Cancer‐associated pH‐responsive tetracopolymeric micelles composed of poly(ethylene glycol)‐b‐poly(L‐histidine)‐b‐poly(L‐lactic acid)‐b‐poly(ethylene glycol)

To create a novel vector for specifically delivering anticancer therapy to solid tumors, we used diafiltration to synthesize pH‐sensitive polymeric micelles. The micelles, formed from a tetrablock copolymer [poly(ethylene glycol)‐b‐poly(L ‐histidine)‐b‐poly(L ‐lactic acid)‐b‐poly(ethylene glycol)] consisted of a hydrophobic poly(L ‐histidine) (polyHis) and poly(L ‐lactic acid) (PLA) core and a hydrophilic poly(ethylene glycol) (PEG) shell, in which we encapsulated the model anticancer drug doxorubicin (DOX). The robust micelles exhibited a critical micellar concentration (CMC) of 2.1–3.5 µg/ml and an average size of 65–80 nm pH 7.4. Importantly, they showed a pH‐dependent micellar destabilization, due to the concurrent ionization of the polyHis and the rigidity of the PLA in the micellar core. In particular, the molecular weight of PLA block affected the ionization of the micellar core. Depending on the molecular weight of the PLA block, the micelles triggering released DOX at pH 6.8 (i.e. cancer acidic pH) or pH 6.4 (i.e. endosomal pH), making this system a useful tool for specifically treating solid cancers or delivering cytoplasmic cargo in vivo. Copyright © 2008 John Wiley & Sons, Ltd.     

A preliminary study for isolation of catalytic antibodies by histidine ligand affinity chromatography as an alternative to conventional protein A/G methods

Catalytic autoimmune antibodies from the sera of lupus patients were purified using histidyl-aminohexyl-Sepharose gel and compared with the antibodies purified with protein A and protein G affinity chromatography. The IgG preparations from the histidine affinity column had a much higher catalytic activity in hydrolyzing the peptide substrate Pro-Phe-Arg-methyl-coumarinamide compared to the antibodies obtained by the conventional protein A/G method. This preservation of catalytic activity is attributed to the gentle buffer conditions used in the histidine ligand method that allowed the integrity of three-dimensional structure of purified catalytic antibodies. Thus, histidine affinity offer a superior method for isolating autoimmune catalytic antibodies.     

Selective Monitoring of the Enzymatic Activity of the Tumor Suppressor Fhit

Cancer is a leading cause of death worldwide. Functional inactivation of tumor suppressor proteins, mainly by mutations in the corresponding genes, is a key event in cancer development. The fragile histidine triade protein (Fhit) is a tumor suppressor that is frequently affected in different cancer types. Fhit possesses diadenosine triphosphate hydrolase activity, but although reduction of its enzymatic activity appears to be important for exerting its tumor suppressor function, the regulation of Fhit activity is poorly understood. Here, we introduce a novel fluorogenic probe that is suited to selectively analyze the enzymatic activity of Fhit in extracts derived from human cells. This novel method will allow in‐depth insight into the mechanisms involved in Fhit regulation in biologically relevant setups and, thus, into its role in the development of cancer.     

Temperature‐induced self‐assembly and metal‐ion stabilization of histidine functional block copolymers

Histidine functional block copolymers are thermally self‐assembled into polymer micelles with poly‐N‐isopropylacrylamide in the core and the histidine functionality in the corona. The thermally induced self‐assemblies are reversible until treated with Cu²⁺ ions at 50 °C. Upon treatment with 0.5 equivalents of Cu²⁺ relative to the histidine moieties, metal‐ion coordination locks the self‐assemblies. The self‐assembly behavior of histidine functional block copolymers is explored at different values of pH using DLS and ¹H NMR. Metal‐ion coordination locking of the histidine functional micelles is also explored at different pH values, with stable micelles forming at pH 9, observed by DLS and imaged by atomic force microscopy. The thermal self‐assembly of glycine functional block copolymers at pH 5, 7, and 9 is similar to the histidine functional materials; however, the self‐assemblies do not become stable after the addition of Cu²⁺, indicating that the imidazole plays a crucial role in metal‐ion coordination that locks the micelles. The reversibility of the histidine‐copper complex locking mechanism is demonstrated by the addition of acid to protonate the imidazole and destabilize the polymer self‐assemblies. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1964–1973     

Binding His-tagged Proteins to NTA Stripes Assembled in 2D DNA Scaffold

Histidine‐tagged proteins were bound onto nitrilotriacetic acid (NTA) stripes on a 2‐D DNA scaffold which involved a ssDNA‐NTA conjugate prepared by click chemistry.     

Reversible and Selective Fluorescence Detection of Histidine Using a Naphthalimide‐Based Chemosensing Ensemble

We described a new ensemble‐approach‐based chemosensor, NCH‐Cu²⁺, for highly selective and reversible detection of histidine (His) in aqueous solution and live cells. The ligand NCH exhibited specific binding with Cu²⁺ ions over other metal ions, accompanied with a 92.2 % fluorescence quenching. The decomplexation of NCH‐Cu²⁺ ensemble by His led to the liberation of the fluorophore, NCH, and thus the fluorescence was recovered. The specific fluorescence enhancement of NCH‐Cu²⁺ towards His showed a good linearity with a detection of limit at 70 nm . Quantification of intracellular His at the single cell level was achieved by microscopy and flow cytometry. Besides the UV/Vis and emission titration, reversibility of the NCH‐Cu²⁺ towards His was further confirmed by imaging and cytometry analysis. In addition, microscopy studies revealed that NCH‐Cu²⁺ was distributed in the lysosome of live cells, where it could be employed as a fluorescent biosensor for imaging of His at subcellular level.     

Heterodimers of Histidine and Amantadine as Inhibitors for Wild Type and Mutant M2 Channels of Influenza A

Inhibitors bearing the imidazole, adamantane and related structures were synthesized and tested against WT, S31N and S31N‐L26I mutant M2 channels. Although amantadine ( 1 ) only inhibited WT M2 channel, compound 6 containing the imidazole and adamantane groups showed good inhibitory activity to WT and mutant M2 channels. The stereochemistry and basic pK_a of α‐amine are important for the activity of inhibitors and our data showed that derivatives of natural histidine are more active for M2 channels than those of unnatural histidine. The significance of our present results is that we have established a prospective strategy of drug discovery of WT and mutant M2 channels against influenza A.     

Electromagnetic induction detector for capillary electrophoresis and its application in pharmaceutical analysis

A new electromagnetic induction detector for capillary electrophoresis and its application are described. The detector is consisted of an inductor, a resistor, a high-frequency signal generator and a high-frequency millivoltmeter. The conditions affecting the response of the detector, including dimension of the magnetic ring, position of the capillary, number of coil turns, frequency, excitation voltage and value of the resistor were examined and optimized. The feasibility of the proposed detector was evaluated by detection of inorganic ions and separation of amino aids. Its quantification applicability was investigated by determination of aspirin and paracetamol in pharmaceutical preparation (Akafen powder). The primary factors affecting separation efficiency, which include variety of buffer, buffer concentration, injection time and injection height and separation voltage, were researched. Experimental results demonstrated that this new detector showed a well-defined correlation between sample concentrations and responses (r = 0.997-0.999), with detection limits of 30 μmol L⁻¹ for aspirin and 10 μmol L⁻¹ for paracetamol, as well as good reproducibility and stability. Compared with currently available detection techniques, this new detector has several advantages, such as simple construction, no complicated elements, ease of assembly and operation, and potential for universal applications. It can be an alternative to the traditional methods in the quality control of the pharmaceutical preparations.