pH-responsive Properties Research Articles

Self-Assembly of Amphiphilic Compounds as a Versatile Tool for Construction of Nanoscale Drug Carriers.

This review focuses on synthetic and natural amphiphilic systems prepared from straight-chain and macrocyclic compounds capable of self-assembly with the formation of nanoscale aggregates of different morphology and their application as drug carriers. Since numerous biological species (lipid membrane, bacterial cell wall, mucous membrane, corneal epithelium, biopolymers, e.g., proteins, nucleic acids) bear negatively charged fragments, much attention is paid to cationic carriers providing high affinity for encapsulated drugs to targeted cells. First part of the review is devoted to self-assembling and functional properties of surfactant systems, with special attention focusing on cationic amphiphiles, including those bearing natural or cleavable fragments. Further, lipid formulations, especially liposomes, are discussed in terms of their fabrication and application for intracellular drug delivery. This section highlights several features of these carriers, including noncovalent modification of lipid formulations by cationic surfactants, pH-responsive properties, endosomal escape, etc. Third part of the review deals with nanocarriers based on macrocyclic compounds, with such important characteristics as mucoadhesive properties emphasized. In this section, different combinations of cyclodextrin platform conjugated with polymers is considered as drug delivery systems with synergetic effect that improves solubility, targeting and biocompatibility of formulations.

In situ assembly of Mt-HAP drug carrier with pH-responsive sustained release properties

The Mt-HAP composites were achieved by combining layered montmorillonite (Mt) and hydroxyapatite (HAP) nanoparticles produced by in situ assembly technique. Amoxicillin (AMX) loading and release experiment proved that the synthetic Mt-HAP composites demonstrated high drug loading ability and pH-responsive sustained release property. The AMX load of original Mt was 18.5 mg g−1, while that of Mt-HAP grew to 49.1 mg g−1. Experiments in simulated gastric fluid (pH 1.2) release indicated that Mt drug carrier having a higher release rate of AMX within the initial 2 h. But after that, the drug release rate of AMX from Mt-HAP has a greater value (about 65% over 12 h) than that of Mt (about 50% over 12 h) because of the dissolution of HAP under acidic circumstance. However, the cumulative sustained release rate of Mt-HAP in simulated intestinal fluid (pH 6.8) over 12 h was only 30%, and the drug release amount of Mt was still about 49%. Compared to Mt@AMX, the drug release rate of Mt-HAP @ AMX is sensitive to changes in pH. The findings claimed that the Mt-HAP composite exhibited extreme potential as a drug carrier for controllable drug delivery.

PH-responsive SERS substrates based on AgNP-polyMETAC composites on patterned self-assembled monolayers

Patterned silver nanoparticle (NP)-poly[2-(methacryloyloxy)ethyl] trimethyl ammonium chloride (AgNP-polyMETAC) composites were prepared by electrochemical lithography, surface-initiated atom-transfer radical polymerization (SI-ATRP) and NP growth inside the polymer brushes. For this purpose, polymer brushes of poly[2-(methacryloyloxy)ethyl] trimethyl ammonium chloride (polyMETAC) were utilized as strong electrolyte brush system. These were introduced in form of patterned polymer brushes to create pH-responsive surface enhanced Raman scattering SERS substrates. It is well-known that the charges of strong polyelectrolyte chains are usually insensitive to pH changes, hence, rarely strong polyelectrolyte brushes have been utilized so far to study pH-responsive properties of such films. Here pH-insensitive polyMETAC brushes exhibit pH-sensitive properties and can be used as pH-responsive surfaces for SERS applications due to the embedding of AgNPs into the polymer brushes. When increasing the pH, the assembly of the AgNPs transfers from quasi two-dimensional (2D) aggregates, attaching mainly to the polymer surface, into a three-dimensional (3D) assembly, where the particles are penetrating into the brushes. These changes result in significant alterations of the SERS efficiency of the polymer brush composite. At pH 5, the enhancement of the Raman scattering approaches its maximum. The fabricated SERS substrates show a high sensitivity as well as good experimental reliability at different pH values. Moreover, electrochemical lithography was utilized to fabricate patterned SERS substrate, which allows an easy combination of multiple other functionalities in hierarchical structuring steps. In addition, the microstructure is in our studies beneficial because of a simplified and reliable characterization of the polymer brushes at defined sample areas. The introduction of the microstructured brush system is regarded moreover attractive for the development of high-throughput platforms for rapid, automated screening and analysis applications.

Preparation and Characterization of Zein-Based Nanoparticles via Ring-Opening Reaction and Self-Assembly as Aqueous Nanocarriers for Pesticides.

Herein, we prepared and compared two water-soluble amphiphilic zein-based nanocarrier systems with avermectin (AVM) payload to enhance pesticide's water-dispersity, foliage wettability, adhesion, anti-UV, and pH-responsive controlled release property. Ethylene glycol diglycidyl ether (EGDE) and diethanolamine (DEA) were utilized to conjugate with hydrophobic zein via a ring-opening reaction and then encapsulated with AVM via a hydrophobic interaction to fabricate a nanopesticide marked as AVM@Zein-EGDE/DEA. For the sake of further improving the nanocarrier's performance, sodium carboxymethyl cellulose (CMC) was grafted with methyl methacrylate (MMA) and 2-hydroxyethyl methacrylate (HEMA) to form a kind of copolymer CMC-g-P(HEMA-MMA), which was applied to conjugate with Zein-EGDE via a ring-opening reaction. Likewise, another nanopesticide system named AVM@Zein-EGDE/CMC-g-P(HEMA-MMA) was obtained through hydrophobic interactions as well as the electrostatic effect. Various techniques were utilized to confirm chemical interaction, thermal behavior, structural characteristics, and stability. The results showed that AVM encapsulated in Zein-EGDE/CMC-g-P(HEMA-MMA) possessed a larger particle size with an average value of 180-254 nm than AVM loaded in Zein-EGDE/DEA with 144-175 nm but had better stability in aqueous solution. Also, AVM loaded in Zein-EGDE/CMC-g-P(HEMA-MMA) enhanced the encapsulation efficiency, and both of them exhibited excellent pH-responsive sustained release behavior. Besides, the former improved wettability on a cucumber leaf surface and enhanced adhesion ability compared to AVM@Zein-EGDE/DEA because of CMC-g-P(HEMA-MMA) with hydrophobic segments. Similarly, anti-UV performance was also enhanced owing to CMC-g-P(HEMA-MMA) as an additional protective layer. More importantly, the encapsulation of Zein-EGDE/DEA and Zein-EGDE/CMC-g-P(HEMA-MMA) as protective barriers for AVM still retained a similar toxicity level. Overall, we demonstrated the proof of concept for the application of amphiphilic zein-based nanomaterials as aqueous nanocarriers for hydrophobic pesticides.

Engineering polyzwitterion with acylsulfonamide-based betaine structure for protonated switch of surface chemistry at tumoral pH and reductive responsive drug release of polymeric micelles

The surface chemistry of stimulus-responsive nanoparticles plays an important role in mediating nano-bio interactions in cancer nanomedicine by targeting the unique features of the tumor microenvironment, such as low extracellular pH. To develop therapeutic nanoparticles with high sensitivity and instant response to slight pH differences in the systemic circulation, we produced a novel polyzwitterion with acylsulfonamide-based betaine structure by one-step modification of polycarboxybetaine (PCB) with benzene sulfonamide. The zwitterionic micellar shells show high antifouling in the blood circulation and acutely convert into positive charge via acylsulfonamide protonation, thereby improving cell affinity at tumor sites. Moreover, a disulfide bond between the shell and poly-ε-caprolactone (PCL) core allows for reductive-responsive release of doxorubicin (DOX) after internalization of the polymeric micelles. Finally, in vitro and in vivo competition assays demonstrated that dual responsive drug-loaded micelles have better anticancer efficiency than free DOX or micelles without zwitterionic pH-responsive properties. Thus, we have developed a simple and valuable strategy to enhance pH sensitivity of micellar carriers for cancer treatment.

Asymmetric modification of cellulose nanocrystals with PAMAM dendrimers for the preparation of pH-responsive hairy surfaces

In this work, we present a straightforward method to attach a globular dendrimer at the reducing end of cellulose nanocrystals obtained from tunicates (t-CNC). We investigated the first four generations of poly(amidoamine) dendrimers (PAMAMs G0 to G3) to obtain hybrid t-CNCs. The aggregation behavior of hybrid t-CNCs was studied by dynamic light scattering (DLS) and scanning transmission electron microscopy (STEM); and interactions of these asymmetric nanoparticles with gold surface were elucidated using quartz crystal microbalance with dissipation (QCM-D) and surface plasmon resonance (SPR). Hybrid t-CNCs formed hairy layers onto gold surface combining the properties of rigid rod-like nanocrystals with globular and flexible PAMAM dendrimers. Moreover, the presence of amino groups provided pH-responsive properties to hybrid t-CNCs, and QCM-D results revealed reversible swelling/deswelling behavior. Thereby, we achieved to synthesize tree-shaped functional bio-based materials that adsorbed on gold and formed pH-responsive hairy surfaces.

Biodegradable cationic nanogels with tunable size, swelling and pKa for drug delivery.

Cationic polymers have garnered significant interest for their utility in intracellular drug delivery and gene therapy. However, due to their associated toxicities, novel synthesis approaches must be explored to develop materials that are biocompatible. The novel library of nanoparticles synthesized in this study exhibit tunable hydrodynamic diameters, composition and pH-responsive properties as a function of synthesis parameters. In addition, differences in the responsiveness of these nanoparticles under different pH conditions affords greater control over intracellular drug release.

Preparation and properties of thermo- and pH-responsive polypeptide bearing OEG and aldehyde pendants

OEGylated polypeptide bearing triethylene glycol monomethylether (OEG3) and poly(ethylene glycol) methyl ether 350 (OEG7) were first prepared by copper-mediated 1,3-dipolar cycloaddition. 1H NMR, FTIR, and GPC results indicated the successful conjugation of oligo(ethylene glycol) (OEG) pendants with high grafting efficiency (≥ 98%). Variable temperature UV–vis spectroscopy revealed a reversible lower critical solution temperature (LCST)-type phase transition of the resulting polypeptides. The LCST-type cloud point temperature (Tcp) in the range of 20–60 °C can be readily tuned by changing the OEG3 and OEG7 composition. Thermo- and pH-responsive polypeptide was prepared by first conjugating of OEG and 6-aldehyde hexyl pendants, then crosslinking in the presence of 1,6-hexanediamine, yielding OEGylated polypeptide bearing pH-labile imine bonds. The resulting polypeptide showed pH-responsive property and less pronounced thermoresponsive property at high pH values (i.e., ≥ 6.15) and noticeable thermo- and pH- dual responsive properties at low pH values (i.e., ≤ 5.80).

Designing, structural determination and biological effects of rifaximin loaded chitosan- carboxymethyl chitosan nanogel

Due to the poor solubility and permeability of rifaximin (RFX), it is not effective against intracellular pathogens although it shows strong activity against most bacteria. To develop an effective mucoadhesive drug delivery system with a targeted release in bacterial infection site, RFX-loaded chitosan (CS)/carboxymethyl-chitosan (CMCS) nanogel was designed and systematically evaluated. FTIR, DSC, and XRD demonstrated that the nanogel was formed by interactions between the positively charged NH3+ on CS and CMCS, and the negatively charged COO on CMCS. RFX was encapsulated into the optimized nanogel in amorphous form. The nanogel was a uniform spherical shape with a mean diameter of 171.07 nm. It had excellent sustained release, strong mucin binding ability, and pH-responsive properties of quicker swelling and release at acidic pH. It showed low hemolytic ratio and high antioxidant activity. The present investigation indicated that the CS-nanogel could be potentially used as a promising bacterial responsiveness drug delivery system.

Copper nanoclusters@Al3+ complexes with strong and stable aggregation-induced emission for application in enzymatic determination of urea.

The aggregates of glutathione-capped CuNCs induced by Al3+ (named CuNCs@Al3+ complexes) show a stable aggregation-induced emission (AIE) for about 1month. Their fluorescence maintains a high level in the pH range 4.0 to 7.0, while it quenches as pH increases from 7.0 to 7.7 or decreases from 4.0 to 3.0. Under urease-catalyzed hydrolysis, urea produces ammonia, which can be further hydrolyzed to yield OH-. This leads to a pH increase of the immediateenvironment. Hence, the CuNCs@Al3+ complexes are asuitable probe to determine urea. The fluorescence of CuNCs@Al3+ complexes quenches linearly at 585nm with the excitation wavelength at 340nm when the concentration of urea increases from 20 to 150μM. The limit of detection (LOD) of urea is 5.86μM. This sensitivity is superior to other reported works due to the narrow pH response range of CuNCs@Al3+ complexes. This method has been successfully applied for measuring urea in human urine samples with satisfactory recoveries. Graphic abstract Schematic representation of urea determination based on pH-responsive property of copper nanoclusters@Al3+ complexes. Ammonia is produced in the hydrolysis of urea by urease, and it is further hydrolyzed to yield OH-, leading to increasing pH of the environment.

Biomimetic synthesis of vaterite CaCO3 microspheres under threonine for preparation of pH-responsive antibacterial biofilm

Abstract

PH-Responsive Properties of Asymmetric Nanopapers of Nanofibrillated Cellulose.

Inspired by plant movements driven by the arrangement of cellulose, we have fabricated nanopapers of nanofibrillated cellulose (NFC) showing actuation under pH changes. Bending was achieved by a concentration gradient of charged groups along the film thickness. Hence, the resulting nanopapers contained higher concentration of charged groups on one side of the film than on the opposite side, so that pH changes resulted in charge-dependent asymmetric deprotonation of the two layers. Electrostatic repulsions separate the nanofibers in the nanopaper, thus facilitating an asymmetric swelling and the subsequent expanding that results in bending. Nanofibrillated cellulose was modified by 2,2,6,6-tetramethylpiperidin-1-yloxyl radical (TEMPO) oxidation at two reaction times to get different surface concentrations of carboxylic acid groups. TEMPO-oxidized NFC was further chemically transformed into amine-modified NFC by amidation. The formation of graded nanopapers was accomplished by successive filtration of NFC dispersions with varying charge nature and/or concentration. The extent of bending was controlled by the charge concentration and the nanopaper thickness. The direction of bending was tuned by the layer composition (carboxylic acid or amine groups). In all cases, a steady-state was achieved within less than 25 s. This work opens new routes for the use of cellulosic materials as actuators.

Improved Gastric Acid Resistance and Adhesive Colonization of Probiotics by Mucoadhesive and Intestinal Targeted Konjac Glucomannan Microspheres

AbstractThe low survival rate in harsh stomach conditions and short retention in intestine of probiotics greatly limit their health benefits. To solve this problem, thiolated oxidized konjac glucomannan (sOKGM) microspheres is designed with pH responsive and mucoadhesive properties. First, an increased survival rate of probiotics by sOKGM microspheres encapsulation in simulated gastric fluid (SGF) is discovered in contrast to the zero‐survival rate of naked probiotics. sOKGM/probiotics even show a higher survival rate in SGF compared with commercial Bb12 formulation. Further, an enhanced mucoadhesion of probiotics to intestinal mucus by mediated interactions with sOKGM is confirmed by isotherm titration calorimetry, rheology, and tensile measurements. The in vivo intestinal transition experiment indicates a prolonged retention of probiotics at intestine by sOKGM encapsulation. Moreover, in vivo evaluation of enhanced colonization and proliferation by sOKGM/probiotics is demonstrated by the fecal and intestinal bacteria copy number via quantitative polymerase chain reaction (qPCR) detection. Further investigation of the alleviation of constipation by sOKGM containing Bifidobacterium animalis subsp. lactis A6 suggests that sOKGM increases the abundance of Bifidobacterium, balanced intestinal flora, and alleviated constipation in mice compared with other formulations. sOKGM with both enhanced gastric acid resistance and adhesion colonization at intestine can effectively improve the function of probiotics.

Self-Assembled Supramolecular Micelles with pH-Responsive Properties for More Effective Cancer Chemotherapy.

pH-Responsive hydrogen-bonded supramolecular micelles, composed of a water-soluble poly(ethylene glycol) polymer with two terminal sextuple hydrogen bonding groups, can spontaneously organize in aqueous media to give well-defined, uniformly sized spherical micelles. The supramolecular micelles exhibit a number of unique physical characteristics, such as interesting amphiphilic behavior, desirable micellar size and nanospherical morphology, excellent biocompatibility, tailorable drug-loading capacities, and high structural stability in media containing serum or red blood cells. In addition, the drug release kinetics of drug-loaded micelles can be easily manipulated to achieve the desired release profile by regulating the environmental pH, thus these micelles are highly attractive candidates as an intelligent drug carrier system for cancer therapy. Cytotoxicity assays showed that the drug-loaded micelles induced pH-dependent intracellular drug release and exerted strong antiproliferative and cytotoxic activities toward cancer cells. Importantly, cellular uptake and flow cytometric analyses confirmed that a mildly acidic intracellular environment significantly increased cellular internalization of the drug-loaded micelles and subsequent drug release in the cytoplasm and nucleus of cancer cells, resulting in more effective induction of apoptotic cell death. Thus, this system may provide an efficient route toward achieving the fundamental properties and practical realization of pH-sensitive drug-delivery systems for chemotherapy.

Novel Self-Healing Hydrogel with Injectable, pH-Responsive, Strain-Sensitive, Promoting Wound-Healing, and Hemostatic Properties Based on Collagen and Chitosan.

Collagen (COL)-chitosan (CS) composite hydrogels are attracting increasing attention because of their great potential for application as biomaterials. However, conventional COL-CS hydrogels were easily disabled for lack of fully reversible linking in their networks. In this work, we developed a kind of self-healing hydrogel for wound dressing, composed of COL, CS, and dibenzaldehyde-modified PEG2000 via dynamic imine bonds, and the COL/CS hydrogels showed good thermal stability, injectability, and pH sensitivity, ideally promoting wound-healing performance and hemostatic ability. Furthermore, the hydrogel could monitor multiple human motions, especially the facial expression via strain sensitivity. This work offers a new perspective for the biomass-based hydrogels applied in medical field as wound dressing.

A novel biodegradable Mg-1Zn-0.5Sn alloy: Mechanical properties, corrosion behavior, biocompatibility, and antibacterial activity

To meet the growing demand for antibacterial implants for bone-implant-associated infection therapy and avoid the adverse effects of secondary surgery, a degradable platform with pH responsiveness and ion-associated antibacterial properties was constructed. A small amount of Sn added to Mg-1Zn alloy reduces the biocorrosion rate, which can be attributed to Sn participation in outer-layer film formation, significantly reducing the biocorrosion rate and hydrogen evolution rate after implantation in vivo . These Mg alloys, which are susceptible to degradation in the acidic bacterial microenvironment, degrade by releasing Mg, Zn and Sn, producing favorably alkaline and antibacterial conditions. Samples with the composition of Mg-1Zn-0.5Sn were found to be beneficial for promoting initial cell adhesion and proliferation, resulting in improved biocompatibility and biosafety. The biocompatibility of this alloy was confirmed by the healthy behavior of animals and the absence of acute or chronic toxicity in the liver, spleen, and kidneys. Our results demonstrate that Mg-1Zn-0.5Sn is safe for biological systems, enabling its efficacious use in biomedical applications.

Oxygen Self-Sufficient Core-Shell Metal-Organic Framework-Based Smart Nanoplatform for Enhanced Synergistic Chemotherapy and Photodynamic Therapy.

The abnormal angiogenesis and insufficient oxygen supply in solid tumors lead to intratumoral hypoxia, which severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a multifunctional nanoplatform (ZDZP@PP) based on a zeolitic imidazolate framework-67 (ZIF-67) core as a hydrogen peroxide catalyst, a zeolitic imidazolate framework-8 (ZIF-8) shell with a pH-responsive property, and a polydopamine-poly(ethylene glycol) (PDA-PEG) layer for improving the biocompatibility is fabricated for not only relieving tumor hypoxia but also enhancing the efficacy of combination chemo-photodynamic therapy. The chemotherapy drug doxorubicin (DOX) and photosensitizer protoporphyrin IX (PpIX) are encapsulated in different layers independently; thus, a unique two-stage stepwise release becomes possible. Moreover, the nanoplatform can effectively decompose hydrogen peroxide to produce oxygen and thus relieve tumor hypoxia, which further facilitates the production of cytotoxic reactive oxygen species (ROS) by PpIX under laser irradiation. Both in vitro and in vivo experimental results confirm that the combination chemo-photodynamic therapy with the ZDZP@PP nanoplatform can provide more effective cancer treatment than chemotherapy or PDT alone. Consequently, the oxygen self-sufficient multifunctional nanoplatform holds promising potential to overcome hypoxia and treat solid tumors in the future.

Injectable and Self-Healing Nanocomposite Hydrogels with Ultrasensitive pH-Responsiveness and Tunable Mechanical Properties: Implications for Controlled Drug Delivery.

Injectable, self-healing, and pH-responsive hydrogels are great intelligent drug delivery systems for controlled and localized therapeutic release. Hydrogels that show pH-sensitive behaviors in the mildly acidic range are ideal to be used for the treatment of regions showing local acidosis like tumors, wounds and infections. In this work, we present a facile preparation of an injectable, self-healing, and supersensitive pH-responsive nanocomposite hydrogel based on Schiff base reactions between aldehyde-functionalized polymers and amine-modified silica nanoparticles. The hydrogel shows fast gelation within 10 s, injectability, and rapid self-healing capability. Moreover, the hydrogel demonstrates excellent stability under neutral physiological conditions, while a sharp gel-sol transition is observed, induced by a faintly acidic environment, which is desirable for controlled drug delivery. The pH-responsiveness of the hydrogel is ultrasensitive, where the mechanical properties, hydrolytic degradation, and drug release behaviors can alter significantly when subjected to a slight pH change of 0.2. Additionally, the hydrogel's mechanical and pH-responsive properties can be readily tuned by its composition. Its excellent biocompatibility is confirmed by cytotoxicity tests toward human dermal fibroblast cells (HDFa). The novel injectable, self-healing, and sensitive pH-responsive hydrogel serves as a promising candidate as a localized drug carrier with controlled delivery capability, triggered by acidosis, holding great promise for cancer therapy, wound healing, and infection treatment.

Green Synthesis of Superior Molecular Fluorophores from Chitosan Assisted with Cellulase for Cell Nucleus Imaging and Photosensitive Printing

In this study, a facile and green route was designed using hydrolyzed chitosan as precursor to fabricate superior molecular state fluorophores based on the Maillard reaction (MR). The fluorophores exhibit excitation-dependent photoluminescence behavior, emitting multicolor fluorescence. The CCK-8 assay shows the low cytotoxicity of the Maillard reaction products (MRPs). The properties of the MRPs were associated with the molecular size. The high-molecular-weight fraction (>10 kDa) contains a large quantity of brown products which cause fluorescence quenching by an inner-filter effect. The medium-molecular-weight fraction (5–10 kDa) is able to permeate into the living cells and specifically stains the nucleus for stable imaging. The low-molecular-weight fraction (<3 kDa) possesses a dramatically high quantum yield of 30.4% and excellent ion stability, as well as a pH-responsive property; it can serve as a potential pH sensor and fluorescent ink for photosensitive printing. The potential applications of MRPs fractions in different fields are proposed, significantly improving the utilization efficiency. Additionally, this work provides a new perspective on designing and preparing large-scale metal-free fluorescence materials with high safety and good water solubility in a green and mild manner.

Super-assembled core-shell mesoporous silica-metal-phenolic network nanoparticles for combinatorial photothermal therapy and chemotherapy

Multimodal combinatorial therapy merges different modes of therapies in one platform, which can overcome several clinical challenges such as premature drug loss during blood circulation and significantly improve treatment efficiency. Here we report a combinatorial therapy nanoplatform that enables dual photothermal therapy and pH-stimulus-responsive chemotherapy. By super-assembly of mesoporous silica nanoparticles (MSN) with metal-phenolic networks (MPN), anti-cancer drugs can be loaded in the MSN matrix, while the outer MPN coating allows dual photothermal and pH-responsive properties. Upon near-infrared light irradiation, the MSN@MPN nanoplatform exhibits excellent photothermal effect, and demonstrates outstanding pH-triggered drug release property. In vitro cell experiments suggest the MSN@MPN system exhibits superior biocompatibility and can effectively kill tumor cells after loading anti-cancer drugs. Consequently, the MSN@MPN system shows promising prospects in clinical application for tumor therapy.