Targeting bone microenvironments for treatment and early detection of cancer bone metastatic niches.

Bone tissues are the main metastatic sites of many cancers, and bone metastasis is an important cause of death. When bone metastasis occurs, dynamic interactions between tumor cells and bone tissues promote changes in the tumor-bone microenvironments that are conducive to tumor growth and progression, which also promote several related diseases, including pathological fracture, bone pain, and hypercalcemia. Accordingly, it has obvious clinical benefits for improving the cure rate and reducing the occurrence of related diseases through targeting bone microenvironments for the treatment and early detection of cancer bone metastasis niches. In this review, we briefly analyzed the relationship between bone microstructures and tumor metastasis, as well as microenvironmental changes in osteoblasts, osteoclasts, immune cells, and extracellular and bone matrixes caused when metastatic tumor cells colonize bones. We also discuss novel designs in nanodrugs for inhibiting tumor proliferation and migration through targeting to tumor bone metastases and abnormal bone-microenvironment components. In addition, related researches on the early detection of bone and multi-organ metastases by nanoprobes are also introduced. And we look forward to providing some useful proposals and enlightenments on nanotechnology-based drug delivery and probes for the treatment and early detection of bone metastasis.

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

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.

Construction and evaluation of detachable bone-targeting MOF carriers for the delivery of proteasome inhibitors.

Tumor bone metastasis is an important cause of tumor recurrence and death. Although bone-targeting nanoparticles decorated with targeting ligands have shown good affinity for bone tissues with the properties of adhesion to the bone matrix, it is not easy to detach from the surface of the bone matrix in the tumor-bone microenvironment, attributed to the robust coordination force between the targeting ligands, such as bisphosphates with bone-deposited calcium. This may hinder the transport of nanoparticles from bone tissue to bone metastatic tumors. In this research, we designed a bone-targeting nanocarrier with detachable bone-targeting character for the therapy of bone metastases. The nanoparticles were constructed by using ZIF-8 and bone-targeting and MMP enzyme sensitive polypeptide-modified hyaluronic acid as a carrier and proteasome inhibitor Bortezomib (BTZ) as cargo. The results show that the constructed D8-M3-HA-ZIF8@BTZ nanoparticles possessed several favorable properties such as good colloidal stability, acid-sensitive drug release, D8 peptide mediated bone targeting and MMP enzyme-responsive desorption. Besides, nanoparticle endocytosis and cytotoxicity were enhanced through HA-mediated targeting to CD44 over-expressing tumor cells. Altogether, this study provides a potential cascade targeting strategy for improving the delivery effects of bone targeted nanoparticles for the delivery of proteasome inhibitors.