Development of a controllable drug delivery system is imperative and important to reduce the side-effects and enhance the therapeutic efficacy of drugs. Metal–organic frameworks (MOFs) and nanoscale MOFs (NMOFs), as porous hybrids constructed by polydentate bridging ligands and metal-connecting nodes, have attracted significant attention from the scientific community due to their tailorable compositions and structures, excellent porosity, and easier surface modification. Significant progress has been achieved in the past decade, but most attempts still remain in the proof-of-concept stage. This review highlights the latest advances in NMOFs for drug delivery systems and classifies the current drug-loading method into three strategies according to the location of the cargos and cargo-carrier interactions: encapsulation strategy, direct assembly strategy, and post-synthesis strategy. Each feature and the latest advances in these strategies are highlighted. Finally, the challenges and future perspectives in this field have been discussed.

Nanoscale metal–organic frameworks for drug delivery: a conventional platform with new promise

The industrial use of enzymes generally necessitates their immobilization onto solid supports. The well-known high affinity of enzymes for metal-organic framework (MOF) materials, together with the great versatility of MOFs in terms of structure, composition, functionalization and synthetic approaches, has led the scientific community to develop very different strategies for the immobilization of enzymes in/on MOFs. This review focuses on one of these strategies, namely, the one-pot enzyme immobilization within sustainable MOFs, which is particularly enticing as the resultant biocomposite Enzyme@MOFs have the potential to be: (i) prepared in situ, that is, in just one step; (ii) may be synthesized under sustainable conditions: with water as the sole solvent at room temperature with moderate pHs, etc.; (iii) are able to retain high enzyme loading; (iv) have negligible protein leaching; and (v) give enzymatic activities approaching that given by the corresponding free enzymes. Moreover, this methodology seems to be near-universal, as success has been achieved with different MOFs, with different enzymes and for different applications. So far, the metal ions forming the MOF materials have been chosen according to their low price, low toxicity and, of course, their possibility for generating MOFs at room temperature in water, in order to close the cycle of economic, environmental and energy sustainability in the synthesis, application and disposal life cycle.

Sustainable One-Pot Immobilization of Enzymes in/on Metal-Organic Framework Materials

Nanocatalytic cancer therapy based on chemodynamic therapy, which converts hydrogen peroxide (H2O2) into toxic reactive oxygen species via the Fenton-like reaction, is regarded as a promising therapeutic strategy due to its specific response toward the tumor microenvironment (TME). However, the H2O2 concentration in TME (100 μM to 1 mM) is insufficient and introducing enough H2O2 or H2O2-generating agents is challenging. In view of this, we report a drug delivery system, CaO2/DOX@Cu/ZIF-8@HA (CDZH), which is capable of targeted H2O2 self-supply and exhibits outstanding chemo/chemodynamic synergetic therapy capability. CaO2/DOX@Cu/ZIF-8@HA is synthesized by fabricating biodegradable Cu/ZIF-8 shell-encapsulated CaO2 nanoparticles, loading chemotherapy drug doxorubicin, and coating a hyaluronic acid shell. In an acidic tumor microenvironment, the CDZH nanostructures targeted the release of doxorubicin, Cu2+, and CaO2. Doxorubicin affects chemotherapy and bioimaging, and CaO2 supplies H2O2 through a Cu-Fenton-like reaction to generate hydroxyl radicals with high oxidation activity for chemodynamic therapy. In brief, the drug delivery system combined targeted H2O2 self-supply and targeted bioimaging possess the potential of an efficient synergistic strategy for chemodynamic therapy and chemotherapy.

Metal-organic framework-encapsulated nanoparticles for synergetic chemo/chemodynamic therapy with targeted H2O2 self-supply.

Slow-Release of Curcumin Induced by Core–Shell Mesoporous Silica Nanoparticles (MSNs) Modified MIL-100(Fe) Composite

Along with the increasing incidence of cancer and drawbacks of traditional drug delivery systems (DDSs), developing novel nanocarriers for sustained targeted-drug release has become urgent. In this regard, metal–organic frameworks (MOFs) have emerged as potential candidates due to their structural flexibility, defined porosity, lower toxicity, and biodegradability. Herein, a FeMn-based ferromagnetic MOF was synthesized from a preassembled Fe2Mn(μ3-O) cluster. The introduction of the Mn provided the ferromagnetic character to FeMn-MIL-88B. 5-Fluoruracil (5-FU) was encapsulated as a model drug in the MOFs, and its pH and H2S dual-stimuli responsive controlled release was realized. FeMn-MIL-88B presented a higher 5-FU loading capacity of 43.8 wt % and rapid drug release behavior in a tumor microenvironment (TME) simulated medium. The carriers can rapidly release loaded drug of 70% and 26% in PBS solution (pH = 5.4) and NaHS solution (500 μM) within 24 h. The application of mathematical release models indicated 5-FU release from carriers can be precisely fitted to the first-order, second-order, and Higuchi models of release. Moreover, the cytotoxicity profile of the carrier against human embryonic kidney cells (HEK293T) suggests no adverse effects up to 100 μg/mL. The lesser toxic effect on cell viability can be attributed to the low toxicity values [LD50 (Fe) = 30 g·kg–1, (Mn) = 1.5 g·kg–1, and (terephthalic acid) = 5 g·kg–1] of the MOFs structural components. Together with dual-stimuli responsiveness, ferromagnetic nature, and low toxicity, FeMn-MIL-88B MOFs can emerge as promising carriers for drug delivery applications.

Programmable Drug Release from a Dual-Stimuli Responsive Magnetic Metal–Organic Framework

In the present work, the porous metal-organic framework (MOF) Basolite®F300 (Fe-BTC) was tested as a potential drug-releasing depot to enhance the solubility of the anticancer drug paclitaxel (PTX) and to prepare controlled release formulations after its encapsulation in amphiphilic methoxy poly(ethylene glycol)-poly(e-caprolactone) (mPEG-PCL) nanoparticles. Investigation revealed that drug adsorption in Fe-BTC reached approximately 40%, a relatively high level, and also led to an overall drug amorphization as confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The dissolution rate of PTX-loaded MOF was substantially enhanced achieving a complete (100%) release within four days, while the neat drug only reached a 13% maximum rate (3–4 days). This PTX-Fe-BTC nanocomposite was further encapsulated into a mPEG-PCL matrix, a typical aliphatic amphiphilic copolyester synthesized in our lab, whose biocompatibility was validated by in vitro cytotoxicity tests toward human umbilical vein endothelial cells (HUVEC). Encapsulation was performed according to the solid-in-oil-in-water emulsion/solvent evaporation technique, resulting in nanoparticles of about 143 nm, slightly larger of those prepared without the pre-adsorption of PTX on Fe-BTC (138 nm, respectively). Transmission electron microscopy (TEM) imaging revealed that spherical nanoparticles with embedded PTX-loaded Fe-BTC nanoparticles were indeed fabricated, with sizes ranging from 80 to 150 nm. Regions of the composite Fe-BTC-PTX system in the infrared (IR) spectrum are identified as signatures of the drug-MOF interaction. The dissolution profiles of all nanoparticles showed an initial burst release, attributed to the drug amount located at the nanoparticles surface or close to it, followed by a steadily and controlled release. This is corroborated by computational analysis that reveals that PTX attaches effectively to Fe-BTC building blocks, but its relatively large size limits diffusion through crystalline regions of Fe-BTC. The dissolution behaviour can be described through a bimodal diffusivity model. The nanoparticles studied could serve as potential chemotherapeutic candidates for PTX delivery.

Dissolution Enhancement and Controlled Release of Paclitaxel Drug via a Hybrid Nanocarrier Based on mPEG-PCL Amphiphilic Copolymer and Fe-BTC Porous Metal-Organic Framework

Pillared graphenes are stacked graphene layers separated by spacers, or “pillars”, of various types and have attracted significant attention in material science. In graphene networks, the pillars are used to increase interlayer distances and control their electronic conductivity, mechanical strength, and chemical reactivity. Such materials are currently investigated for a wide range of potential applications, including optoelectronics, flexible electronics, energy storage, catalysis, and sensing. In this work, we deal with the optical behavior of a special class of these promising materials, in which graphene sheets, piled one on top of the other, are covalently connected by diamino organic molecules via carbon–nitrogen single bonds. In particular, we studied elemental molecular quantities strongly related to molecules and materials’ linear and nonlinear optical profiles. Properties such as optical gaps, UV–vis absorption spectra, excited states, and the first dipole hyperpolarizabilities have been computed and analyzed within the density functional theory framework. The obtained results suggest that both the linear and the nonlinear optical profiles of graphene architectures interconnected by conventional organic diamino molecules are dominated by the optical responses of the graphene layers. On the other hand, the diamino pillars are indirectly involved, in the optical behavior of these species, through local structural modifications on the framework of the graphene sheets as a result of the cross-linking process. Specifically, the performed computations, conducted in large finite graphene flakes of specific aromaticity patterns, exposed that local structural patterns may trigger surprisingly strong variations with respect to their optical absorption profiles, excited states, and nonlinear optical behavior. Such local structural patterns involve intercyclic carbon–carbon single bonds formed between sp3-hybridized carbon atoms belonging to two neighboring aromatic sextets. As far as the nonlinear optical properties are concerned, Kohn–Sham coupled perturbed computations on systems of various cross-linking patterns showed that NLO-inactive graphene sections, in terms of quadratic nonlinear optical responses, could be converted to materials of important nonlinearities. Finally, no evident dependence of the optical absorption profiles was observed with respect to the type (aromatic, conjugated, or fully saturated) of the pillar used. 

Emilia Papasouli

Papers

Dissolution Enhancement and Controlled Release of Paclitaxel Drug via a Hybrid Nanocarrier Based on mPEG-PCL Amphiphilic Copolymer and Fe-BTC Porous Metal-Organic Framework

On the Optical Properties of Diamino-Pillared Graphene Architectures