Mineralization of pH-Sensitive Doxorubicin Prodrug in ZIF-8 to Enable Targeted Delivery to Solid Tumors

Abstract

The zeolitic imidazolate framework (ZIF-8), composed of zinc ion and dimethylimidazole, is widely used in drug delivery because of the easy fabrication process and the good biosafety. However, ZIF-8 suffers from low affinity to nonelectric-rich drugs and does not have surface functional groups. Here, to deliver doxorubicin (DOX) with ZIF-8 to specific target sites, DOX was first modified with a pH-sensitive linker containing two carboxyl groups to form the inactive prodrug CAD and subsequently seeded inside ZIF-8 by a 5 min mineralization process. CAD has high affinity to ZIF-8 because of the carboxyl groups and can anchor to the ZIF-8 surface to enable the surface modification with folic acid for tumor targeting. Moreover, the DOX release is precisely controlled by three steps of acidic pH response, with the dissociation of the FA layer, the breakdown of the ZIF-8 structure, and the cleavage of the pH-sensitive linker in prodrug. This novel “prodrug-ZIF-8” strategy has opened a new horizon in drug delivery.

Delivery of Protein Kinase A by CRISPRMAX and Its Effects on Breast Cancer Stem-Like Properties

“…When we use nanoparticles for combining EMT-targeting and conventional chemotherapy, we cannot always carry out the commonly used strategy that is the so-called “one-stop solution”, which loads two drugs in one nanoparticle at the same time [ 26 ], but need to consider taking a sequential solution strategy in terms of delivering combinational therapeutics in a single nanoparticle. Therefore, using nanoparticles for combinational therapy remains challenging.…”

“…Except for liposomes, there are also many other functionalized nanosystems that can be used to deliver enzymes, such as polymer nanoparticles [ 23 ], polymersomes [ 24 ], mesoporous nanoparticles [ 25 ], metal-organic framework (MOF) with biomineralization [ 26 ], DNA nanoparticles [ 27 , 28 ], emulsions [ 29 ], etc. In detail, for mesoporous silica nanoparticles (MSNs), it is reported that enzymes can be loaded in the cavity of the pores in a size-selective adsorption manner [ 46 ].…”

“…When administering the complex solution, PKA enzymes and CRISPRMAX can be mixed at room temperature before delivery into the targeted cancer cells. Solid nanoparticles, such as MOF, can store biologically active enzymes in vitro for a long time [ 26 , 48 ], of which the synthesis process is relatively easy to manipulate. However, compared with LNPs, it is not yet easy to perform a high-throughput preparation of enzyme-MOF complexes and functional screening in seeded cells.…”

“…The effects of PKA-loaded CRISPRMAX complexes in breast cancer cells and normal breast cells on the chemoresistance of PTX (Arisun ChemPharm, Xi’an, China) and DOX (Arisun ChemPharm) were determined by WST-1 cell viability assay [ 26 ]. Breast cancer cells and MCF-10A cells were seeded in 96-well plates (5000 cells per well, except MDA-MB-231 cells were seeded at the density of 2000 cells per well, three parallel wells for each concentration) in complete growth medium containing 5% FBS, and cultured in the cell incubator overnight.…”

“…In fact, there are many other functionalized nanosystems that can be used to deliver proteins/enzymes. For example, in our research group, we have developed different platforms for protein delivery, including: (a) liposomes [ 22 ], (b) polymer nanoparticles [ 23 ], (c) polymersomes [ 24 ], (d) mesoporous nanoparticles [ 25 ], (e) metal-organic framework with biomineralization [ 26 ], (f) DNA nanoparticles [ 27 , 28 ], (g) emulsions [ 29 ], etc. However, in the end, we selected the commercial CRISPRMAX, because CRISPRMAX has the following advantages.…”