pH-responsive Molecule Research Articles

Development of pH-Responsive Hyaluronic Acid-Conjugated Cyclodextrin Nanoparticles for Chemo-/CO-Gas Dual Therapy.

In this study, we fabricated γ-cyclodextrin (γCD)-based nanoparticles (NPs) for dual antitumor therapy. First, γCD (the backbone biopolymer) was chemically conjugated with low-molecular-weight hyaluronic acid (HA; a tumoral CD44 receptor-targeting molecule) and 3-(diethylamino)propylamine (DEAP; a pH-responsive molecule), termed as γCD-(DEAP/HA). The obtained γCD-(DEAP/HA) self-assembled in aqueous solution, producing the γCD-(DEAP/HA) NPs. These NPs efficiently entrapped paclitaxel (PTX; an antitumor drug) and triiron dodecacarbonyl (FeCO; an endogenous cytotoxic gas molecule) via hydrophobic interactions between PTX and FeCO with the unprotonated DEAP molecules in γCD-(DEAP/HA) and a possible host-guest interaction in the γCD rings. The release of PTX and FeCO from the NPs resulted from particle destabilization at endosomal pH, probably owing to the protonation of DEAP in the NPs. In vitro studies using MCF-7 tumor cells demonstrated that these NPs were efficiently internalized by the cells expressing CD44 receptors and enhanced PTX/FeCO-mediated tumor cell apoptosis. Importantly, local light irradiation of FeCO stimulated the generation of cytotoxic CO, resulting in highly improved tumor cell death. We expect that these NPs have potential as dual-modal therapeutic candidates with enhanced antitumor activity in response to acidic pH and local light irradiation.

Dual-responsive shape memory polymer arrays with smart and precise multiple-wetting controllability

Smart-controlled surface wettability from superhydrophilicity to superhydrophobicity has been extensively explored, and stimulus-responsive strategies have been widely accepted as a useful method to realize reversibility. However, achieving smart and precise wetting control remains challenging because most previous studies focused on stimulating single surface chemistry or microstructures. Herein, a dual-stimulus-responsive strategy that can synergistically stimulate surface chemistry and microstructures is demonstrated on the pH-responsive molecule poly(2-(diisopropylamino)ethyl methacrylate (PDPAEMA)-modified temperature-triggered shape memory polymer (SMP) arrays. The responsive PDPAEMA and SMP can provide the surface with tunable surface chemistry and microstructures, respectively. Thus, the wetting of the surface between various states can be reversibly and precisely controlled from superhydrophilicity to superhydrophobicity with contact angle (CA) differences of less than 15° under the cooperative effect between the adjustable surface microstructure and chemistry. The surface is further utilized as a platform to create gradient wettings based on its excellent controllability. Therefore, this work presents a strategy for surface wetting control by combining tunable surface microstructures and chemistry. The prepared samples with a special wetting controllability can be applied to numerous fields, including adaptive liquid microlenses, accurate drug release, and selective catalysis. This work also proposes novel expectations in designing smart functional surfaces.

A pH-responsive bioassay for sensitive colorimetric detection of adenosine triphosphate based on switchable DNA aptamer and metal ion–urease interactions

A facile and economic colorimetric strategy was designed for ATP detection by rationally using urease, a pH-responsive molecule, and a metal-mediated switchable DNA probe. By utilizing metal ions as a modulator of urease activity, the concentration of ATP is translated into pH change, which can be readily visualized by naked eye. An unmodified single-stranded DNA probe was designed, which consists of a target binding sequence and two flanked cytosine (C)-rich sequences. This C-rich single-stranded DNA can form a hairpin structure triggered by Ag+ ions via C-Ag+-C base mismatch. Upon introduction of ATP, Ag+-coordinated hairpin DNA structure will be broken and release the included Ag+, thus inhibiting the activity of urease. Conversely, urease can hydrolyze urea and raise pH value of the solution, resulting in the color change of the sensing solution. The proposed assay allows determination of ATP as low as 1.6nM and shows a satisfactory result in human serum. Because of simple operation and low cost of this method, we believe it has a potential in point-of-care (POC) testing in resource-limited areas. Schematic illustration of pH-responsive colorimetric sensor for ATP detection based on switchable DNA aptamer and metal ion-urease interactions.

Morpholine-Substituted Rhodamine Analogue with Multi-Configurational Switches for Optical Sensing of pH Gradient under Extreme Acidic Environments.

Superior pH-responsive molecules are required for the development of functional materials applicable to advanced molecular technologies. Despite having been widely developed, many rhodamine-based pH-responsive molecules exhibit a single configurational switch for "turn-on". Herein, we report a new type of rhodamine-based pH-responsive molecule with multi-configurational switches displaying stable two-step structural and color conversion in response to pH. This rhodamine analogue could be successfully applied to optical sensing of pH gradient under extreme acidic environments both in solution and on hydrogel through high-contrast color change. We demonstrated that this multi-responsive character enabled optical memory of different pH information.

Au Nanoclusters and Photosensitizer Dual Loaded Spatiotemporal Controllable Liposomal Nanocomposites Enhance Tumor Photodynamic Therapy Effect by Inhibiting Thioredoxin Reductase.

Photodynamic therapy (PDT) is a minimally invasive therapeutic procedure of tumors with high selectivity and low side effect. However, it is usually not efficient in long-lasting tumor control. One of the main reasons is tumor cells develop some protective mechanisms that help them to deal with oxidative stress in the environment. The thioredoxin system in cancer is an important antioxidant defense system. Au nanoclusters could effectively inhibit thioredoxin reductase (TrxR) in tumor cell cytoplasm. Herein, Au nanoclusters and photosensitizer Chlorine 6 (Ce6) are co-loaded in spatiotemporal controllable liposomal nanocomposites. pH responsive molecule inserted in lipid bilayer greatly contributes to the instability of the lipid membrane in lysosomal at low pH environment. Then the payloads can rapidly release into cytoplasm. Au nanoclusters effectively inhibit TrxR in cytoplasm and enhance the photodynamic-induced intracellular reactive oxygen-free radical concentration, improving the effect of PDT. Breast cancer is chosen as a tumor model and the Au nanoclusters and photosensitizer co-loaded liposomal nanocomposites are studied to improve the effect of PDT both in vitro and in vivo, and its corresponding mechanism is investigated. This study develops a new application of gold nanoclusters and provides a new train of thoughts for enhancing the effect of PDT.

Dynamic disordering of liposomal cocktails and the spatio-temporal favorable release of cargoes to circumvent drug resistance

Multidrug resistance (MDR) has been a major impediment to the success of cancer chemotherapy. Extensive efforts have been devoted to the development of drug delivery systems using nanotechnology to reverse MDR in cancer. However, the spontaneous release of drug payloads was always a slow process, which leads to the low intracellular drug concentration resulting in consequent drug insensitivity. To circumvent this limitation, we described a liposomal cocktail (LMDHV) constructed by a pH-responsive molecule (i.e., malachite green carbinol base (MG)) and liposome conjugated with Her-2 antibody for codelivery of doxorubicin (DOX) and verapamil (VER) to suppress drug resistance in Her-2 positive breast cancer. MG inserted in the bilayer as pH responders greatly contributed to the destabilization of the vesicle membrane in low pH, followed by the rapid release of the payloads. LMDHV showed 6-fold reversal efficiency in DOX resistant breast cancer owing to the efficient tumor targeting delivery and rapid burst release of drug intracellularly. Compared to tumor inhibition ratio of treated groups by free DOX (32.4 ± 7.4%), our designed kinetically favorable drug release system exhibited significantly (P < 0.01) enhanced tumor inhibition ratio up to 83.9 ± 12.5%, which is attributed to the remarkably increased drug concentration in cells. The spatio-temporal favorable release of drugs resulted in synergistic inhibition of tumor growth in xenografts. We envision that this new type of liposomal cocktail might be potentially utilized to circumvent drug resistance in the future.

Molecular structural transformation regulated dynamic disordering of supramolecular vesicles as pH-responsive drug release systems

The spontaneous release of drug payloads in the whole body always results in the compromised drug bioavailability and ultimate therapeutic efficacy. To achieve enhanced therapeutic efficacy and reduced side effects, pH-responsive targeted drug delivery systems have been studied due to their enhanced tumor accumulation and controllable maximum drug release feature. The present study described a co-assembly constructed by a pH responsive molecule (i.e., malachite green carbinol base (MG)) and liposome for highly efficient doxorubicin (DOX) release in tumor cells (MG–DOX⊂L). The structural transformation of MG effectively regulates the drug release profile in acidic environment. The pH-responsive sensitivity of co-assembly can be fine-tuned by altering the mixing ratios of building blocks with pH responders (i.e., MG molecules). MG–DOX⊂L was beneficial for the DOX release at pH5.0 and showed a higher cytotoxicity in KB cells owing to the pH-responsive drug release in acidic organelles following endocytosis pathway. In vivo tumor targetability and growth inhibition were evaluated in KB cell-xenografted nude mice. We have demonstrated that effective tumor growth inhibition in vivo is attributed to the synergistic contributions from highly efficient cellular entry and responsive intracellular release of DOX from MG–DOX⊂L.

PH-Wave Propagation in the Microchannel Modified with pH-Responsive Molecule

We have successfully induced pH wave propagation in microchannel by using a mixed reaction solution containing Na2S2O3, KBrO3, and NaOH. The use of microchannel with different channel width made clear that the narrower channel enabled faster pH wave propagation. The observed acceleration effect was discussed in terms of proton diffusion confinement in the microchannel, which would lead an increase in apparent proton production rate. Furthermore, we have succeeded in the generation of waves of structural change of molecules immobilized on the microchannel wall by the pH wave propagation, which enables us to design future micro-devices that can work autonomously without external biases. [DOI: 10.1380/ejssnt.2012.50]

Functionalization of carbon nanotubes with a pH-responsive molecule to produce a pHsensor

Carbon nanotubes were functionalized with the ratiometric pH-responsive dye molecule6,8-dihydroxy-1,3-pyrenedisulfonic acid disodium salt, which enabled them to indicatepH values over the range of pH 5.6–8.3. The nanotubes were coated with a layer ofelectron-donating ZnPc, which strengthened the CNT–dye interaction. The range ofpH response is relevant for biological systems, which makes the nanotubes suitable for awide range of applications within nanobiotechnology.

Improved synthesis of diethyl ferrocenylphosphonate, crystal structure of (FcPO 3Et 2) 2 · ZnCl 2, and electrochemistry of ferrocenylphosphonates, FcP(O)(OR) 2, FcCH 2P(O)(OR) 2, 1,1′-fc[P(O)(OR) 2] 2 and [FcP(O)(OEt) 2] 2 · ZnCl 2 (Fc = (η 5C 5H 5)Fe(η 5C 5H 4), fc = (η 5C 5H 4)Fe(η 5C 5H 4), R = Et, H)

An improved synthesis of diethyl ferrocenylphosphonate using the t BuLi/ t BuOK system at low temperature is reported and the structure of [FcPO 3Et 2] 2 · ZnCl 2 complex is described. The electrochemical behaviour of FcP(O)(OEt) 2, 1,1′-fc[P(O)(OEt) 2] 2, FcCH 2P(O)(OEt) 2, and their corresponding acids were compared. Each of them shows a reversible one-electron transfer reaction. Ferrocenylbisphosphonate is more difficult to oxidize than ferrocenylphosphonate due to the presence of two electron-withdrawing substituents. A methylene spacer between the ferrocenyl unit and the phosphonate group renders the compound easier to oxidize. The acids are easier to oxidize than the esters, and their salts, in which the phosphonate group behave as an electron-donating group, are even easier to oxidize than the ferrocene. The ferrocenylphosphonic acid may be, then, considered as a redox-active pH responsive molecule.