Nanozyme-natural enzymes cascade catalyze cholesterol consumption and reverse cancer multidrug resistance

Abstract

Multidrug resistance is still a major obstacle to cancer treatment. The most studies are to inhibit the activity of the drug transporter P-glycoprotein (P-gp), but the effect is not ideal. Herein, a nanosystem was built based on cascade catalytic consumption of cholesterol. Cholesterol oxidase (natural enzyme, COD) was immobilized on the carrier (NH2-MIL-88B, MOF) through amide reaction, COD catalyzed the consumption of cholesterol, the reaction product H2O2 was further produced by the MOF with its peroxidase-like activity to produce hydroxyl radicals (•OH) with killing effect. Due to the high expression of CD44 receptor on the surface of tumor cells, we encapsulated chondroitin sulfate gel shell (CS-shell) with CD44 targeting and apoptosis promoting effect on the surface of DOX@MOF-COD nanoparticles, which can accurately and efficiently deliver the drugs to the tumor site and improve the effect of reversing drug resistance. Taking drug-resistant cell membrane as "breakthrough", this paper will provide a new idea for reversing multidrug resistance of tumor. Graphical Abstract

Nanozymes with biomimetically designed properties for cancer treatment

“…Most research focuses on the inhibition of P -glycerin activity during drug transport, but its effect is also very unsatisfactory. Du et al 178 developed an enzyme-driven DOX@MOF-COD@CS nanosystem (Fig. 13E).…”

Metal–organic gels: recent advances in their classification, characterization, and application in the pharmaceutical field

“…The protection of bioactive substances. Bioactive substances, including peptides, 169 enzymes, 189 and siRNA, 170 are usually inactivated by the strong acidic environment in the stomach after oral administration. Porous MOGs have many host-guest molecular interaction sites, which enable them to encapsulate and fix bioactive components.…”

“…The structural designability and porosity of MOGs allow them to encapsulate drugs selectively or mix numerous components to specifically recognize the CD44 receptors, resulting in targeted tumor therapy. According to the above-mentioned strategy, Du and colleagues 189 built a MOG nanosystem based on the catalytic cascade consumption of cholesterol. The cholesterol oxidase (natural enzyme, COD) was immobilized in NH 2 -MIL-88B (a nanoenzyme MOF with peroxidase activity) by amide reaction, and then wrapped in a chondroitin sulfate gel shell with CD44-targeting and apoptosis-inducing effects.…”

Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance

“…This DDS was delivered to cancer cells with CD44 overexpression owing to the targeting ability of HA towards CD44, and then released Zr (IV)-based porphyrinic MOF and CHC for enhanced photodynamic therapy (PDT) effect. Du et al synthesized DOX@NH 2 -MIL-88B-COD@CS NPs, which were loaded with cholesterol oxidase (COD), DOX, and chondroitin sulfate (CS) gel shell [ 39 ] . The COD catalyzed the degradation of cholesterol on the cell membrane to weaken the bio-barrier of cell membrane, thus facilitating the delivery of NPs into the cell.…”

“…In particular, MOFs have shown great potential and advantages as nanocarriers for drug delivery and protection, such as encapsulation of drugs, direct assembly of drug molecules as organic ligands [35] , post synthesis [33] , and surface modification [36] . Up to now, the MOF-based drug delivery system (DDS) has been employed to deliver drugs such as cisplatin [37] , doxorubicin (DOX) [38][39][40] , biomolecular agents [2,[41][42][43] , and immunosuppressants [44,45] . Both single and multiple drug delivery using MOF-based DDS is available [36,46] , and combined therapeutic approaches with multiple mechanisms are also commonly performed [47] .…”