Intervention with the Bone-Associated Tumor Vicious Cycle through Dual-Protein Therapeutics for Treatment of Skeletal-Related Events and Bone Metastases

Abstract

Bone metastasis is a common metastasis site such as lung cancer, prostate cancer, and other malignant tumors. The occurrence of bone metastases of lung cancer is often accompanied by bone loss, fracture, and other skeletal-related events (SREs) caused by tumor proliferation and osteoclast activation. Furthermore, along with the differentiation and maturation of osteoclasts in the bone microenvironment, it will further promote the occurrence and development of bone metastasis. Protein drugs are one of the most promising therapeutic pharmaceuticals, but in vivo delivery of protein therapeutics still confronts great challenges. In order to more effectively conquer bone metastases and alleviate SREs, herein, we constructed biomineralized metal–organic framework (MOF) nanoparticles carrying protein toxins with both bone-seeking and CD44-receptor-targeting abilities. More importantly, through combination with Receptor Activator of Nuclear Factor-κ B Ligand (RANKL) antibody, in vivo results demonstrated that these two protein agents not only enhanced the detraction effects of protein toxin agents as ribosome-inactivating protein (RIP) on bone metastatic tumor cells but also exhibited synergistic intervention of the crosstalk between bone cells and tumor cells and reduced SREs such as bone loss. Collectively, we expect that this strategy can provide an effective and safe option in regulating bone-tumor microenvironments to overcome bone metastasis and SREs.

Premetastatic Niche Mimicking Bone‐On‐A‐Chip: A Microfluidic Platform to Study Bone Metastasis in Cancer Patients

“…This result is consistent with the vicious cycle in which osteoclasts promote the proliferation of tumor cells and tumor cells promote osteoclast differentiation. [ 40 ] The difference in cytokine secretion of MSCs and RAW264.7 cells determines the fate of tumor cells, which is critical to cell selection in BOC design. Notably, pretreatment with CM increased the number of protrusions in both the Gel‐MSC and Gel‐RAW groups (Figure 5G), which indicated the successful modulation of CM for local BME.…”

Metal–Organic Framework‐Integrated Composites for Bone Tissue Regeneration

“…Osteoclast inhibitors, such as bisphosphonates or receptor activator of nuclear factor kappa‐B ligand inhibitors, can be encapsulated within MOFs and selectively released at the site of BTE. [ 85 ] For instance, Pang et al. designed BT‐isMOF nanoparticles that bind to bone tissue, allowing precise control over the timing and dosage of anti‐resorptive agents, in this case, zoledronic acid (ZOL).…”

Current status and prospects of metal–organic frameworks for bone therapy and bone repair

“…Combined with RANKL, the antibody interfered with the malignant cycle of bone tumours and inhibited two times the tumour cell proliferation and osteoclast maturation. 49 The methods of the alendronate and hyaluronic acid-coated nano-ions achieved two-step targeting of bone metastatic tumour cells favouring the reduction of protein toxin damage to non-malignant cells in the bone microenvironment. They also showed through in vivo results that the combination of these two protein agents not only enhanced the inhibitory effect of protein toxin agents such as ribosomal inactivating protein (RIP) on bone metastatic tumour cells, but also synergistically interfered with the crosstalk between bone cells and tumour cells, reducing bone-related events such as bone loss.…”

“…Some selected representative examples for bone therapy are Uio-66–NH 2 , 60 Sr/PTA–MOF, 61 BT–isMOF, 45 MTX–TA/Fe 3+ @HA MOF, 66 V-RZCD, 38 and ALN–HA–ZIF-8@Sap. 49 For bone repair, we selected Zr–MOFs, 78 SF–DEX@ZIF8–Ti, 73 bio-MOF-1, 123 IL4–MOF@CaP, 107 TNT–ZIF-67@OGP 118 and DEX@Zn–Mg/MOF74. 85 As can be seen from Fig.…”