Bortezomib-catechol conjugated prodrug micelles: combining bone targeting and aryl boronate-based pH-responsive drug release for cancer bone-metastasis therapy

Abstract

The treatment of metastatic tumors is highly desirable in clinics, which has also increased the interest in the design of nanoscale drug delivery systems. Bone metastasis is one of the most common pathways in the metastasis of breast cancer, and it is also an important cause for tumor recurrence and death. The aryl boronate group, as an acid-labile linker, has been introduced into nano-assemblies in recent years. Especially, as a proteasome inhibitor anticancer drug with a boric acid group, bortezomib can facilitate the formation of pH-sensitive aryl boric acid ester linkage with the catecholic group. In this study, bortezomib-loaded micelles with bone targeting properties were constructed for the treatment of breast cancer bone metastasis. The mixed micelles employed alendronate (ALN) as the bone-targeting ligand and encapsulated bortezomib-catechol conjugates as the cargo. In vitro and in vivo studies showed that compared with free drugs or control micelles, these prodrug micelles (ALN-NP) exhibited many favorable properties such as reduced systemic toxicity and improved therapeutic effects. Therefore, ALN-NP is promising as a nanovehicle for bone-targeting delivery of chemotherapeutic drugs. Furthermore, this study offers a novel strategy combining bone targeting and aryl boronate-based pH-responsive drug release for anti-metastasis therapy.

Supramolecular Caffeic Acid and Bortezomib Nanomedicine: Prodrug Inducing Reactive Oxygen Species and Inhibiting Cancer Cell Survival

“…It has been recently discovered that BTZ is inhibited by naturally occurring polyphenols coming from natural diet. This nanoparticle formulation strategy shields the active boronic acid site of BTZ while in circulation and could increase its pharmacokinetic effects [26]. Another salient feature of the nanomedicine was the complementary effects of its components.…”

“…Another salient feature of this strategy is that the binding of BTZ to CA is pH-reversible under acidic pH, and the cancer cell's intracellular and tumor environment acidic condition can be exploited as a stimulus to deliver the drug payload [24], liberating BTZ from CA and ensuring that both components can enact their anticancer properties [25]. This kind of drug formulation is also known as a prodrug approach, where the drug itself, in this case the nanomedicine, cannot act as an anticancer compound, due to the inhibitory effects of the boronic acid-catechol conjugation components on each other [26]. Bortezomib and caffeic acid cannot both become anticancer agents until the nanomedicine has been metabolized inside the body through the acidic condition of the tumor and the intracellular pH of cancer cells.…”

The optimized drug delivery systems of treating cancer bone metastatic osteolysis with nanomaterials

“…Bone offers metastatic cells unique microenvironments termed 'niches' (Croucher et al, 2016;Ahangar et al, 2019). The slow blood flow in bone, mechanical property, various chemokines, and growth factors are beneficial to tumor cells' growth (Zhu et al, 2018;Turpin et al, 2020). In the osteolytic microenvironment, the 'vicious circle' between cancer cells, osteoblasts, and osteoclasts facilitates the activation of osteoclasts and suppresses the action of osteoblasts.…”

“…Inhibit cathepskin K (Saracino et al, 2016); (Duong et al, 2014) BTZ Inhibit NF-kB pathway in osteoclast (Zhu et al, 2018); (Wang, Cai, et al, 2018)…”

Block copolymer prodrugs: Synthesis, self‐assembly, and applications for cancer therapy

“…Notably, among these drugs without carbonyl groups, drugs were frequently modified by introduction of carbonyl groups for the following conjugation. In addition to widely used hydrazone bonds, the pH‐responsive bonds such as Schiff base structure (Mao et al, ), acetal bonds (Gu et al, ), and aryl boronate (Zhu et al, ) were also explored to conjugate anticancer drugs to prepare pH‐responsive BCPs.…”