tumor macrophage rather than osteoclast. The antitumor experiments in vivo exhibited that the dual targeted ZIF-8 nanoparticle effectively inhibited bone resorption and tumor progress, thereby improving the bone microenvironment. Therefore, this single but versatile nanoparticle provided a promising therapeutic scheme for bone metastasis treatment.