Polymeric Membrane Electrodes Using Calix[4]pyrrole Bis/Tetra-Phosphonate Cavitands as Ionophores for Potentiometric Acetylcholine Sensing with High Selectivity.

A handful of bis/tetra-phosphonate calix[4]pyrroles with recognition sites embedding in hydrophobic cavitands were evaluated for the first time as ionophores for polymeric membrane Ach+-selective electrodes. Highly selective potentiometric Ach+ could be achieved over its analogues, especially for Ch+, which differs only by an acetate tail from Ach+. The superior performance of the proposed ISEs might be ascribed to a dual-site binding mode, in which the trimethylammonium head and acetate tail were accommodated by the phosphonate group-bridged aryl walls and the bowl-shaped aromatic cavity, through cation-π/charge-dipole interaction and the convergent four N-H···O hydrogen bonds, respectively. To gain more insight into the performance of the proposed ISEs, the cation-ionophore complex constants in the membrane phase were determined, and the binding affinity trend correlates well with the selectivity pattern. These results suggest that conformational preorganization of the ionophores and complementary weak interactions do change the selectivity of the ionophores. Studies on the influence of the sample solution pH demonstrated that the developed ISEs can be employed in a wide pH range of 4.0-9.6 with a fast response (<60 s), good reversibility, and long lifetime. Optimizing the membrane components, such as ionophores, lipophilic additives, and plasticizers, yielded ISEs, showing Nernstian responses to Ach+ with improved linear ranges and detection limits (a slope of -59.5 mV/dec in the linear range of 1 × 10-6-1 × 10-2 M with a detection limit of 3 × 10-7 M), which led to the success of the determination of Ach+ in spiked urine and milk samples.

Superparamagnetic Reduction/pH/Temperature Multistimuli-Responsive Nanoparticles for Targeted and Controlled Antitumor Drug Delivery.

Multistimuli-responsive polymeric nanoparticles with core-shell architecture were prepared by coating superparamagnetic Fe3O4 nanoparticle cores with reduction/pH dual-responsive poly(methacrylic acid) (PMAA) as shells and thermal-responsive poly(N-isopropylacrylamide) (PNIPAM) as a "gatekeeper" on the surface via two-stage distillation precipitation polymerization. The Fe3O4@PMAA nanoparticles were synthesized using N,N-bis(acryloyl)cystamine (BACy) as cross-linker which would be easily biodegradable in the presence of dithiothreitol (DTT) or glutathione (GSH). The cumulative release profile was investigated under different conditions, such as media pH, reductive agents, and temperature, with doxorubicin hydrochloride (DOX) as a model anticancer drug. They showed a low leakage of DOX at pH 7.4 (less than 11% in 24 h), while the release significantly accelerated at pH 5.0 and 10 mM GSH (over 60% in 5 h), realizing the "triggered release" of drug in the targeted tissues. The nanoparticles exhibited excellent biocompatibility while the DOX-loaded nanoparticles showed great promise of antitumor efficacy as free DOX by the MTT assay and CLSM analysis. The results suggest that the novel biodegradable nanoparticles with high drug loading capacity and multiresponsive controlled release capability could serve as an excellent gene/drug delivery system candidate for cancer therapy.

Self-assembled metal-polyphenolic based multifunctional nanomedicine to improve therapy treatment of pancreatic cancer by inhibition of glutamine metabolism.

Cancer poses a significant threat to human health and life. Chemotherapy, immunotherapy and chemodynamic therapy (CDT) are effective treatments for cancer. However, the presence of metabolic reprogramming via glutamine in tumor cells limits their therapeutic effectiveness. Herein, we propose an effective assembly strategy to synthesize a novel metal-polyphenolic based multifunctional nanomedicine (Fe-DBEF) containing Pluronic F127 stable ferric ion crosslinked epigallocatechin gallate (EGCG) nanoparticles loaded with GLS1 inhibitor bis-2-(5-phenylacetamino-1,3,4-thiadiazole-2-yl) ethyl sulfide (BPTES) and chemotherapy drug doxorubicin (DOX). Our study demonstrates that Fe-DBEF nanomedicine exhibits high efficiency anti-proliferation properties in pancreatic cancer through a combination of in vitro cell experiments, human organoid experiments and KPC animal experiments. Notably, Fe-DBEF nanomedicine can reduce the production of glutathione (GSH) in tumor cells, thereby reducing their resistance to ROS therapy. Additionally, excessive ROS production also aggravates DNA damage caused by DOX, synergistically sensitizing chemotherapy and promoting apoptosis for efficient treatment of pancreatic cancer. Overall, our findings suggest that inhibiting glutamine metabolism to increase the sensitivity of chemotherapy/CDT using metal-polyphenolic based multifunctional nanomedicine provides a promising combination of multiple therapeutic means for treating pancreatic cancer.

Biocompatible magnetic and molecular dual-targeting polyelectrolyte hybrid hollow microspheres for controlled drug release.

Well-defined biocompatible magnetic and molecular dual-targeting polyelectrolyte hybrid hollow microspheres have been accomplished via the layer-by-layer (LbL) self-assembly technique. The hybrid shell was fabricated by the electrostatic interaction between the polyelectrolyte cation, chitosan (CS), and the hybrid anion, citrate modified ferroferric oxide nanoparticles (Fe3O4-CA), onto the uniform polystyrene sulfonate microsphere templates. Then the magnetic hybrid core/shell composite particles were modified with a linear, functional poly(ethylene glycol) (PEG) monoterminated with a biotargeting molecule (folic acid (FA)). Afterward the dual targeting hybrid hollow microspheres were obtained after etching the templates by dialysis. The dual targeting hybrid hollow microspheres exhibit exciting pH response and stability in high salt-concentration media. Their pH-dependent controlled release of the drug molecule (anticancer drug, doxorubicin (DOX)) was also investigated in different human body fluids. As expected, the cell viability of the HepG2 cells which decreased more rapidly was treated by the FA modified hybrid hollow microspheres rather than the unmodified one in the in vitro study. The dual-targeting hybrid hollow microspheres demonstrate selective killing of the tumor cells. The precise magnetic and molecular targeting properties and pH-dependent controlled release offers promise for cancer treatment.

Preparation of aggregation-resistant biocompatible superparamagnetic noncovalent hybrid multilayer hollow microspheres for controlled drug release.

Biocompatible superparamagnetic polyelectrolyte hybrid hollow microspheres ((CS/Fe(3)O(4)-CA)(3)-CS-NH-CH(2)-PEG) were successfully prepared by PEGylation of multilayered polyelectrolyte hybrid shell encapsulated polystyrene sulfonate (PSS) microsphere templates fabricated by the layer-by-layer self-assembly of chitosan (CS) and citrate modified ferroferric oxide magnetic nanoparticles (Fe(3)O(4)-CA), after etching the templates by dialysis. Their hollow structure with diameter of about 200 nm was confirmed by TEM analysis. The pH and ionic strength responsive properties were retained after the PEGylation of the hollow microspheres. Furthermore, their biocompatibility and stability against aggregation and fusion in media with high ionic strength were distinctly improved. A typical anti-inflammatory drug, ibuprofen, was used for drug loading, and the release behaviors of ibuprofen in a simulated body fluid (SBF) were studied. The results indicate that the biocompatible superparamagnetic polyelectrolyte hybrid hollow microspheres ((CS/Fe(3)O(4)-CA)(3)-CS-NH-CH(2)-PEG) have a high drug loading capacity and favorable release property for ibuprofen; thus, they are very promising for application in drug delivery.

Fabrication of flocculation-resistant pH/ionic strength/temperature multiresponsive hollow microspheres and their controlled release.

pH/ionic strength/temperature multiresponsive hollow microspheres were successfully prepared by the Ce(IV) initiated grafting polymerization of N-isopropylacrylamide (NIPAm) onto the multilayered polyelectrolyte shells encapsulating the polystyrene sulfonate (PSS) microsphere templates fabricated by the layer-by-layer assembly of chitosan (CS) and alginate (SAL), after etching the templates by dialysis. The hollow structure of the obtained multiresponsive hollow microspheres was characterized by transmission electron microscopy (TEM), which indicated that the inner diameter of the hollow microspheres was about 200 nm. The environmental responsive properties of the multiresponsive hollow microspheres were characterized with dynamic light scattering (DLS) in an aqueous system. The introduction of poly(N-isopropylacrylamide) (PNIPAm) brushes onto the pH/ionic strength dual-responsive hollow microspheres achieved temperature-responsive characteristics. It also could prevent flocculation among the obtained multiresponsive hollow microspheres in a solution with higher salt concentration. Their controlled release of drug molecules (a model hydrophobic drug, dipyridamole (DIP)) was also investigated.

Embedding of Functionalized Coordination Cages and a Molecular Knot in a Polymeric Membrane for Potentiometric Sensing of Environmentally Important Oxyanions and Halides.

Three kinds of coordination cages and a molecular knot with inductively activated +P-H, N-H, or C-H hydrogen bond donors anchoring in the functionalized cavities were inspected as ionophores to develop polymeric membrane ISEs for potentiometric sensing of environmentally important oxyanions and halides. The proposed ISEs displayed significant preference for perrhenate, phosphate, or chloride with a selectivity pattern distinctively different from the sequence depending on the Gibbs free energy of hydration owing to the high degree of shape, charge, and size selectivity originating from the rigidity and complementarity of the binding cavities. To gain further insight into the response characters of the proposed ISEs, the binding constants of ionophore-anion complexes in the membrane phase were investigated, and the binding affinity, together with the Hofmeister series, correlates well with the determined selectivity pattern of the proposed ISEs. Optimizing the composition of the membrane such as lipophilic additives and plasticizers produced ISEs displaying Nernstian/near-Nernstian potentiometric responses to primary anions with a wide linear range, improved detection limits, good reversibility, and satisfying lifetime. Potentiometric determination of perrhenate, phosphate, and chloride in river water, mineral water, and artificial serum samples was achieved with good recovery and accuracy using the proposed ISEs, demonstrating their potential for real-life applications. These results will shed new light on how novel ionophores could be designed for potentiometric sensing and broaden the scope of host-guest chemistry of coordination cages and molecular knots.

pH-responsive intramolecular FRET-based self-tracking polymer prodrug nanoparticles for real-time tumor intracellular drug release monitoring and imaging.

An intramolecular fluorescence resonance energy transfer (FRET)-based macromolecular theranostic prodrug was designed by directly conjugating Doxorubicin (DOX) as the FRET acceptor onto the naphthalimide side groups in the fluorescent copolymer PPEGMA20-PNAP8 as the FRET energy donor via an acid-labile imine bond, without a fluorogenic linker. The proposed PPEGMA20-PNAP8-DOX theranostic prodrug showed a high DOX content of 24.3% owing to a conjugation efficiency of > 93% under mild conjugation conditions. It could easily self-assemble into unique theranostic nanoparticles with a Dh of 71 nm. The theranostic nanoparticles showed excellent pH-triggered DOX release performance with very low premature drug leakage of 6.3% in normal physiological medium over 129 h, while>91% of the conjugated DOX was released in the acidic tumor intracellular microenvironment. MTT assays indicated the enhanced antitumor efficacy of the proposed theranostic nanoparticles compared with free DOX. Furthermore, because drug release was triggered by pH, orange fluorescence was restored to the blue fluorescence of the backbone copolymer. Such self-tracking pH-responsive colorful fluorescence variations during intracellular drug delivery and release are expected to allow real-time tumor intracellular drug release monitoring and imaging diagnosis.

Absolutely "off-on" fluorescent CD-based nanotheranostics for tumor intracellular real-time imaging and pH-triggered DOX delivery.

Carbon dots (CDs) have attracted intense attention in tumor nanotheranostics recently; however, those nanotheranostics exhibited similar fluorescence in both normal and tumor tissues, limiting their practical application. In the present work, absolutely "off-on" fluorescent CD-based nanotheranostics was designed for tumor intracellular real-time imaging and pH-triggered DOX delivery via both static quenching by the crosslinking of benzaldehyde-containing diblock copolymers and dynamic quenching because of the surrounding conjugated DOX molecules. The proposed PPEGMA42-b-PFPMA122-(CDs)-DOX nanotheranostics did not exhibit fluorescence in a normal physiological medium, while strong fluorescence recovery occurred in the tumor intracellular microenvironment due to pH-triggered disintegration, releasing the CDs and DOX. The pH-triggered DOX release and absolute "off-on" fluorescence make the proposed nanotheranostics promising for tumor-specific pH-triggered DOX delivery and imaging.

Design, postpolymerization conjugation and self-assembly of a di-block copolymer-based prodrug for tumor intracellular acid-triggered DOX release.

A novel di-block copolymer-based prodrug was designed by atom transfer radical polymerization (ATRP) of glycidyl methacrylate (GMA) with a polyethylene glycol-based initiator (PEG-Br), postpolymerization aldehyde-modification, and doxorubicin (DOX) conjugation via an acid-labile imine bond. The polyprodrug could self-assemble into core-shell structured nanoparticles with the PEG block as the hydrophilic shell and the DOX-containing block as the hydrophobic core. The longer hydrophobic block resulted in a higher drug content but a bigger particle size, although all the four polyprodrug nanoparticles showed excellent fast pH-triggered DOX release owing to the auto-acceleration mechanism because of the transformation from the hydrophobic to semi-hydrophobic block during DOX release, with a cumulative release of >79% in the simulated tumor microenvironment within 12 h and a premature drug leakage of <14%. So the PEG-P(GMA-CBA)51-DOX polyprodrug with a middle hydrophobic block length was optimized as a promising drug delivery system (DDS), with a hydrodynamic diameter around 250 nm and a high DOX content of 30.35%. The in vitro cellular experiments indicated that the PEG-P(GMA-CBA)51-DOX polyprodrug nanoparticles could efficiently deliver DOX into the cell nuclei and show an enhanced anti-tumor efficacy on the HepG2 cells compared to the free DOX.

Stimuli-responsive hybrid cluster bombs of PEGylated chitosan encapsulated DOX-loaded superparamagnetic nanoparticles enabling tumor-specific disassembly for on-demand drug delivery and enhanced MR imaging.

Facile approach was established to fabricate the hybrid cluster bombs of PEGylated chitosan encapsulated doxorubicin (DOX)-loaded superparamagnetic nanoparticles as tumor-specific theranostics for targeted DOX delivery and magnetic resonance (MR) imaging, by simply co-precipitation of poly(ethylene glycol) modified chitosan (CS-PEG), oleylamine modified Fe3O4 (OA-Fe3O4) nanoparticles and DOX. In presence of OA-Fe3O4, the particle size of the DOX/OA-Fe3O4@CS-PEG cluster bombs decreased to around 80 nm from 300 nm of the DOX/CS-PEG nanoparticles, with high drug-loading capacity (DLC) of 24.3% and saturation magnetization (Ms) of 4.11 emu/g, respectively. The in vitro evaluation results indicated that the blank OA-Fe3O4@CS-PEG clusters showed excellent cytocompatibility, while the DOX/OA-Fe3O4@CS-PEG clusters could be uptaken into HepG2 cells to deliver DOX into the cell nuclei with enhanced anti-cancer efficacy in comparison with free DOX. In the tumor intracellular micro-environment, the stimuli-responsive hybrid cluster bombs disassembled and re-self-assembled into the OA-Fe3O4 nanoparticle clusters with higher Ms for MR imaging-guided diagnosis, owing to the tumor-specific DOX release and dissolution of CS-PEG.

Novel biocompatible pH-stimuli responsive superparamagnetic hybrid hollow microspheres as tumor-specific drug delivery system.

Novel biocompatible pH-stimuli responsive superparamagnetic hybrid hollow microspheres have been designed via the layer-by-layer (LbL) self-assembly technique via the electrostatic interaction between the poly(ethylene glycol) grafted chitosan (CS-g-PEG) as polycation and the citrate modified ferroferric oxide nanoparticles (Fe3O4-CA) as hybrid anion onto the uniform polystyrene sulfonate (PSS) microsphere templates. The well-defined hybrid hollow microspheres ((CS-g-PEG/Fe3O4-CA)4/CS-g-PEG) were obtained after etching the templates by washing with DMF. They possessed superparamagnetic characteristics with a saturation magnetization of 37.23emu/g, and exhibited excellent stability in high ion-strength media and pH dependent DOX release. Their unique structure and outstanding performance make them potential platform for tumor-specific delivery in the tumor diagnostic and therapy.

Double-walled hollow polymeric microspheres with independent pH and temperature dual-responsive and magnetic-targeting function from onion-shaped core-shell structures.

The magnetic-targeting stimuli-responsive hollow polymeric microspheres show unique performance as the intelligent carriers for the site specific controlled delivery of drugs or genes. In the work, the well-defied dual-responsive double-walled hollow microspheres with movable magnetic cores were prepared from the penta-layer onion-shaped core-shell microspheres. Their double-walled shells were independent, with the pH-responsive crosslinked poly(methacrylic acid) (PMAA) layer as the inner shell and the temperature responsive crosslinked poly(N-isopropylacrylamide) (PNIPAM) layer as the outer shell. The combination of the pH and temperature dual-responsive and the magnetic-targeting function make the hollow microspheres to be the most promising intelligent carriers in the biomedical fields.

Polymeric nanocapsules with controllable crosslinking degree via combination of surface-initiated atom transfer radical polymerisation and photocrosslinking techniques.

The crosslinked polystyrene nanocapsules with controllable crosslinking degree have been prepared by the ultraviolet (UV)-induced photocrosslinking of the polystyrene grafted silica nanoparticles (SN-PS), which was obtained by the surface-initiated atom transfer radical polymerisation of styrene from the modified silica nanoparticle templates, after the silica templates were etched with hydrofluoric acid. The effect of the UV-irradiating time on the inner diameter of the nanocapsules, and the degree of crosslinking and the thickness of the shells was investigated. The dynamic light scattering results showed that the degree of crosslinking of the obtained nanocapsules increased with the prolongation of the UV-irradiation time, therefore the inner diameter of the nanocapsules increased. However, the percentage of grafting of the crosslinked polymer shells decreased with increasing the UV-irradiation time because of the photodecomposition of the polystyrene grafted during the UV-irradiated crosslinking process, according to the thermogravimetric analysis.