- γ-Glutamyl PAMAM Dendrimer as Versatile Precursor for Dendrimer-Based Targeting Devices
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Poly(amidoamine) (PAMAM) dendrimers are highly branched spherical polymers that have a unique surface of primary amine groups and provide a versatile design for targeted delivery of pharmaceuticals and imaging agents. Acetylation or succinylation of surface amine groups of PAMAM dendrimer derivatives is frequently performed to reduce nonspecific uptake. However, since targeting molecules, drugs/imaging agents, and acylating reagents react with the amine groups on dendrimer, such modification may limit the number of targeting molecules and/or drugs or may result in insufficient charge reduction. In this study, a γ-glutamyl PAMAM dendrimer was designed and synthesized as a new precursor for targeting device. The relationship between surface electrical properties of the PAMAM dendrimer derivatives and pharmacokinetics was also determined. A PAMAM dendrimer (generation 4.0) was modified with a small number of Bolton-Hunter reagent to prepare Phe-P (pI 9.2). The amine residues of Phe-P were a?-glutamylated to prepare Glu-P (pI 7.1). The α-amine residues of Glu-P were then acetylated or succinylated to prepare Ac-Glu-P (pI 5.3) or Suc-Glu-P (pI 3.6). For comparison, Phe-P was acetylated or succinylated to prepare Ac-P (pI 6.0) or Suc-P (pI 5.1). All the PAMAM dendrimer derivatives exhibited similar molecular size (7.2 to 7.8 nm) except for Ac-P (5.1 nm). The biodistribution studies were performed after radioiodination of each PAMAM dendrimer derivative with Na[125I]I. When injected intravenously to mice, both [125I]Ac-P and [125I]Suc-P exhibited prolonged radioactivity levels in the blood and significantly lower hepatic and renal radioactivity levels than those of [125I]Phe-P. Both [ 125I]Glu-P and [125I]Ac-Glu-P showed residence times in the blood similar to those of [125I]Ac-P and [125I]Suc-P. However, [125I]Glu-P also registered higher radioactivity levels in the kidney. High hepatic and renal radioactivity levels were observed with highly anionic [125I]Suc-Glu-P. These results indicate that, while the manipulation of pI between 5 to 6 would be appropriate to enhance blood retention and reduce renal and hepatic uptake, the amount of primary amine residues on dendrimer surface may also play a crucial role in their renal uptake. The findings in this study show that γ-glutamyl PAMAM dendrimers would constitute versatile precursors to prepare PAMAM dendrimer-based targeting devices due to their neutral molecular charge (pI 7.1) and the presence of a large number of α-amine residues available for conjugation of targeting molecules and drugs/imaging agents.
- Uehara, Tomoya,Ishii, Daisuke,Uemura, Tomoe,Suzuki, Hiroyuki,Kanei, Tomoko,Takagi, Kyoko,Takama, Masashi,Murakami, Masahiro,Akizawa, Hiromichi,Arano, Yasushi
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- Selenocysteine as a Substrate, an Inhibitor and a Mechanistic Probe for Bacterial and Fungal Iron-Dependent Sulfoxide Synthases
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Sulfoxide synthases are non-heme iron enzymes that participate in the biosynthesis of thiohistidines, such as ergothioneine and ovothiol A. The sulfoxide synthase EgtB from Chloracidobacterium thermophilum (CthEgtB) catalyzes oxidative coupling between the side chains of N-α-trimethyl histidine (TMH) and cysteine (Cys) in a reaction that entails complete reduction of molecular oxygen, carbon–sulfur (C?S) and sulfur–oxygen (S?O) bond formation as well as carbon–hydrogen (C?H) bond cleavage. In this report, we show that CthEgtB and other bacterial sulfoxide synthases cannot efficiently accept selenocysteine (SeCys) as a substrate in place of cysteine. In contrast, the sulfoxide synthase from the filamentous fungus Chaetomium thermophilum (CthEgt1) catalyzes C?S and C?Se bond formation at almost equal efficiency. We discuss evidence suggesting that this functional difference between bacterial and fungal sulfoxide synthases emerges from different modes of oxygen activation.
- Flückiger, Sebastian,Goncharenko, Kristina V.,Liao, Cangsong,Lim, David,Seebeck, Florian P.,Stampfli, Anja R.
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- POLYMER OF GAMMA-GLUTAMYL TRANSPEPTIDASE CATALYZING HYDROLYSIS-INDUCED CHARGE REVERSAL AND ITS APPLICATION IN THE FIELD OF DRUG DELIVERY
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This present invention relates to a polymer of γ-glutamyl transpeptidase catalyzing hydrolysis-induced charge reversal. The polymer comprises a γ-glutamyl transpeptidase-responsive element represented by Formula (I). When the polymer is used as drug carrier for anticancer drug, it can have a long circulation time in the blood, and can realize a charge reversal from negatively charged or the neutral to positively charged around the tumor blood vessel region, so that the positively charged polymer effectively penetrates deep into the tumor tissue, fast entering into the tumor cells, and greatly improves the therapeutic effect of the drug on the tumor. This overcomes the problems of slow diffusion of traditional polymer drug carriers in tumors and weak interaction with tumor cells, and has great significance in the field of anticancer treatment in the medical field.
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Paragraph 0077
(2020/07/23)
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- COMPOSITIONS OF SELENOORGANIC COMPOUNDS AND METHODS OF USE THEREOF
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The present application relates to compositions comprising selenium compounds, such as 5'-Methylselenoadenosine, Se-Adenosyl-L-homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of Formula (I), Formula (II), or Formula (III), and combinations thereof, and methods of using the same for modulating glucose metabolism in a subject.
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Paragraph 0260; 0261
(2017/04/04)
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- COMPOSITIONS OF SELENOORGANIC COMPOUNDS AND METHODS OF USE THEREOF
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The present application relates to compositions comprising selenium compounds, such as 5'-Methylselenoadenosine, Se-Adenosyl-L -homocysteine, Gamma- glutamyl-methylseleno-cysteine, a compound of formula (I), formula (II), a compound of formula (III) and combinations thereof, and methods of using the same in enhancing mitochondrial function, or treating mitochondrial dysfunction.
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Page/Page column 76
(2015/10/05)
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- COMPOSITIONS COMPRISING SELENIUM AND USE OF SAME FOR THE TREATMENT AND PREVENTION OF DISEASE OR CONDITIONS ASSOCIATED WITH MITOCHONDRIAL DYSFUNCTION
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The present application relates to compositions comprising selenium (e.g., selenium enriched yeast and selenium containing compounds obtained or derived therefrom) and methods of using the same to treat and inhibit obesity, diabetes and related conditions
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Page/Page column 124
(2014/09/29)
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- Amino acid and peptide synthesis and functionalization by the reaction of thioacids with 2,4-dinitrobenzenesulfonamides
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(Formula Presented) Readily prepared amino thioacids react at room temperature in DMF in the presence of cesium carbonate with 2,4- dinitrobenzenesulfonamides to give amides. When the sulfonamide is derived from an amino acid the method results in peptide bond formation, whereas the use of carbohydrate derived sulfonamides gives neoglycoconjugates.
- Crich, David,Sana, Kasinath,Guo, Songpo
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p. 4423 - 4426
(2008/03/12)
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- Synthesis and NMR Characterization of the Trypanosomatid Metabolite, N1,N8-Bis(glutathionyl)spermidine Disulphide (Trypanothione Disulphide)
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An optimized chemical synthesis of the novel trypanosomatid metabolite, N1,N8-bis(glutathionyl)spermidine (trypanothione disulphide) is described, and its solution structure has been investigated by NMR spectroscopy.The 1H, 13C, and
- Henderson, Graeme B.,Glushka, John,Cowburn, David,Cerami, Anthony
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p. 911 - 914
(2007/10/02)
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