pH‐Responsive Drug‐Delivery Systems

In many biomedical applications, drugs need to be delivered in response to the pH value in the body. In fact, it is desirable if the drugs can be administered in a controlled manner that precisely matches physiological needs at targeted sites and at predetermined release rates for predefined periods of time. Different organs, tissues, and cellular compartments have different pH values, which makes the pH value a suitable stimulus for controlled drug release. pH‐Responsive drug‐delivery systems have attracted more and more interest as “smart” drug‐delivery systems for overcoming the shortcomings of conventional drug formulations because they are able to deliver drugs in a controlled manner at a specific site and time, which results in high therapeutic efficacy. This focus review is not intended to offer a comprehensive review on the research devoted to pH‐responsive drug‐delivery systems; instead, it presents some recent progress obtained for pH‐responsive drug‐delivery systems and future perspectives. There are a large number of publications available on this topic, but only a selection of examples will be discussed.     

The Critical Effect of Niobium Doping on the Formation of Mesostructured TiO2: Single‐Crystalline Ordered Mesoporous Nb‐TiO2 and Plate‐like Nb‐TiO2 with Ordered Mesoscale Dimples

Highly ordered mesoporous niobium‐doped TiO₂ with a single‐crystalline framework was prepared by using silica colloidal crystals with ca. 30 nm in diameter as templates. The preparation of colloidal crystals composed of uniform silica nanoparticles is a key to obtain highly ordered mesoporous Nb‐doped TiO₂. The XPS measurements of Nb‐doped TiO₂ showed the presence of Nb⁵⁺ and correspondingly Ti³⁺. With the increase in the amount of doped Nb, the crystalline phase of the product was converted from rutile into anatase, and the lattice spacings of both rutile and anatase phases increased. Surprisingly, the increase in the amount of Nb led to the formation of plate‐like TiO₂ with dimpled surfaces on one side, which was directly replicated from the surfaces of the colloidal silica crystals.     

Synthesis of Silicate Zeolite Analogues Using Organic Sulfonium Compounds as Structure‐Directing Agents

A microporous crystalline silica zeolite of the MEL structure type and three other zeolite analogues composed of germanosilicate frameworks were synthesized using tributylsulfonium, triphenylsulfonium, or tri(para‐tolyl)sulfonium as the structure‐directing agent. The germanosilicates thus obtained had ISV, ITT, or a new zeolite structure depending on the synthesis conditions. The structure of the new germanosilicate was solved using X‐ray powder diffraction data with the aid of a charge‐flipping method. The solution indicated a crystal structure belonging to the P63/mmc space group with cell parameters of a=16.2003 Å and c=21.8579 Å. After calcination, the new germanosilicate material exhibited two types of accessible micropores with diameters of 0.61 and 0.78 nm.     

Towards the Rational Design of Efficient Organic Structure‐Directing Agents for Zeolite Synthesis

Zeolites are crystalline microporous materials with application in diverse fields, especially in catalysis. The ability to prepare zeolites with targeted physicochemical properties for a specific catalytic application is a matter of great interest, because it allows the efficiency of the entire chemical process to be increased (higher product yields, lower undesired by‐products, less energy consumption, and cost savings, etc). Nevertheless, directing the zeolite crystallization towards the material with the desired framework topology, crystal size, or chemical composition is not an easy task, since several variables influence the nucleation and crystallization processes. The combination of accumulated knowledge, rationalization, and innovation has allowed the synthesis of unique zeolitic structures in the last few years. This is especially true in terms of the design of organic and inorganic structure‐directing agents (SDAs). In this Minireview we will present the rationale we have followed in our studies to synthesize new zeolite structures, while putting this in perspective with the advances made by other researchers of the zeolite community.     

Drug–Polymer Interactions in Hydrogel‐based Drug‐Delivery Systems: An Experimental and Theoretical Study

In drug‐delivery systems, drug transport is a key step, but the interpretation of the transport mechanism is still controversial. Here, we investigated a promising hydrogel library loaded with the anticonvulsant drug ethosuximide (ESM). The self‐diffusion coefficient of ESM was measured using two methods: a direct and advanced measurement with a pulsed field gradient spin‐echo (PFGSE) method, using an NMR spectrometer equipped with high‐resolution magic angle spinning (HR‐MAS) probe, and an indirect one based on fitting in vitro drug‐delivery data. Starting from the experimental data a mathematical model without fitted parameters was developed and all the phenomena involved, that is, adsorption and diffusion, were considered. At low drug concentrations, adsorption prevails and consequently the diffusivity in the gels is lower than that in water. At high drug concentrations, where all adsorption sites are saturated, the diffusion in the gels is similar to that in a water solution. This study may pave the way for better device design.     

A Designed 5‐Fluorouracil‐Based Bridged Silsesquioxane as an Autonomous Acid‐Triggered Drug‐Delivery System

Two new prodrugs, bearing two and three 5‐fluorouracil (5‐FU) units, respectively, have been synthesized and were shown to efficiently treat human breast cancer cells. In addition to 5‐FU, they were intended to form complexes through H‐bonds to an organo‐bridged silane prior to hydrolysis‐condensation through sol–gel processes to construct acid‐responsive bridged silsesquioxanes (BS). Whereas 5‐FU itself and the prodrug bearing two 5‐FU units completely leached out from the corresponding materials, the prodrug bearing three 5‐FU units was successfully maintained in the resulting BS. Solid‐state NMR (²⁹Si and ¹³C) spectroscopy show that the organic fragments of the organo‐bridged silane are retained in the hybrid through covalent bonding and the ¹H NMR spectroscopic analysis provides evidence for the hydrogen‐bonding interactions between the prodrug bearing three 5‐FU units and the triazine‐based hybrid matrix. The complex in the BS is not affected under neutral medium and operates under acidic conditions even under pH as high as 5 to deliver the drug as demonstrated by HPLC analysis and confirmed by FTIR and ¹³C NMR spectroscopic studies. Such functional BS are promising materials as carriers to avoid the side effects of the anticancer drug 5‐FU thanks to a controlled and targeted drug delivery.     

Carrier‐Free Delivery of Precise Drug–Chemogene Conjugates for Synergistic Treatment of Drug‐Resistant Cancer

Combinatorial antitumor therapies using different combinations of drugs and genes are emerging as promising ways to overcome drug resistance, which is a major cause for the failure of cancer treatment. However, dramatic pharmacokinetic differences of drugs greatly impede their combined use in cancer therapy, raising the demand for drug delivery systems (DDSs) for tumor treatment. By employing fluorescent dithiomaleimide (DTM) as a linker, we conjugate two paclitaxel (PTX) molecules with a floxuridine (FdU)‐integrated antisense oligonucleotide (termed chemogene) to form a drug–chemogene conjugate. This PTX–chemogene conjugate can self‐assemble into a spherical nucleic acid (SNA)‐like micellular nanoparticle as a carrier‐free DDS, which knocks down the expression of P‐glycoprotein and subsequently releases FdU and PTX to exert a synergistic antitumor effect and greatly inhibit tumor growth.     

Self‐Rolled Polymer Tubes: Novel Tools for Microfluidics,Microbiology, and Drug‐Delivery Systems

Recent work on the fabrication of tubular microstructures via self‐rolling of thin, bilayer polymer films is reviewed. A bending moment in the films arises due to the swelling of one component of the bilayer in a selective solvent. The inner diameters of the tubes vary from hundreds of nanometers to dozens of micrometers. The position of the tubes on the substrate and their length can be preset by photolithographic patterning of the bilayer. Prior to rolling, the bilayers can be exposed to different methods of surface functionalization, providing opportunities for engineering the microtube inner surfaces for use in microfluidic circuits and “microbiological” applications. The self‐rolling approach is promising for the development of novel drug‐ and cell‐delivery systems, as well as for tissue engineering.     

Seed‐Assisted,One‐Pot Synthesis of Hollow Zeolite Beta without Using Organic Structure‐Directing Agents

Hollow aluminosilicate zeolite beta was successfully synthesized by adding CIT‐6, that is, zincosilicate zeolite, which has the same topology as beta, as seeds to the Na‐aluminosilicate gel without the need for organic structure‐directing agents. One important factor in the successful organic structure‐directing agent (OSDA)‐free synthesis of hollow beta crystals is the solubility of the seed crystals in alkaline media. CIT‐6 was less stable than aluminosilicate zeolite beta in alkaline media and the solubility changed depending on whether the crystals were calcined or not. The hollow beta could be obtained by using the uncalcined CIT‐6 seed crystals. The volumes of intra‐crystalline voids were tuned by changing the reaction time and the initial gel compositions, such as the SiO₂/Al₂O₃ and Na₂O/SiO₂ ratios. We estimated that the intra‐crystalline voids were formed through the dissolution of the seed crystals, just after the crystal growth of new beta on the outer surface of the seeds. In addition, new crystal growth toward inside of the void was also observed by TEM. On the basis of the characterization data, such as chemical analysis, N₂‐adsorption/desorption measurements, and TEM observation, a formation mechanism of the intra‐crystalline voids is proposed and discussed.     

Mobility of Green Fluorescent Protein in Hydrogel‐Based Drug‐Delivery Systems Studied by Anisotropy and Fluorescence Recovery After Photobleaching

Modified hydroxyethyl starch is photo‐crosslinked in the presence of a green fluorescent protein (GFP) (mTagGFP) to obtain loaded hydrogels as model for a drug‐delivery system. An important factor for the protein release is the crosslinking density since a dense network should lead to hindered diffusion. To obtain information on the rotational and translational diffusion of GFP in the hydrogel, mTagGFP is analyzed by fluorescence anisotropy and fluorescence recovery after photo‐bleaching experiments using two‐photon excitation. The mTagGFP shows a viscosity‐retarded rotational and strongly hindered translational diffusion, depending on the polymer concentration. A comparison of anisotropy studies with mTagGFP‐loaded microparticles and hydrogel disks allows the polymer concentration to be determined for the microparticles, which has been previously unknown.

     

Pentafluorophenyl Ester‐based Polymersomes as Nanosized Drug‐Delivery Vehicles

In this work, activated ester chemistry is employed to synthesize biocompatible and readily functionalizable polymersomes. Via aminolysis of pentafluorophenyl methacrylate‐based precursor polymers, an N‐(2‐hydroxypropyl) methacrylamide (HPMA)‐analog hydrophilic block is obtained. The precursor polymers can be versatile functionalized by simple addition of suitable primary amines during aminolysis as demonstrated using a fluorescent dye. Vesicle formation is proven by cryoTEM and light scattering. High encapsulation efficiencies for hydrophilic cargo like siRNA are achieved using dual centrifugation and safe encapsulation is demonstrated by gel electrophoresis. In vitro studies reveal low cytotoxicity and no protein adsorption‐induced aggregation in human blood serum occurs, making the vesicles interesting candidates as nanosized drug carriers.

     

Multifunctional Core‐Shell‐Corona‐Type Polymeric Micelles for Anticancer Drug‐Delivery and Imaging

We have developed core‐shell‐corona‐type polymeric micelles that can integrate multiple functions in one system, including the capability of accommodating hydrophobic dyes into core and hydrophilic drug into the shell, as well as pH‐triggered drug‐release. The neutral and hydrophilic corona sterically stabilizes the multifunctional polymeric micelles in aqueous solution. The mineralization of calcium phosphate (CaP) on the PAA domain not only enhances the diagnostic efficacy of organic dyes, but also works as a diffusion barrier for the controlled release.     

Advances in Exosomes‐Based Drug Delivery Systems

Exosomes, a subgroup of extracellular vesicles, are important mediators of long‐distance intercellular communication and are involved in a diverse range of biological processes such as the transport of lipids, proteins, and nucleic acids. Researchers, seeing the problems caused by the toxic effects and clearance of synthetic nanoparticles, consider exosomes as an interesting alternative to such nanoparticles in the specific and controlled transport of drugs. In recent years, there have been remarkable advances in the use of exosomes in cancer therapeutics or for treating neurological diseases, among other applications. The objective of this work is to analyze studies focused on exosomes used in drug delivery system, present and future applications in this field of research are discussed based on the results obtained.     

Formation of a Single‐Crystal Aluminum‐Based MOF Nanowire with Graphene Oxide Nanoscrolls as Structure‐Directing Agents

An innovative strategy is proposed to synthesize single‐crystal nanowires (NWs) of the Al³⁺ dicarboxylate MIL‐69(Al) MOF by using graphene oxide nanoscrolls as structure‐directing agents. MIL‐69(Al) NWs with an average diameter of 70±20 nm and lengths up to 2 μm were found to preferentially grow along the [001] crystallographic direction. Advanced characterization methods (electron diffraction, TEM, STEM‐HAADF, SEM, XPS) and molecular modeling revealed the mechanism of formation of MIL‐69(Al) NWs involving size‐confinement and templating effects. The formation of MIL‐69(Al) seeds and the self‐scroll of GO sheets followed by the anisotropic growth of MIL‐69(Al) crystals are mediated by specific GO sheets/MOF interactions. This study delivers an unprecedented approach to control the design of 1D MOF nanostructures and superstructures.     

Hierarchical Hollow Hydroxyapatite Microspheres: Microwave‐Assisted Rapid Synthesis by Using Pyridoxal‐5′‐Phosphate as a Phosphorus Source and Application in Drug Delivery

Three‐dimensional (3D) hydroxyapatite (HAP) hierarchical nanostructures, in particular hollow nanostructures, have attracted much attention owing to their potential applications in many biomedical fields. Herein, we report a rapid microwave‐assisted hydrothermal synthesis of a variety of hydroxyapatite hierarchical nanostructures that are constructed by the self‐assembly of nanorods or nanosheets as the building blocks, including HAP nanorod‐assembled hierarchical hollow microspheres (HA‐NRHMs), HAP nanorod‐assembled hierarchical microspheres (HA‐NRMs), and HAP nanosheet‐assembled hierarchical microspheres (HA‐NSMs) by using biocompatible biomolecule pyridoxal‐5′‐phosphate (PLP) as a new organic phosphorus source. The PLP molecules hydrolyze to produce phosphate ions under microwave‐hydrothermal conditions, and the phosphate ions react with calcium ions to form HAP nanorods or nanosheets; then, these nanorods or nanosheets self‐assemble to form 3D HAP hierarchical nanostructures. The preparation method reported herein is time‐saving, with microwave heating times as short as 5 min. The HA‐NRHMs consist of HAP nanorods as the building units, with an average diameter of about 50 nm. The effects of the experimental conditions on the morphology and crystal phase of the products are investigated. The hydrolysis of PLP under microwave‐hydrothermal conditions and the important role of PLP in the formation of 3D HAP hierarchical nanostructures are investigated and a possible formation mechanism is proposed. The products are explored for potential applications in protein adsorption and drug delivery. Our experimental results indicate that the HA‐NRHMs have high drug/protein‐loading capacity and sustained drug‐release behavior. Thus, the as‐prepared HA‐NRHMs are promising for applications in drug delivery and protein adsorption.     

Near‐Infrared‐Controlled,Targeted Hydrophobic Drug‐Delivery System for Synergistic Cancer Therapy

Hydrophobicity has been an obstacle that hinders the use of many anticancer drugs. A critical challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. In this study, we have developed a targeted near‐infrared (NIR)‐regulated hydrophobic drug‐delivery platform based on gold nanorods incorporated within a mesoporous silica framework (AuMPs). Upon application of NIR light, the photothermal effect of the gold nanorods leads to a rapid rise in the local temperature, thus resulting in the release of the entrapped drug molecules. By integrating chemotherapy and photothermotherapy into one system, we have studied the therapeutic effects of camptothecin‐loaded AuMP‐polyethylene glycol‐folic acid nanocarrier. Results revealed a synergistic effect in vitro and in vivo, which would make it possible to enhance the therapeutic effect of hydrophobic drugs and decrease drug side effects. Studies have shown the feasibility of using this nanocarrier as a targeted and noninvasive remote‐controlled hydrophobic drug‐delivery system with high spatial/temperal resolution. Owing to these advantages, we envision that this NIR‐controlled, targeted drug‐delivery method would promote the development of high‐performance hydrophobic anticancer drug‐delivery system in future clinical applications.     

Thermosensitive Micelles Based on Folate‐Conjugated Poly(N‐vinylcaprolactam)‐block‐Poly(ethylene glycol) for Tumor‐Targeted Drug Delivery

Thermosensitive PNVCL‐b‐PEG block copolymer coupled with folic acid was prepared as an anti‐cancer drug carrier. This polymer self‐assembled into stable micelles in aqueous solutions at above 33 °C. At 37 °C, the release profile of PNVCL‐b‐PEG‐FA micelles showed a slower and more controlled release of the entrapped 5‐FU than that at 25 °C. The blank and 5‐FU‐loaded PNVCL‐b‐PEG‐FA micelles did not induce remarkable cytotoxicity against the EA.hy 926 human endothelial cell line; however, 5‐FU‐loaded PNVCL‐b‐PEG‐FA micelles showed a cytotoxicity effect against 4T1 mouse mammary carcinoma cells due to the availability of loaded anti‐cancer drugs delivered to the inside of the cancer cells by the folate‐receptor‐mediated endocytosis process.

     

Stimuli Responsive Scaffolds Based on Carboxymethyl Starch and Poly(2‐Dimethylaminoethyl Methacrylate) for Anti‐Inflammatory Drug Delivery

The purpose of the study is to obtain multicomponent polyelectrolyte hydrogels with optimal synergistic properties by combining a modified starch with a synthetic one. Thus, new low‐cost and biocompatible semi‐interpenetrating polymer network (semi‐IPN) hydrogels of carboxymethyl starch and poly(2‐dimethylaminoethyl methacrylate) are prepared and investigated. The synthesized hydrogels are studied with respect to the specific characteristics of the gels: swelling kinetics, thermal analysis, viscoelastic characteristics, and their ability to be used as a matrix in drug delivery systems. Therefore, the semi‐IPN gels are loaded with ibuprofen, followed by additional tests to assess the in vitro drug release. The cytocompatibility of the hydrogels with respect to their composition is evaluated in vitro on fibroblast cell culture. The investigations confirm the obtainment of new semi‐IPN hydrogels with pH and temperature responsiveness, good mechanical strength, and potential for use as drug delivery systems or transdermal patches.     

A Trimodal Closomer Drug‐Delivery System Tailored with Tracing and Targeting Capabilities

The construction and application of a unique monodisperse closomer drug‐delivery system (CDDS) integrating three different functionalities onto an icosahedral closo‐dodecaborane [B₁₂]^2? scaffold is described. Eleven B‐OH vertices of [closo‐B₁₂(OH)₁₂]^2? were used to attach eleven copies of the anticancer drug chlorambucil and the targeting vector glucosamine through a bifurcating lysine linker. The remaining twelfth vertex was used to attach a fluorescent imaging probe. The presence of multiple glucosamine units offered a monodisperse and highly water‐soluble CDDS with a high payload of therapeutic cargo. This array enhanced the penetration of the drug into cancer cells by exploiting the overexpression of GLUT‐1 receptors present on cancer cells. About 15‐fold enhancement in cytotoxicity was observed for CDDS‐1 against Jurkat cells, compared to CDDS‐2, which lacks the GLUT‐1 targeting glucosamine. A cytotoxicity comparison of CDDS‐1 against colorectal RKO cells and its GLUT‐1 knock‐out version confirmed that GLUT‐1 mediates endocytosis. Using fluorescent markers both CDDS‐1 and ‐2 were traced to the mitochondria, a novel target for alkylating agents.     

Controlled Synthesis of Ultrathin Lanthanide Oxide Nanosheets and Their Promising pH‐Controlled Anticancer Drug Delivery

Various lanthanide oxides (Sm₂O₃ and Gd₂O₃) nanostructures were synthesized by a facile hydrothermal method. The loss of surfactants on the nanocrystals surface, followed by the resultant assembly is responsible for the formation of ultrathin nanosheets. Owing to strong surface effects, the different morphologies of the Sm₂O₃:5 % Eu and Gd₂O₃:5 % Eu nanocrystals present unique photoluminescence properties. As a proof‐of‐concept application, the as‐obtained Sm₂O₃ and Gd₂O₃ ultrathin nanosheets exhibit promising pH‐controlled anticancer drug‐delivery behavior.