Chemical modification of bradykinin-polymer conjugates for optimum delivery of nanomedicines to tumors.

We recently prepared pH-responsive HPMA copolymer conjugates of bradykinin (P-BK), which release BK in response to the acidic tumor microenvironment, and found that administration of P-BK increased the tumor accumulation and therapeutic efficacy of nanomedicine. Because the release of BK from P-BK determines its onset of action, P-BKs with different release rates were prepared, and their properties were evaluated. The release kinetics were significantly altered by substitution proximal to hydrazone bond, release constant of methyl-substituted P-BK (P-MeBK) was approximately 4- and 80-fold higher than that of cyclopropyl-substituted P-BK (P-CPBK) and phenyl-substituted P-BK (P-PhBK).

Peptidyl-prolyl cis-trans isomerase A participates in the selenium transport into the rat brain.

Selenium, an essential micronutrient, plays vital roles in the brain. Selenoprotein P (SELENOP), a major plasma selenoprotein, is thought to transport selenium to the brain. However, Selenop-knockout mice fed a diet containing an adequate amount of selenium shows no objective neurological dysfunction which is observed in the selenium-deficient diet-fed Selenop-knockout mice.

Acid-responsive HPMA copolymer-bradykinin conjugate enhances tumor-targeted delivery of nanomedicine.

Obstructed blood flow and erratic blood supply in the tumor region attenuate the distribution and accumulation of nanomedicines in the tumor. Therefore, improvement of these conditions is crucial for efficient drug delivery. In this study, we designed and synthesized a novel N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugate of BK, which possessed adequate systemic stability and tumor-selective action required to improve the accumulation of nanomedicines in the tumor.

Preparation of Enzymatically Highly Active Pegylated-D-Amino Acid Oxidase and Its Application to Antitumor Therapy.

Background: D-Amino acid oxidase (DAO) is an H2O2-generating enzyme, and tumor growth suppression by selective delivery of porcine DAO in tumors via the cytotoxic action of H2O2 has been reported. DAO isolated from Fusariumspp. (fDAO) shows much higher enzyme activity than porcine DAO, although the application of fDAO for antitumor treatment has not yet been determined.

Highly effective anti-tumor nanomedicines based on HPMA copolymer conjugates with pirarubicin prepared by controlled RAFT polymerization.

Here, we describe innovative synthesis of well-defined biocompatible N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer carriers and their drug conjugates with pirarubicin intended for controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with dispersity close to 1 and molar mass close to renal threshold with minimal synthesis steps. The developed synthesis enables preparation of tailored polymer nanomedicines with highly enhanced biological behavior in vivo, especially the biodistribution, urine elimination, tumor accumulation and anticancer activity.

Discovery of inner centromere protein-derived small peptides for cancer imaging and treatment targeting survivin.

Survivin belongs to the inhibitor of apoptosis protein family, which is consistently overexpressed in most cancer cells but rarely expressed in normal adult tissues. Therefore, the detection and inhibition of survivin are regarded as attractive strategies for cancer-specific treatment. In this study, we designed and synthesized 7-19 residues of inner centromere protein (INCENP)-derived small peptides (INC peptides) as novel survivin-targeting agents.

Superior Penetration and Cytotoxicity of HPMA Copolymer Conjugates of Pirarubicin in Tumor Cell Spheroid.

-(2-Hydroxypropyl)methacrylamide copolymer conjugates of pirarubicin (THP), P-THP, accumulates selectively in solid tumor tissue by the enhanced permeability and retention (EPR) effect. Despite of high accumulation in solid tumors, some macromolecular antitumor agents show poor therapeutic outcome because of poor tissue diffusion into the tumor as well as obstructed tumor blood flow. Here, we confirmed that cellular uptake of P-THP was 25 times less than that of free THP at 1-4 h incubation time .

Development of Radioiodinated Benzofuran Derivatives for Imaging of Prion Deposits in the Brain.

Prion diseases are fatal neurodegenerative disorders associated with the deposition of abnormal prion protein aggregates (PrP) in the brain tissue. Here, we report the development of I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed tomography (SPECT) imaging probes to detect cerebral PrP deposits. We synthesized and radioiodinated several 5-IBF and 6-IBF derivatives.

In vitro assessment of bioavailability of selenium from a processed Japanese anchovy, Niboshi.

Niboshi is a commonly used foodstuff that is processed from Japanese anchovy (Engraulis japonicus) in Japanese cuisine. It was previously demonstrated that Niboshi and its water extract contained highly bioavailable selenium for selenium deficient mice. In this study, we assessed the selenium bioavailability from the extract of the Niboshi, using cultured cells.

Synthesis and characterization of radioiodinated 3-phenethyl-2-indolinone derivatives for SPECT imaging of survivin in tumors.

Survivin, overexpressed in most cancers, is associated with poor prognosis and resistance to radiation therapy and chemotherapy. Herein, we report the synthesis of three 3-phenethyl-2-indolinone derivatives and their application as in vivo imaging agents for survivin. Of these, 3-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-3-hydroxy-5- iodoindolin-2-one (IPI-1) showed the highest binding affinity (K = 68.

Preparation and in Vitro Analysis of Human Serum Albumin Nanoparticles Loaded with Anthracycline Derivatives.

Nanoparticles prepared using human serum albumin (HSA) have emerged as versatile carriers for improving the pharmacokinetic profile of drugs. The desolvation of HSA using ethanol followed by stabilization through crosslinking with glutaraldehyde is a common technique for preparing HSA nanoparticles, but our knowledge concerning the characteristics (or functions) of HSA nanoparticles and their efficiency when loaded with drugs is limited. To address this issue in more detail, we prepared anthracycline-loaded HSA nanoparticles.

Cardiac myoglobin participates in the metabolic pathway of selenium in rats.

As an essential micronutrient, selenium deficiency is a leading cause of cardiovascular diseases. The heart is continuously beating to deliver blood to the entire body, and this requires a high amount of energy. An adult heart normally obtains 50-70% of its adenosine 5'-triphosphate from fatty acid β-oxidation.

Selenoprotein L-inspired nano-vesicular peroxidase mimics based on amphiphilic diselenides.

In this study, we developed selenoprotein L-inspired nano-vesicular peroxidase mimics based on amphiphilic diselenides. Selenocystine (SeCyst) was used as the starting material for the synthesis of four liposomal membrane-compatible diselenide derivatives (R-Se-Se-R') with two hydrophobic tails and a polar part. The diselenide derivatives were successfully incorporated into the phosphatidylcholine (PC)-based nano-vesicular scaffold.

Characterization of Selenium Species in the Shijimi Clam.

Selenium is an essential trace element for humans and animals. Fish and shellfish are known to be rich in selenium and suppose to be an effective selenium source. In this study, we characterized the selenium species in the Shijimi clam (Corbicula japonica), which is a typical clam eaten in Japan.

Development of a Ge/Ga Generator System Using Polysaccharide Polymers and Its Application in PET Imaging of Tropical Infectious Diseases.

Gallium-68 (Ga) is a positron emitter for clinical positron emission tomography (PET) applications that can be produced by a Ge/Ga generator without cyclotron. However, commercially available Ge/Ga generator systems require multiple steps for the preparation of Ga radiopharmaceuticals and are sometimes plagued by metallic impurities in the Ga eluent. We developed a Ge/Ga generator system using polysaccharide-based adsorbents and direct application of the generator-eluted Ga-citrate to PET imaging of tropical infectious diseases.

Development of radioiodinated acridine derivatives for in vivo imaging of prion deposits in the brain.

Prion diseases are caused by deposition of abnormal prion protein aggregates (PrP) in the central nervous system. This study aimed to develop in vivo imaging probes that can detect cerebral PrP deposits. We synthesized several quinacrine-based acridine (AC) derivatives with 2,9-substitution and radioiodinated them.

Pronounced Cellular Uptake of Pirarubicin versus That of Other Anthracyclines: Comparison of HPMA Copolymer Conjugates of Pirarubicin and Doxorubicin.

Many conjugates of water-soluble polymers with biologically active molecules were developed during the last two decades. Although, therapeutic effects of these conjugates are affected by the properties of carriers, the properties of the attached drugs appear more important than the same carrier polymer in this case. Pirarubicin (THP), a tetrahydropyranyl derivative of doxorubicin (DOX), demonstrated more rapid cellular internalization and potent cytotoxicity than DOX.

Amyloid formation characteristics of GNNQQNY from yeast prion protein Sup35 and its seeding with heterogeneous polypeptides.

Sup35 is a prion-like protein from yeast and shares the ability to transmit its aberrant fold and to aggregate into amyloid fibrils. GNNQQNY from the prion-determining domain of Sup35 was reported to form an amyloid. We first investigated the self-aggregation transition behavior of GNNQQNY to the β-sheet amyloid state under various conditions.

Synthesis of Nanovesicular Glutathione Peroxidase Mimics with a Selenenylsulfide-Bearing Lipid.

In this article, we describe the development of a nanosized-glutathione peroxidase (GPx) mimic based on liposomes of which the amphiphilic selenenylsulfide derivative (R-Se-S-R') was incorporated into a lipid membrane. A lipid membrane-compatible selenenylsulfide derivative, 1-oxo-headecyl-seleno-l-cysteine-methyl--yl--l-penicillamine methyl ester (OHSeP), was synthesized. X-ray photoelectron spectroscopy revealed that the sulfur and selenium atoms of the OHSeP molecule formed a selenenylsulfide linkage.

Synthesis and evaluation of a radioiodinated 4,6-diaryl-3-cyano-2-pyridinone derivative as a survivin targeting SPECT probe for tumor imaging.

Survivin is overexpressed in most of the cancerous tissues but not in terminally differentiated normal tissues, making it an attractive target for diagnosis and therapy of various types of cancers. In this study, we aimed to develop 4,6-diaryl-3-cyano-2-pyridinone (DCP) derivatives, as novel cancer imaging probes that target survivin. Chloro and iodo analogs of DCP (CDCP and IDCP, respectively) were successfully synthesized by using a previously unreported carbon monoxide-free procedure.

A Comprehensive Analysis of Selenium-Binding Proteins in the Brain Using Its Reactive Metabolite.

The intracellular metabolism of selenium in the brain currently remains unknown, although the antioxidant activity of this element is widely acknowledged to be important in maintaining brain functions. In this study, a comprehensive method for identifying the selenium-binding proteins using PenSSeSPen as a model of the selenium metabolite, selenotrisulfide (RSSeSR, STS), was applied to a complex cell lysate generated from the rat brain. Most of the selenium from L-penicillamine selenotrisulfide (PenSSeSPen) was captured by the cytosolic protein thiols in the form of STS through the thiol-exchange reaction (R-SH+PenSSeSPen→R-SSeSPen+PenSH).

Characterisation of radioiodinated flavonoid derivatives for SPECT imaging of cerebral prion deposits.

Prion diseases are fatal neurodegenerative diseases characterised by deposition of amyloid plaques containing abnormal prion protein aggregates (PrP(Sc)). This study aimed to evaluate the potential of radioiodinated flavonoid derivatives for single photon emission computed tomography (SPECT) imaging of PrP(Sc). In vitro binding assays using recombinant mouse PrP (rMoPrP) aggregates revealed that the 4-dimethylamino-substituted styrylchromone derivative (SC-NMe2) had higher in vitro binding affinity (Kd = 24.

Development of alkoxy styrylchromone derivatives for imaging of cerebral amyloid-β plaques with SPECT.

We report here the development of radioiodinated styrylchromone derivatives with alkoxy groups as single photon emission computed tomography (SPECT) imaging probes for cerebral amyloid-β (Aβ) plaques. Among the derivatives, the methoxy derivative 14 and the dimethoxy derivative 15 displayed relatively high affinity for the Aβ(1-42) aggregates with K(i) values of 22 and 46 nM, respectively. Fluorescent imaging demonstrated that 14 and 15 clearly labeled thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice.

An effective method for profiling the selenium-binding proteins using its reactive metabolic intermediate.

Currently, the intracellular reduction and/or transport of selenium still remain unknown. Certain reduced forms of selenium species are thought to be reactive with various endogenous molecules, particularly thiol-containing proteins. In this study, a profiling method for identifying the selenium-binding proteins using L-penicillamine selenotrisulfide (PenSSeSPen) as a model of the selenium metabolic intermediate was applied to the cell lysate generated from the rat liver.

Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT.

We report radioiodinated chalcone derivatives as new SPECT imaging probes for amyloid β (Aβ) plaques. The monoethyleneoxy derivative 2 and allyloxy derivative 8 showed a high affinity for Aβ(1-42) aggregates with Ki values of 24 and 4.5 nM, respectively.