Dual pH Research Articles

Dual pH Probes Without Proximal Esophageal and Pharyngeal Impedance May Be Deficient in Diagnosing LPR

Laryngopharyngeal reflux (LPR) is commonly treated with empiric acid suppression. More evidence points to pepsin in the pathophysiology of LPR. Previous studies have evaluated esophageal impedance in patients who had previously failed high dose proton pump inhibitor (PPI) using older catheters without proximal esophageal (just under the upper esophageal sphincter) and pharyngeal impedance sensors. The aim of this study was to compare what traditional diagnostic tools, used for esophageal reflux, would detect and diagnose compared with what a combined hypopharyngeal-esophageal MII catheter with dual pH (HEMII-pH) can detect in the esophagus and pharynx in patients with suspected LPR. Forty-two subjects with presumed LPR were referred for HEMII-pH testing. The number of distal and proximal esophageal impedance events, number of pharyngeal impedance events, symptom correlation, and event acidity were recorded. Previous normative values (>1 pharyngeal impedance events every 24 hours) were used to designate what was pathological LPR on HEMII-pH. Forty-two total subjects had pharyngeal impedance sensor data recorded. Twelve (28.6%) of the subjects were tested while taking high-dose PPI therapy. The mean number of proximal esophageal events was 23.3. The mean number of pharyngeal impedance events was 10. Thirty-four subjects (81%) tested positive for pharyngeal reflux. All patients who tested positive using traditional proximal impedance criteria also tested positive using pharyngeal criteria. Of patients who tested negative using traditional criteria, 72% were positive based on pharyngeal criteria. HEMII-pH catheters should be considered in patients with LPR symptoms. Traditional criteria used for diagnosing esophageal reflux may not translate into LPR.

Dual stimuli-responsive polysulfone membranes with interconnected networks by a vapor-liquid induced phase separation strategy

Dual pH- and thermo-responsive polysulfone (PSf) membranes with three-dimensionally interconnected networks are fabricated by introducing poly(acrylic acid-co-N-isopropylacrylamide) (P(AA-NIPAm)) into the membrane surfaces and pore walls during membrane formation via a vapor-liquid induced phase separation (V-LIPS) process. After introducing the copolymers of P(AA-NIPAm), the fabricated membranes exhibit impressive open network pores on the surfaces, meanwhile their cross-sectional structure turns from classical asymmetric finger-like structure into bi-continuous nanopores throughout the whole thickness of membrane, due to high solution viscosity and low mass transfer rate of VIPS process. Furthermore, pure water permeation tests show that the pure water permeation (Lp) and the molecular weight cutoff (MWCO) of the fabricated PSf/P(AA-NIPAm) membranes increases sharply as the solution pH decreases from 12.5 to 1.5 and the feed temperature increases from 25 to 50 °C, attributing to the increasing pore size. With the decreasing mass ratio of AA to NIPAm, the pH-responsive coefficient decreases, while the temperature- responsive coefficient increases. In particular, for the fabricated membrane with the mass ratio of AA to NIPAm of 3 to 2, Lp changes from ∼16.0 to ∼821.4 L m−2 h−1 bar−1 and MWCO increases from ∼223.1 to ∼1493.2 kDa, as the filtration experiments are operated with feed pH and temperature of 12.5/25 °C and 1.5/50 °C respectively. The results proposed in this study provide a novel mode for design and development dual responsive porous membranes in situ, which will enable good separation of various materials and expand the scope of membrane applications.

Multifunctional graphene-based magnetic nanocarriers for combined hyperthermia and dual stimuli-responsive drug delivery

The synthesis of hydrophilic graphene-based yolk-shell magnetic nanoparticles functionalized with copolymer pluronic F-127 (GYSMNP@PF127) is herein reported to achieve an efficient multifunctional biomedical system for mild hyperthermia and stimuli-responsive drug delivery. In vitro tests revealed the extraordinary ability of GYSMNP@PF127 to act as smart stimuli-responsive multifunctional nanomedicine platform for cancer therapy, exhibiting (i) an outstanding loading capacity of 91% (w/w, representing 910 μg mg−1) of the chemotherapeutic drug doxorubicin, (ii) a high heating efficiency under an alternating (AC) magnetic field (intrinsic power loss ranging from 2.1–2.7 nHm2 kg−1), and (iii) a dual pH and thermal stimuli-responsive drug controlled release (46% at acidic tumour pH vs 7% at physiological pH) under AC magnetic field, in just 30 min. Additionally, GYSMNP@PF127 presents optimal hydrodynamic diameter (DH = 180 nm) with negative surface charge, high haemocompatibility for blood stream applications and tumour cellular uptake of drug nanocarriers. Due to its physicochemical, magnetic and biocompatibility properties, the developed graphene-based magnetic nanocarrier shows high promise as dual exogenous (AC field)/endogenous (pH) stimuli-responsive actuators for targeted thermo-chemotherapy, combining magnetic hyperthermia and controlled drug release triggered by the abnormal tumour environment. The presented strategy and findings can represent a new way to design and develop highly stable added-value graphene-based nanostructures for the combined treatment of cancer.

BODIPY-derived ratiometric fluorescent sensors: pH-regulated aggregation-induced emission and imaging application in cellular acidification triggered by crystalline silica exposure

Modification of classic fluorophore to possess the emission transitions between aggregation-induced emission (AIE) and intrinsic emission offers reliable approach to the design of ratiometric fluorescent sensors. In this study, a proton acceptor benzimidazole was integrated with BODIPY to form three compounds, BBI-1/2/3, which demonstrated the AIE (~595 nm, Iagg) in neutral aqueous medium and intrinsic BODIPY emission (~510 nm, Iint) in acidic medium. All the three showed the ratiometric pH sensing behavior in a dual excitation/dual emission mode, yet BBI-3 displayed still the dual emission ratiometric pH sensing ability. The pH-dependent emission ratio Iint/Iagg of the three were fully reversible, and no interference was observed from normal abundant chemical species in live cells. Their different pKa (BBI-1, pKa 4.4; BBI-2, pKa 2.7; BBI-3, pKa 3.6) suggested that the substituents on benzimidazole moiety were essential to govern their functioning pH range. The ratiometric imaging of BBI-1 in A549 cells provided an effective intracellular pH (pHi) calibration formula corresponding to emission ratio of Iint/Iagg. Ratiometric pHi imaging in A549 cells upon small particle exposure confirmed the particle-induced cellular acidification with this formula. Both particle size and the chemical nature of the particle contribute to the observed acidification effect. The synchronization of lysosome disruption to cellular acidification in A549 cells upon crystalline silica exposure was directly observed for the first time with BBI-1, showing the potential application of BBI-1 in the study of silicosis and other related diseases. This study demonstrated that endowing fluorophore with AIE/intrinsic emission transition could be a promising strategy for ratiometric sensor design.

Dual temperature and pH responsive nanofiber formulations prepared by electrospinning.

We report a dual-responsive drug delivery system prepared by electrospinning. Blend fibers of poly(N-vinylcaprolactam) (PNVCL) and ethyl cellulose (EC) were first prepared, with the aim of developing thermoresponsive sustained release formulations. Eudragit L100-based fibers were then generated to yield pH-sensitive materials. Attempts to produce three-polymer fibers of EC, PNVCL and Eudragit were unsuccessful, and therefore hybrid mats containing two fiber populations (one made of PNVCL/EC, one comprising Eudragit) were instead fabricated by twin-jet electrospinning. Analogous drug-loaded versions of all the formulations were also prepared containing ketoprofen (KET). The fibers were largely smooth and homogeneous, and the addition of KET did not affect their morphology. The PNVCL-containing fiber mats changed from being hydrophilic to hydrophobic when the temperature was increased through the lower critical solution temperature of 33 °C. In vitro drug release profiles showed that the hybrid fiber mats were able to combine the properties of the three polymers, exhibiting both pH-sensitive and thermosensitive properties with sustained release. In addition, they were found to be nontoxic and suitable for cell growth. This study therefore demonstrates that PNVCL/EC/KET-Eudragit/KET multicomponent fiber mats comprise effective and biocompatible materials for targeted drug delivery.

Abstract 3727: Dual acidic pH targeted mesoporous silica nanoparticles for noninvasive detection of triple negative breast cancer

Abstract Purpose: Current screening methods for triple negative breast cancer suggest the presence and size of tumor, but do not identify the tumor microenvironment. The inability to determine precise tumor location and position following diagnosis impedes medical confidence in surgical resection and radiation therapy. Theranostic nanoparticles can be targeted for dye and drug delivery to facilitate non-invasive characterization and treatment of malignancies. Combinational use of nanomedicine and Multispectral Optoacoustic Tomography (MSOT) renders high resolution images through ultrasonic detection of thermoelastic dye expansion (the optoacoustic effect). Approaches in nanomedicine are steadily growing, but clinical evaluation relies on minimizing off-target accumulation and controlling cargo release. We evaluated a mesoporous silica nanoparticles with pH-sensitive chitosan gatekeeper and tumor targeting V3 pH low-insertion peptide (V3 pHLIP) conjugation (V3-CMSN-780) for dual acidic pH targeted delivery to triple negative breast cancer. Methods: Mesoporous silica nanoparticles were synthesized around a structural skeleton of hexadecyltrimethylammonium bromide (CTAB). CTAB was removed from the particles through repeated dialysis. Subsequent particles were characterized with digital light scattering (DLS) and zetasizer to confirm particle size and zeta potential. Mesoporous nanoparticles were then coated with chitosan for extracellular acidic pH selectivity and functionalized with variant 3 pH low-insertion peptide (V3 pHLIP) to promote anchoring of the particle to tumor cells. Functionalized nanoparticles (V3-CMSN) were loaded with NIR 780 (5 mg/mL) and delivered to MDA-MB-231 and MDA-MB-468 malignant cell lines at pH 7.4, 6.8, and 6.6 to confirm pH-sensitive dye release into the cells with Near Infrared fluorescent imaging. V3-CMSN treated cells were inserted into tissue mimicking phantoms which were evaluated using MSOT. Results: The size of V3-CMSN-780 was 35 d. nm with a zeta potential of 25 mV. V3-CMSN were loaded with 780 dye with a dye loading efficiency of 77%. Cellular uptake of V3-CMSN-780 within MDA-MB-231 cells was 2152 a.u., 5242 a.u., and 3639 a.u. at pHs 7.4, 6.8, and 6.6, respectively, based NIR fluorescent imaging. Treatment of MDA-MB-231 cells with V3-CMSN-780 within tissue mimicking phantoms also confirmed acidic pH selectivity of the particles with a 6X and 4X accumulation of particles at pH 6.8 and 6.6 as compared to pH 7.4. While similar results were observed in MDA-MB-468 cells with NIR fluorescent imaging, MSOT imaging indicated that MDA-MB-468 cells treated at pH 6.8 and 6.6 had increased 780 signal, 110X and 16X, incomparison to pH 7.4. Conclusion: Successful dual targeting of breast tumor cells provides a foundation for later in vivo and ex vivo studies using V3-780-CMSNs to deliver diagnostic and therapeutic cargo to malignant breast tissue. Citation Format: Joshua T. Hayes, Abhilash Samykutty, Molly McNally, Alexandra Thomas, Akiko Chiba, William Grizzle, Karen M. Winkfield, Lacey R. McNally. Dual acidic pH targeted mesoporous silica nanoparticles for noninvasive detection of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3727.

Highly uniform ultrasound-sensitive nanospheres produced by a pH-induced micelle-to-vesicle transition for tumor-targeted drug delivery

Although gas-filled microbubbles with high echogenicity are widely applied inclinical ultrasonography, the micron scale particle size impedes their use in the treatment of solid tumors,which are accessible to objects less than several hundred nanometers. We herein propose an unusual approach involving apH-induced core–shell micelle-to-vesicle transition to prepare ultrasound-sensitive polymeric nanospheres (polymersomes in structure) possessing multiple features, including nanosize, monodispersity, and incorporation of a phase-transitional imaging agent into the aqueous lumen. These features are not achievable via the conventional double-emulsion method for polymersome preparation. The nanospheres were constructed based on a novel triblock copolymer with dual pH sensitivity. The liquid-to-gas phase transition of the imaging agent induced by external low-frequency ultrasound may destroy the nanospheres for a rapid drug release, with simultaneous tissue-penetrating drug delivery inside a tumor. These effects may provide new opportunities for the development of an effective cancer therapy with few adverse effects.

Redox- and pH-Responsive Nanoparticles Release Piperlongumine in a Stimuli-Sensitive Manner to Inhibit Pulmonary Metastasis of Colorectal Carcinoma Cells

Redox-responsive nanoparticles having a diselenide linkage were synthesized to target pulmonary metastasis of cancer cells. Methoxy poly(ethylene glycol)-grafted chitosan (ChitoPEG) was crosslinked using selenocystine-acetyl histidine (Ac-histidine) conjugates (ChitoPEGse) for stimuli-responsive delivery of piperlongumine (PL). ChitoPEGse nanoparticles swelled in an acidic environment and became partially disintegrated in the presence of H2O2, resulting in an increase of particle size and in a size distribution having multimodal pattern. PL release increased under acidic conditions and in the presence of H2O2. Uptake of ChitoPEGse nanoparticles by CT26 cells significantly increased in acidic and redox state. PL-incorporated ChitoPEGse nanoparticles (PL NPs) showed similar anticancer activity in vitro against A549 and CT26 cells compared to PL itself. PL NP showed superior anticancer and antimetastatic activity in an in vivo CT26 cell pulmonary metastasis mouse model. Furthermore, an immunofluorescence imaging study demonstrated that PL NP conjugates were specifically delivered to the tumor mass in the lung. Conclusively, ChitoPEGse nanoparticles were able to be delivered to cancer cells with an acidic- or redox state-sensitive manner and then efficiently targeted pulmonary metastasis of cancer cells since ChitoPEGse nanoparticles have dual pH- and redox-responsiveness.

Regulating dual temperature- and pH-responsibility constructed from core-shell mesoporous hybrid silica (P(NIPAM-co-AA)@BMMs) via adjusting AA incorporation onto NIPAM

The mesoporous hybrid silicas (P@BMMs) with core-shell structure were successfully synthesized via seed polymerization method using bimodal mesoporous silica materials (BMMs) as core and dual pH- and temperature-responsive poly(N-isopropylacryl-acrylamide)-co-poly(acrylic acid) (P(NIPAM-co-AA)) copolymer as shell. Meanwhile, the obtained P@BMMs were physicochemically and morphologically characterized via X-ray diffraction, N2 adsorption-desorption isotherms, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared, ultraviolet visible diffused reflection spectrum, small angle X-ray scattering (SAXS), dynamic light scattering, and thermogravimetric analysis techniques. The results indicated that P(NIPAM-co-AA) was successfully coated onto the mesoporous surface of used BMMs, while the uniform mesoporous structure of obtained P@BMMs was still preserved. Using ibuprofen (IBU) as a model drug, the influence of the P(NIPAM-co-AA) shell on the release kinetics of IBU was explored, and its performances elucidated that the P@BMMs nanoparticles presented an apparent thermo/pH-responsive properties, which could be regulated via adjusting mass ratio of AA to NIPAM, and their IBU-release kinetic profiles were favorable to Korsmeyer-Peppas model. Specially, SAXS patterns were employed to evaluate the fractal evolution of P@BMMs along with releasing time, showing the decline tendency for mass fractal value from 2.89 to 2.56 during the release time of 0.25–24 h.

A hemicyanine-based optical probe for biomembranes and intracellular pH sensing

The hemicyanine-based fluorescent probe L3 was demonstrated as a suitable membrane physiological pH probe. L3 easily interacted with the lipid components and anchored in inner membrane and gave a red fluorescence signal (~ 650 nm) in neutral or acidic pH, while the emission switching off when intramembrane pH varied to basic. Moreover, the absorption color of L3 changed from purple red to colorless with increasing pH. Thus L3 served as the pH-dependent modulator, a dual optical biomembranes pH sensing probe, showing good linear relationship in physiological pH range 7.0–8.5 or 7.5–9.0. The liposomes prepared under random pH and suspensions of gastric cancer cells (HGC-27) samples were used for verification of proposed intracellular pH sensing method, and satisfied results were obtained.

Charge reversible and biodegradable nanocarriers showing dual pH-/reduction-sensitive disintegration for rapid site-specific drug delivery.

Dual pH-/reduction-sensitive biodegradable poly(methacrylic acid-co-N,N-bis(acryloyl)cystamine)/chitosan/dimethylmaleic anhydride-modified chitosan (PMAABACy/CS/CS-DMMA) nanoparticles with PMAABACy cores as carriers and dimethylmaleic anhydride-modified chitosan as charge reversible shells were rationally designed. PMAABACy cores using N,N-Bis(acryloyl)cystamine (BACy) as a crosslinker and methacrylic acid (MAA) as a monomer were fabricated via a mild and facile one-pot distillation-precipitation polymerization. After that, CS and CS-DMMA were alternately adsorbed on the surface of PMAABACy cores through a mild self-assembly. The results from TEM and DLS reveal that the PMAABACy/CS/CS-DMMA nanoparticles with desired size and hydrodynamic diameter. And then the nanoparticles exhibit the excellent drug-loading capacity and encapsulation efficiency toward anti-cancer agent doxorubicin (DOX), whereas be rapidly triggered to realize the GSH-sensitive site-specific release via the destruction of sulfide cross-linked structure in response to the intracellular environment of tumor cells. Furthermore, their surface charges could transfer from negative in neutral or basic medium to positive in acidic medium to enhance cellular uptake. Most importantly, the excellent anticancer activity has been also revealed using confocal laser scanning microscope (CLSM) analysis, namely successfully delivering DOX molecules to the cell nucleus. These experimental results indicate that such the novel dual pH-/reduction-sensitive biodegradable PMAABACy/CS/CS-DMMA with surface charge reversal have great potential as a desired anticancer drug carrier for cancer therapy.

Dual pH and glucose sensitive gel gated mesoporous silica nanoparticles for drug delivery

A low molecular weight gelator with dual pH and glucose sensitive moieties was synthesized. The gelator penetrated in the mesopores of silica nanoparticles (MSNs) and formed low molecular weight gel (LMWG) as gate to fabricate dual pH and glucose responsive nano drug delivery system. Antidiabetic drug was loaded in the gel caped MSNs, the drug release was responsive to the pH and glucose levels and the drug release could be controlled via the stimuli sensitivity of gel.

Tackling Poor Specificity of Cocaine Color Tests by Electrochemical Strategies.

This paper presents electrochemical strategies for the fast screening of cocaine and most common cutting agents found in seized drug samples. First, a study on the performance of Scott color tests on cocaine and a wide range of cutting agents is described. The cutting agents causing false positive or false negative results when in mixture with cocaine are identified. To overcome the lack of specificity of color tests, we further propose a fast screening strategy by means of square wave voltammetry on disposable graphite screen printed electrodes, which reveals the unique fingerprint of cocaine and cutting agents. By employing a forward and backward scan and by a dual pH strategy, we enrich the electrochemical fingerprint and enable the simultaneous detection of cocaine and cutting agents. The effectiveness of the developed strategies was tested for the detection of cocaine in seized cocaine samples and compared with the color tests. Moreover, we prove the usefulness of square wave voltammetry for predicting possible interfering agents in color tests, based on the reduction peak of cobalt thiocyanate. The developed electrochemical strategies allow for a quick screening of seized cocaine samples resulting in a selective identification of drugs and cutting agents.

High-temperature annealing enabled iridium oxide nanofibers for both non-enzymatic glucose and solid-state pH sensing

As a new class of multifunctional material, high-temperature annealing enabled iridium oxide nanofibers (IrO2 NFs) were synthesized and then employed as the sensing element to fabricate a novel dual glucose and pH sensor in this study. The as-prepared IrO2 NFs were systematically characterized using scanning electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Raman spectroscopy, while the electrochemical and electrocatalytic performance of the IrO2 NFs based dual sensor toward pH and glucose sensing were evaluated using open circuit potential, cyclic voltammetry and amperometric techniques, respectively. The IrO2 NFs not only possess good and reversible pH sensitivity as expected, but also demonstrate the electrocatalytic activity toward glucose which was presumably attributed to the crystallinity enabled by high-temperature annealing effect during the preparation of IrO2 NFs. This unique dual functionality enables us to develop a sensor which can be applied for both non-enzymatic glucose and solid-state pH sensing. The experiment results show that the IrO2 NFs based dual sensor exhibits a Nernst constant close to a theoretical value with excellent reversibility in pH titration, while it also possesses a sensitivity of 22.22 μA mM-1 cm−2, a limit of detection of 2.9 μM (S/N = 3), and good selectivity against various interferents in non-enzymatic glucose detection. Its good accuracy for detecting glucose in human serum sample was also demonstrated by comparing to commercial glucose meter. All these features indicate that the high-temperature annealed IrO2 NF is a promising multifunctional sensing material in the development of an integrated solid-state pH sensor and non-enzymatic glucose sensor.

Mechanically strong dual responsive nanocomposite double network hydrogel for controlled drug release of asprin.

Mechanically strong dual/multi-stimuli-responsive smart hydrogels have attracted extensive attention in recent years. A novel tough, mechanical strong and biocompatible dual pH- and temperature- responsive poly (N-isopropylacrylamide) /clay (laponite XLG)/carboxymethyl chitosan (CMCTs) /genipin nanocomposite double network hydrogel was synthesized through a facile, one-pot free radical polymerization initiated by the ultraviolet light, using clay and the natural molecular-genipin as the cross-linkers instead of toxic organic molecules. Crucial factors, the content of CMCTs, clay and genipin, for synthesizing the mechanical strong hydrogels were investigated. When the content of CMCTs, clay and genipin were 5 wt%, 33.3 wt% and 0.175 wt%, respectively (to the weight of N-isopropylacrylamide), these prepared hydrogels exhibited a high tensile strength of 137.9 kPa at the failure strain of 446.1%. Furthermore, the relationship between swelling and deswelling rate of the synthesized hydrogels and the above crucial factors were also studied. Besides, the synthesized hydrogels displayed a considerable controlled release property of asprin by tuning their inner crosslink density. Owing to this property, they may have great potential in the drug delivery systems.

Stimuli-responsive behavior of smart copolymers-grafted magnetic nanoparticles: Effect of sequence of copolymer blocks

Abstract In this work, surface-initiated atom transfer radical polymerization (SI-ATRP) is used to synthesize smart copolymer-grafted Fe3O4 magnetic nanoparticles (MNPs). To do this, MNPs is modified with (3-aminopropyl)triethoxysilane (ATPES) and α-bromoisobutyryl bromide (BIBB) to yield MNPs@APTES and MNPs@BIBB nanoparticles. Then, ATRP-initiator-grafted nanoparticles are used in polymerization of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and N-isopropylacrylamide (NIPAAm) as stimuli-responsive monomers to obtain MNPs@PDMAEMA and MNPs@PNIPAAm respectively. Homopolymer-grafted MNPs are used as macroinitiators to produce smart copolymers-grafted MNPs named MNPs@P(DMAEMA-b-NIPAAm) and MNPs@P(NIPAAm-b-DMAEMA) those have different sequences of copolymer blocks. Successful synthesis of different structures is proved by means of different methods including FT-IR, TGA, VSM, XRD, FE-SEM, and TEM. All homopolymer- and copolymer-grafted MNPs are subjected to variation of pH and temperature to investigate stimuli-responsive behavior of hybrid structures. Although no surprising result is investigated for MNPs@PDMAEMA and MNPs@PNIPAAm nanoparticles, copolymer-grafted MNPs showed a dual pH- and temperature-sensitive behavior where copolymer sequence is important to define smart characteristic of hybrid MNPs.

Hydrogel-Based Fluorescent Dual pH and Oxygen Sensors Loaded in 96-Well Plates for High-Throughput Cell Metabolism Studies

In this study, we developed fluorescent dual pH and oxygen sensors loaded in multi-well plates for in-situ and high-throughput monitoring of oxygen respiration and extracellular acidification during microbial cell growth for understanding metabolism. Biocompatible PHEMA-co-PAM materials were used as the hydrogel matrix. A polymerizable oxygen probe (OS2) derived from PtTFPP and a polymerizable pH probe (S2) derived from fluorescein were chemically conjugated into the matrix to solve the problem of the probe leaching from the matrix. Gels were allowed to cure directly on the bottom of 96-well plates at room-temperature via redox polymerization. The influence of matrix’s composition on the sensing behaviors was investigated to optimize hydrogels with enough robustness for repeatable use with good sensitivity. Responses of the dual sensing hydrogels to dissolved oxygen (DO) and pH were studied. These dual oxygen-pH sensing plates were successfully used for microbial cell-based screening assays, which are based on the measurement of fluorescence intensity changes induced by cellular oxygen consumption and pH changes during microbial growth. This method may provide a real-time monitoring of cellular respiration, acidification, and a rapid kinetic assessment of multiple samples for cell viability as well as high-throughput drug screening. All of these assays can be carried out by a conventional plate reader.

Crosslinked casein-based micelles as a dually responsive drug delivery system

Crosslinked casein micelles with a dual pH and protease drug triggered release can be applied as a promising hydrophobic drug carrier material.

Tunable Intracellular Degradable Periodic Mesoporous Organosilica Hybrid Nanoparticles for Doxorubicin Drug Delivery in Cancer Cells.

In this work, a dual (pH and redox)-sensitive cystamine-integrated periodic mesoporous organosilica (Cys-PMO) hybrid nanoparticle has been developed and subsequently loaded with doxorubicin (Dox) as an anticancer drug for intracellular cancer drug delivery. The formation of Cys-PMO was confirmed by FTIR, 13C (CP-MAS), and 29Si MAS NMR spectroscopic techniques. X-ray diffraction and transmission electron microscopy confirmed that the Cys-PMO hybrid nanoparticles possessed mesoscopically ordered 2D hexagonal (P6mm) symmetry with cylindrical shape morphology. The N2 sorption isotherm showed that the Cys-PMO hybrid nanoparticles have a large surface area (691 m2 g-1), pore diameter (3.1 nm), and pore volume (0.59 cm3 g-1). As compared to conventional mesoporous silica materials and other PMO nanoparticles, the developed Cys-PMO hybrid nanoparticles have the capability of holding a high Dox content 50.6% (15.2 mg of Dox per 30 mg of Cys-PMO) at an optimized concentration (20 mg Dox) and avoid premature drug release under extracellular conditions. In vitro, the treatment of HeLa cells with Dox-encapsulated Cys-PMO hybrid nanoparticles results in a significantly greater cytotoxicity in response to intracellular acidic pH and a redox environment due to the degradation of disulfide bonds available in the framework of Cys-PMO hybrid nanoparticles. Further, confocal microscope images show the colocalization of Dox-loaded Cys-PMO hybrid nanoparticles inside the HeLa cells. Upon internalization inside HeLa Cells, the Cys-PMO use intracellular pH and redox environments to release Dox to the nucleus. Thus, the pH and reduction sensitivity of Cys-PMO hybrid nanoparticles make them suitable for intracellular drug delivery applications.

Smart pH/temperature Sensitive Hydrogels with Tailored Transition Temperature

Dual pH- and temperature-sensitive hydrogels have been prepared based on N-isopropylacrylamide (NIPAAm) and either potassium 5-methacryloyloxy-pentanoate (M4K) or potassium11-methacryloyloxy-undecanoate (M10K) as comonomers. The gels containing M10K (longer methylene chain) showed a slightly lower swelling capacity than the gels containing M4K. Hydrogels were produced with specific phase transition temperature (Tcr) in the range from 12 to 76 oC for NIPAAm-C4 hydrogels (containing M4K) and from 16 to 36 oC for NIPAAm-C10 hydrogels (containing M10K) by controlling: the type and comonomer content, and the pH of water. The type of transition changes from discontinuous (below the critical pH of the acid comonomer) to continuous (above de critical pH of the acid comonomer). The title hydrogel materials are promising candidates for biomedical applications.