Silane-Functionalized Metal-Organic Frameworks for Stimuli-Responsive Drug Delivery Systems: A New Universal Strategy.

A new universal strategy for silane functionalization of metal-organic frameworks (MOFs) was developed. It was demonstrated that silanes were coupled both with terminal hydroxyl (OH) groups and with bridging OH groups of metal-oxo clusters of MOFs through condensation reactions between the silanols of hydrolyzed silanes and the terminal/bridging OH groups to form metal-O-Si bonds. A wide variety of functionalization of MOFs with conventional silanes can be realized by combining synthesis reactions in the solution phase and chemical modifications on the surface. Multivalent supramolecular nanovalves based on the host-guest chemistry of cyclodextrin polymer (CDP) and benzimidazole stalks silanized on the nanoscale MOF (NMOF) surface were successfully constructed. The CDP-valved NMOFs showed the excellent performance of low pH- and α-amylase-responsive controlled drug release. In vitro and in vivo results demonstrated that the CDP-valved NMOFs had a significant inhibitory effect on tumor growth and almost no damage/toxicity to normal tissues. The silanization strategy is universal and opens up a new way for the functionalization of MOFs, which are endowed with a wide variety of applications spanning gas storage, chemical sensing, adsorption and separation, heterogeneous catalysis, and drug delivery.

Ultrathin Porous Nitrogen-Doped Carbon-Coated CuSe Heterostructures for Combination Cancer Therapy of Photothermal Therapy, Photocatalytic Therapy, and Logic-Gated Chemotherapy.

The construction of nanoplatforms for the multimodal cancer therapy still remains an enormous challenge. Ultrathin porous nitrogen-doped carbon coated stoichiometric copper selenide heterostructures (CuSe/NC) are prepared using a facile and green one-pot hydrothermal method. Interestingly, CuSe/NC itself can achieve both photothermal therapy (PTT) and photocatalytic therapy (PCT) under irradiation of a single near-infrared (NIR) light (808 nm), which is convenient and safe for clinical applications. Importantly, the triple-enhanced NIR light-activated PCT, including O2-independent free radicals, Fenton-like reaction, and glutathione (GSH) depletion, breaks through the limitations of hypoxia and overexpressed GSH in cancer cells. Furthermore, CuSe/NC is loaded with doxorubicin (DOX) via metal coordination and then decorates with DNA to construct the CuSe/NC-DOX-DNA nanoplatform. Surprisingly, the facile nanoplatform has an advanced biocomputing capability of an "AND" Boolean logic gate with the smart "AND" logic controlled release of DOX upon combined stimuli of pH and GSH for precise cancer chemotherapy. The synergistic mechanism of proton-mediated ligand exchange between DOX and GSH is proposed for the "AND" logic controlled drug release from CuSe/NC-DOX-DNA. In vitro and in vivo studies demonstrate that CuSe/NC-DOX-DNA has excellent anticancer efficacy and negligible toxicity. This innovative nanoplatform with multienhanced anticancer efficacy provides a paradigm for combination cancer therapy of PTT, PCT, and chemotherapy.

Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery.

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host-guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.

Biomimicking Dual-Responsive Extracellular Matrix Restoring Extracellular Balance through the Na/K-ATPase Pathway.

Biomedical implant mimicking the physiological extracellular matrix (ECM) is a new strategy to modulate the cell microenvironment to improve implant integrity and longevity. However, the biomimicking ECM suffers from low sensitivity to pathological change and low efficiency to restore the physiological state in vivo. To overcome these problems, reactive oxygen species (ROS) and K+ dual-responsive micro-/nanofibers that encapsulate ascorbic acid-2-glucoside (AA-2G) are fabricated on an elastomer substrate with electrospinning to mimic the ECM. The strategy is based on the fact that ROS and K+ dual responsiveness enhance the sensitivity of the ECM to pathological changes and delivery of AA-2G from the ECM to cell membrane promotes reactivating Na/K-ATPase and shifting cellular diseased conditions to the normal state. We demonstrate that the ROS and K+-responsive tripolymer of poly(ethylene glycol)diacrylate, 1,2-ethanedithiol, and 4-nitrobenzo-18-crown-6-ether (PEGDA-EDT-BCAm) are synthesized successfully; the ECM composed of acylated poly(caprolactone)/PEGDA-EDT-BCAm/AA-2G micro-/nanofibers is prepared through reactive electrospinning; the ECM is sensitive to ROS and K+ concentration in the microenvironment to release AA-2G, which targets the membrane to remove the excessive ROS and reactivate Na/K-ATPase; as a result, the ECM reduces oxidative stress and restores the extracellular physiological state both in vitro and in vivo. This work provides basic principles to design an implant that can adjust the extracellular microenvironment while avoiding pathogenicity to improve implant integrity and longevity in vivo.

Construction of K+ responsive surface on SEBS to reduce the hemolysis of preserved erythrocytes.

Hemolysis of stored erythrocytes is a big obstacle for the development of new plasticizer-free polymer containers. Hemolysis is mainly caused by cell membrane oxidation and cation leaks from the intracellular fluid during storage. To construct an anti-hemolytic surface for a plasticizer-free polymer, we fabricated 2-O-α-d-glucopyranosyl-l-ascorbic acid (AA-2G)-loaded polycaprolactone (PCL)-crown ether micro/nanofibers on the surface of styrene-b-(ethylene-co-butylene)-b-styrene (SEBS). Our strategy is based on the sensitive response of the crown ether to leaked potassium, causing the release of AA-2G, the AA-2G can then remove the excess ROS, maintaining the Na/K-pump activity and the cell integrity. We demonstrated that the PCL-crown ether micro/nanofibers have been well prepared on the surface of SEBS; the micro/nanofibers provide a sensitive response to excess K+ and trigger the rapid release of AA-2G. AA-2G then acts as an antioxidant to reduce the excess ROS and maintain the Na/K-pump activity to mitigate cation leaks, resulting in the reduced hemolysis of the preserved erythrocytes. Our work thus provides a novel method for the development of plasticizer-free polymers for the storage of erythrocytes, and has the potential to be used to fabricate long-term anti-hemolytic biomaterials for in vivo use.