- Synthesis of α-Amino Acid N-Carboxyanhydrides
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A simple phosgene- and halogen-free method for synthesizing α-amino acid N-carboxyanhydrides (NCAs) is described. The reaction between Boc-protected α-amino acids and T3P reagent gave the corresponding NCA derivatives in good yield and purity with no detectable epimerization. The process is safe, is easy-to-operate, and does not require any specific installation. It generates nontoxic, easy to remove byproducts. It can apply to the preparation of NCAs for the on-demand on-site production of either little or large quantities.
- Laconde, Guillaume,Amblard, Muriel,Martinez, Jean
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p. 6412 - 6416
(2021/08/30)
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- Theranostic Layer-by-Layer Nanoparticles for Simultaneous Tumor Detection and Gene Silencing
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Layer-by-layer nanoparticles (NPs) are modular drug delivery vehicles that incorporate multiple functional materials through sequential deposition of polyelectrolytes onto charged nanoparticle cores. Herein, we combined the multicomponent features and tumor targeting capabilities of layer-by-layer assembly with functional biosensing peptides to create a new class of nanotheranostics. These NPs encapsulate a high weight percentage of siRNA while also carrying a synthetic biosensing peptide on the surface that is cleaved into a urinary reporter upon exposure to specific proteases overexpressed in the tumor microenvironment. Importantly, this biosensor reports back on a molecular signature characteristic to metastatic tumors and associated with poor prognosis, MMP9 protease overexpression. This nanotheranostic mediates noninvasive urinary-based diagnostics in mouse models of three different cancers with simultaneous gene silencing in flank and metastatic mouse models of ovarian cancer.
- Bhatia, Sangeeta N.,Boehnke, Natalie,Correa, Santiago,Hammond, Paula T.,Hao, Liangliang,Straehla, Joelle P.,Wang, Wade
-
supporting information
p. 2776 - 2783
(2020/01/22)
-
- Block copolymer [(l-GluA-5-BE)-: B -(l-AspA-4-BE)]-based nanoflower capsules with thermosensitive morphology and pH-responsive drug release for cancer therapy
-
Herein, the synthesis of an amino-acid-based di-block copolymer (di-BCP) in-between an l-glutamic acid-5-benzyl ester and l-aspartic acid-4-benzyl ester [(l-GluA-5-BE)-b-(l-AspA-4-BE)] has been reported. However, the synthesis of di-BCP of [(l-GluA-5-BE)-b-(l-AspA-4-BE)] was carried out through the facile modified ring-opening polymerization (ROP) without using any surfactants and harmful chemicals. Interestingly, the synthesized [(l-GluA-5-BE)-b-(l-AspA-4-BE)] has been used to design nanoflower capsules (NFCs) with surface-functionalized nanoflakes and petals. Notably, the simple solvent propanol has been used as a dispersing medium for the di-BCP-based powder to observe morphology of NFCs. Moreover, these amino-acid-based NFCs are biocompatible, biodegradable, and bio-safe for mankind usage. Consequently, di-BCP-based NFCs show changes in morphology with different temperature conditions, i.e., at ~10 °C, ~25 °C (RT), and ~37 °C (body temperature). Furthermore, the average thickness of the surface-functionalized nanopetals has been calculated as ~324 nm (in diameter). Similarly, the average distance between petals is calculated as 3.6 μm and the pore depth is ~21 nm. Additionally, the porosity throughout the surface of capsules in-between nanopetals is an advantageous characteristic feature to improve the drug/paclitaxel (PTX) loading capacity. It is a unique and novel approach to design NFCs, which are a potential payload for nanomedicine and cancer therapy. Furthermore, NFCs were used to evaluate the loading efficacy of drugs and showed ~78% (wt/wt%) of the PTX loading. Moreover, NFCs showed ~74% drug release at physiological body temperature. Thus, NFCs showed remarkable release at acidic pH medium. However, PTX released from NFCs showed greater cell inhibition (i.e., ~79%) with an increase of the PTX concentration after 24 h incubation over HeLa (human epithelial cervical cancer) cells. Besides, PTX released from NFC showed significant (~34%) cell killing capacity. Such promising NFCs are recommended for breast, liver, and lung cancer therapeutics.
- Amgoth, Chander,Chen, Shuai,Malavath, Tirupathi,Tang, Guping
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supporting information
p. 9258 - 9268
(2020/11/03)
-
- A pH and temperature double sensibility of nanometer vesicle and its preparation method and application
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The invention belongs to the fields of high polymer chemistry and biomedical engineering, and particularly discloses a pH and temperature sensitive polymer. The polymer is composed of a hydrophilic polyethylene glycol segment, and a lyophobic poly-(aspartic acid-diethyl-ethylenediamine-co-histamine-co-diisopropyl ethylenediamine) segment, and the ratio of the hydrophilic segment to the lyophobic segment is (1:10)-(1:12). The pH and temperature sensitive polymer can be used for preparing nano-vesicles loaded with hydrophilic anti-tumor drugs or/and ultrasonic contrast agents, and the nano-vesicles can be used for preparing tumor diagnosis drugs or tumor treatment drugs.
- -
-
Paragraph 0044; 0048-0050
(2019/02/19)
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- Photo-thermal chemotherapy and treatment combined microenvironment responsive drug-loading nano micelle preparation method and application
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The invention discloses a photo-thermal chemotherapy and treatment combined microenvironment responsive drug-loading nano micelle preparation method and application. A nano micelle comprises TIID-BT,a medicine active component and an amphiphilic block polymer, and the amphiphilic block polymer refers to polyethylene glycol-polyaspartic acid. By synthesis, a near infrared TIID-BT dye and a DOX chemotherapy drug are loaded on the specific nano micelle at the same time to obtain the nano micelle which is capable of giving play to photo-thermal treatment and chemotherapy at the same time. The nano micelle enables DOX to avoid a combination effect of opsonin and a capturing effect of an MPS system to form a stable and long-acting drug delivery system with high drug loading capacity, and accordingly an antitumor effect of DOX is improved while DOX resistance of tumors is changed. In addition, due to loading of the TIID-BT dye in the nano micelle, in-vivo application effects of the TIID-BT dye are improved, combination of hoto-thermal treatment and chemotherapy is realized, and in-vivo tumor treatment effects are improved due to synergistic effects of DOX and TIID-BT.
- -
-
Paragraph 0046; 0052; 0055-0056
(2019/06/27)
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- Tumor intelligent targeting and environmental double responsiveness siRNA delivery system and its preparation method and application
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The invention particularly discloses an intelligent targeting and environmental dual-responsibility siRNA [short interfering RNA (ribonucleic acid)] delivery system for tumor, a preparation method and application. The siRNA delivery system is characterized in that siRNA is concentrated and compounded in nanometer particle nucleuses by the aid of acid-sensitive amphiphilic three-block polymers, and intermolecular disulfide bonds are formed by PAsp(MEA) on sub-surfaces, so that the siRNA can be protected, and the intelligent targeting and environmental dual-responsibility siRNA delivery system can respond to release of the siRNA in reductive cytoplasm. The acid-sensitive amphiphilic three-block polymers comprise polyethylene glycol block-intermediate block-acid-sensitive block three-block copolymers, intermediate blocks comprise polyaspartate acyl mercaptoethylamine, and acid-sensitive blocks comprise poly (diisopropyl amine) ethyl methacrylate. The intelligent targeting and environmental dual-responsibility siRNA delivery system, the preparation method and the application have the advantages that the siRNA delivery system can be applied to preparing intelligent targeting siRNA nanometer medicines for the tumor and is low in N/P ratio dependence degree, and the siRNA can be quickly and completely released at targets; a novel idea can be provided for gene delivery systems, and the intelligent targeting and environmental dual-responsibility siRNA delivery system, the preparation method and the application have important significance on preparing clinical diagnosis and treatment medicines for the tumor.
- -
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Paragraph 0039; 0040; 0041; 0043
(2019/02/19)
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- Preparation method of drug-loaded nano-micelle capable of releasing anti-cancer drug in tumor matrix as well as product and application of drug-loaded nano-micelle
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The invention relates to a preparation method of a drug-loaded nano-micelle capable of releasing an anti-cancer drug in a tumor matrix as well as a product and an application of the drug-loaded nano-micelle, which belongs to the technical field of drug carriers. The preparation method comprises the following steps: the beta-benzyl aspartate is prepared, benzyloxycarbonyl aspartic anhydride is prepared, a polyaspartic acid benzyl ester polymer is prepared, a carboxylation-polyaspartic acid benzyl ester polymer is prepared, a carboxyl-polyaspartic acid dimethylethylenediamine polymer is prepared, a polyaspartic acid dimethylethylenediamine-polyaspartic acid benzyl ester polymer is prepared, a poly(aspartic acid-dimethylethylenediamine)-poly (aspartic acid-mercaptoethylamine) polymer is prepared, and drug-loaded nano-micelle for releasing an anti-cancer drug in a tumor matrix is prepared. The drug-loaded nano-micelle prepared by the preparation method has double sensitivities of pH sensitivity and reduction sensitivity, can accurately release drugs, and effectively improves the tumor treatment effect.
- -
-
Paragraph 0058-0060
(2019/12/25)
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- Thermoresponsive Alignment Media in NMR Spectroscopy: Helix Reversal of a Copolyaspartate at Ambient Temperatures
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Poly(aspartic acid esters) are known to form either right-or left-handed α-helices depending on the ester group in the side chain, on solvent and/or on temperature. Polyphenethyl-l-aspartates (PPLA) exhibit a helix reversal from the right- to the left-handed form with increasing temperature. We have recently reported the application of polyphenethylaspartates as helically chiral alignment media. The thermoresponsivity observed for these polymers offers the possibility to measure different orientations of analytes before and after helix reversal of the alignment medium at 373 K. Herein we present a synthesized copolymer of phenethyl- and benzylaspartate as a new alignment medium undergoing this helix reversal at 303–313 K. Thus, the measurement of residual dipolar couplings (RDC) before and after the helix reversal is allowed for at ambient temperatures. A complete sign change of all 1H–13C RDCs was observed, which is close to the highest possible difference in NMR spectra.
- Schwab, Mira,Schmidts, Volker,Thiele, Christina M.
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p. 14373 - 14377
(2018/09/20)
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- Polymeric micelles for pH-responsive lutein delivery
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There has been growing interests in nanoparticulate delivery of the natural carotenoid, lutein for anti-cancer therapy. However, the low aqueous solubility of lutein and the poor lutein release from nanocarriers limit its bioavailability and therapeutic o
- Zhang, Dongxue,Wang, Lina,Zhang, Xin,Bao, Decai,Zhao, Yanjun
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p. 281 - 286
(2018/03/26)
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- UNIMOLECULAR NANOPARTICLES FOR EFFICIENT DELIVERY OF THERAPEUTIC CATIONIC PEPTIDES
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Provided herein are peptides comprising an amino acid sequence having at least about 85% sequence identity to RYRPRAPIIAVT (SEQ ID NO: 1). These cationic peptides inhibit PKM2 methylation and may be used in the treatment of breast cancer and other diseases or conditions in which PKM2 is overexpressed. Such PKM2 peptides may be delivered to cancer cells using pH sensitive unimolecular nanoparticles comprising anionic polymers.
- -
-
Paragraph 0125
(2018/09/12)
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- Novel mesoporous silicon sphere co-loaded medicine nano-complex and preparation method thereof
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The invention discloses a novel mesoporous silicon sphere co-loaded medicine nano-complex and a preparation method thereof. The novel mesoporous silicon sphere co-loaded medicine nano-complex is Ce6@MMSN/DOX/Ko143@PAsp-b-PEG-FA; the preparation method comprises the following steps: selecting TEOS (Tetraethyl Orthosilicate) as a silicon source, CTAB (Cetyltrimethyl Ammonium Bromide) as a template agent and n-hexane as a pore expanding agent and synthesizing mesoporous silicon dioxide nanoparticles with a double-pore-channel core-shell structure; carrying out amination modification on the mesoporous silicon dioxide nanoparticles; synthesizing Fe3O4 nanoparticles by adopting an LSS (Liquid-Solid-Solution) phase transfer method and ligand exchange reaction; modifying and embedding superparamagnetic iron oxide nanoparticles on the surface of aminated MSN through nucleophilic substitution, so as to construct magnetic mesoporous silicon dioxide nanoparticles; taking DCC (Dicyclollexyl Carbodiimide) as a condensation agent and covalently binding a photosensitizer Ce6 through amidation; meanwhile, loading a BCRP (Breast Cancer Resistance Protein) inhibitor Ko143; then crossly linking a copolymer FA-PEG-b-PAsp; finally, loading an anti-tumor medicine DOX.
- -
-
Paragraph 0056-0057
(2018/11/26)
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- Large-scale synthesis of α-amino acid-N-carboxyanhydrides
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Hetero- and homopolymers prepared from α-amino acid-N-carboxyanhydrides (NCAs) monomers are widely useful products. The preparation of pure NCA monomers has been extensively studied in the past. Purification methods including repeated crystallizations, extraction, and flash column chromatography have been devised. However, these methods are not easily amendable to large-scale NCA preparations. This article describes the synthesis of numerous highly purified NCAs on a >100 g scale using a simple filtration step through diatomaceous earth (celite). The resulting NCAs provided polyethylene glycol (PEG)–amino acid triblock polymers devoid of low-molecular-weight by-products that were routinely observed when unfiltered batches of NCAs were used. Also disclosed is the preparation of NCAs at ambient temperature. Traditionally, NCA reactions using a phosgene source are heated. This study shows these reactions can be driven by the slight exotherm that forms upon reagent mixing. This eliminates the need for an external heating source, simplifying large-scale reactions.
- Semple, J. Edward,Sullivan, Bradford,Sill, Kevin N.
-
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- Glutathione and endosomal pH-responsive hybrid vesicles fabricated by zwitterionic polymer block poly(L-aspartic acid) as a smart anticancer delivery platform
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Zwitterionic hybrid block copolymer based nanocarriers are ideal candidates for drug delivery applications due the higher resistance to nonspecific protein adsorption in complex media compared to nonionic polymers. Especially, zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) p(MPC) based nanocarriers can maintain its stability during circulation in complex media, such as serum. Thus, a series of bioreducible and pH-responsive zwitterionic/amphiphilic block copolymers, poly(2-methacryloyloxyethyl phosphorylcholine)50-block-poly(L-aspartic acid)n (p(MPC)50–b–p(AA)n) (n = 10, 25, 50, 75), bearing a degradable disulfide linker have been synthesized and exploited as dual-stimuli-responsive drug delivery vehicle of the chemotherapeutic drug, doxorubicin (Dox). Dox was successfully loaded into uniform vesicles (~ 100 nm) fabricated from p(MPC)50–b–p(AA)n and the release performance was investigated under different pH conditions and with a range of concentrations of the reducing agent, 1,4-dithiothreitol (DTT). At physiological conditions, increasing concentrations of DTT resulted in faster Dox release from vesicles. Dox release at elevated DTT concentrations was more effective at pH 5.5 than at pH 7.5. Blank vesicles were non-toxic over a wide concentration range when tested in normal cell lines (0.01–100 μg/mL). Vesicles efficiently encapsulated Dox and the dual stimuli-responsive disassembly results demonstrated controlled and sustained release of Dox tin 4T1 cancer cells to confer dose-dependent cytotoxicity. Thus, the bioreducible and pH sensitive vesicles appear to be a promising theranostic platform for drug delivery applications.
- Johnson, Renjith P.,Uthaman, Saji,Augustine, Rimesh,Zhang, Yu,Jin, Hua,Choi, Chang In,Park, In-Kyu,Kim, Il
-
-
- STIMULI-RESPONSIVE POLYMERIC NANOPARTICLES, METHODS OF MAKING STIMULI-RESPONSIVE POLYMERIC NANOPARTICLES, AND METHODS OF USING STIMULI-RESPONSIVE POLYMERIC NANOPARTICLES
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Embodiments of the present disclosure provide for compositions including polymer particles, methods of making compositions, methods of using the composition, stimuli- responsive methods of delivering agents, and the like.
- -
-
Page/Page column 29
(2017/08/01)
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- Design of Block Copolymer Micellar Aggregates for Co-Delivery of Enzyme and Anticancer Prodrug
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Traditional enzyme–prodrug therapy (EPT) is a two-step strategy, which has many serious deficiencies, so having a one-step EPT treatment becomes a problem of immediate interest. This study aims to achieve an effective co-delivery of horseradish peroxidase (HRP) as a kind of enzyme for prodrug activation and ethyl 3-indoleacetate (EIA) as anticancer prodrug. A ternary block copolymer PEG-PAsp(AED)-CA consisting of poly(ethylene glycol) (PEG), reduction-sensitive poly (N-(2,2′-dithiobis(ethylamine)) aspartamide) PAsp(AED), and cholic acid (CA) was synthesized and assembled into spherical micelles which encapsulated EIA in its hydrophobic core and HRP in a reduction-sensitive interlayer. TEM photographs show that the polymer micelle is around 40 nm, and the cell survival rate test shows that the EIA/HRP polymer micelle is highly lethal to human lung adenocarcinoma cells. Thus, co-delivery of EIA and HRP demonstrates great potential in cancer therapy, offering a structurally simple and highly tunable platform for the synchronous delivery of enzymes and prodrugs in EPT.
- Li, Hongping,Chen, Lulu,Shi, Yuting,Yuan, Binbin,Ma, Yingxia,Wei, Hua,Zhao, Guanghui
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p. 176 - 180
(2017/02/05)
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- Novel preparation method for anti-type-II-diabetes drug sitagliptin
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The invention discloses a novel preparation method for an anti-type-II-diabetes drug sitagliptin. According to the invention, trifluorobenzene with a cheaper price is used as a fluorization reagent and a starting raw material and a basic skeleton of sitagliptin is successfully synthesized through effective acylation of trifluorobenzene and L-aspartic acid; a synthesis route in the invention, from starting raw material and final product, is completely different from schemes disclosed in the prior art; the route is optimized, and easily-available natural L-aspartic acid is used as a chiral source for successful synthesis of an optically pure sitagliptin product; the problems of asymmetric catalysis and complex splitting in the prior art are overcome; the method also effectively overcomes the problem of low yield of the basic skeleton of sitagliptin synthesized via Friedel-Crafts acylation of trifluorobenzene and improves yield; the method is lower in cost, more convenient to operate and more suitable for industrial production; and compared with the prior art, the method is simpler in the synthesis route and better in operability.
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-
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- A transmission for a total of medicine and liquid fluorocarbon polymer nano vesicle and its preparation method and application
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The invention relates to an acid-sensitive amphipathic tri-block polymer. The polymer is composed of a polyethylene glycol-acid sensitive segment 1-acid sensitive segment 2 tri-block copolymer, wherein the acid sensitive segment 1 is poly(acrylamidophenylboronic acid); the acid sensitive segment 2 is poly(aminoacyl dimethyl-ethylenediamine); the molecular weight of the polyethylene glycol is 2000-5000, the molecular weight of the acid sensitive segment is 2000-6000, and the molecular weight of the acid sensitive segment is 1000-2000. The invention further relates to application of the acid sensitive amphipathic tri-block polymer in preparation of polymer nano-vesicle for co-delivering drug and perfluorooctylbromide. The nano-vesicle has a uniform nano-diameter, can stably circulate in a body and can be enriched in a tumor position, has excellent capability of reinforcing ultrasonic development to realize application of ultrasonic development under diagnostic ultrasound, and has ultrasonic sensitivity to stimulate the cavitation effect under a condition of low-frequency high-energy ultrasonic-radiation so as to realize controllable release of drugs.
- -
-
Paragraph 0040; 0044-0046
(2018/01/11)
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- Combinatorial Polymeric Conjugated Micelles with Dual Cytotoxic and Antiangiogenic Effects for the Treatment of Ovarian Cancer
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Emerging treatment paradigms like targeting the tumor microenvironment and/or dosing as part of a metronomic regimen are anticipated to produce better outcomes in ovarian cancer, but current drug delivery systems are lacking. We have designed and evaluated paclitaxel (PTX) and rapamycin (RAP) micellar systems that can be tailored for various dosing regimens and target tumor microenvironment. Individual and mixed PTX/RAP (MIX-M) micelles are prepared by conjugating drugs to a poly(ethylene glycol)-block-poly(β-benzyl l-aspartate) using a pH-sensitive linker. The micelles release the drug(s) at pH 5.5 indicating preferential release in the acidic endosomal/lysosomal environment. Micelles exhibit antiproliferative effects in ovarian cell cancer lines (SKOV-3 (human caucasian ovarian adenocarcinoma) and ES2 (human ovarian clear cell carcinoma)) and an endothelial cell line (HUVEC; human umbilical vein endothelial cells) with the MIX-M being synergistic. The micelles also inhibited endothelial migration and tube formation. In healthy mice, micelles at 60 mg/kg/drug demonstrated no acute toxicity over 21 days. ES2 xenograft model efficacy studies at 20 mg/kg/drug dosed every 4 days and evaluated at 21 days indicate that the individual micelles exhibit antiangiogenic effects, while the MIX-M exhibited both antiangiogenic and apoptotic induction that results in significant tumor volume reduction. On the basis of our results, MIX-M micelles can be utilized to achieve synergistic apoptotic and antiangiogenic effects when treated at frequent low doses.
- Rao, Deepa A.,Mishra, Gyan,Doddapaneni, Bhuvana Shyam,Kyryachenko, Sergiy,Wierzbicki, Igor H.,Ngyuen, Duc X.,Shah, Vidhi,Al Fatease, Adel M.,Alany, Raid G.,Alani, Adam W. G.
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p. 6068 - 6079
(2016/10/22)
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- CISPLATIN COMPLEX AND PREPARATION METHOD THEREOF
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A CDDP complex is formed by complexation of CDDP and a polymer having a structure of Formula (I). The CDDP complex has good biocompatibility and is degradable. A side chain of the polymer is grafted with polyethylene glycol, which gives the CDDP complex good dissolvability. When dissolved in an aqueous medium, the CDDP is protected by a hydrophilic polyethylene glycol chain segment and a hydrophobic amino acid chain segment, which can effectively avoid a sudden release of the CDDP due to the influence of the blood circulation system after intravenous injection, thus improving the stability of the CDDP complex. A carboxyl group contained in the CDDP complex has pH value sensitivity and tends to be deprotonated in a low pH environment, which is advantageous for promoting the release of a drug, and improving the efficiency of the drug.
- -
-
Paragraph 0113
(2015/09/22)
-
- Amino acid modified hyperbranched poly(ethylene imine) with disaccharide decoration as anionic core-shell architecture: Influence of the pH and molecular architecture on solution behaviour
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Dendritic polymers represent a class of materials for prospective drug delivery application. For that purpose we present the synthesis and characterization of hydrophilic, anionic core-shell architectures based on poly(ethylene imine) (PEI) as core molecule and polyamino acid chains (composed of glutamic acid or aspartic acid) as shell component. NCA polymerization is used for coupling polyamino acid chains to PEI scaffold. Modifying these structures with sugar molecules result in the formation of new core-shell architectures combining a mixture of binary and double shell. For their potential biomedical applications the solution properties of these anionic core-shell architectures at various pH values (3-9) were studied by different analytical tools (zeta potential, streaming potential pH titration, DLS, AFM, in-situ AFM, TEM and cryo-TEM). Especially, the sugar-decorated core-shell architectures mainly provide isolated macromolecules over a broad pH range. Furthermore, the anionic core-shell architectures are suited to interact with cationic molecules.
- Striegler, Christin,Franke, Markus,Müller, Martin,Boye, Susanne,Oertel, Ulrich,Janke, Andreas,Schellkopf, Leonard,Voit, Brigitte,Appelhans, Dietmar
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p. 188 - 204
(2015/11/17)
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- A charge-switchable, four-armed polymeric photosensitizer for photodynamic cancer therapy
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A water-soluble, charge-switchable, four-armed polymeric photosensitizer (C4P-PS), in which charge switching is pH dependent, has been designed as a new class of photosensitizer for photodynamic cancer therapy.
- Lee, Chung-Sung,Park, Wooram,Jo, Young Um,Na, Kun
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supporting information
p. 4354 - 4357
(2014/04/17)
-
- Tumor-preferential sustained drug release enhances antitumor activity of block copolymer micelles
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Nanoparticles are widely used as drug carriers for controlled, tumor-targeted delivery of various anticancer agents that have biopharmaceutical limitations such as water solubility and tissue permeability. Growing evidence suggests that nanoparticles not only reduce toxic side effects of anticancer drugs but also improve the therapeutic efficacy as a function of their drug-release profile. The purpose of this study is to confirm such hypothetical effects of tunable drug release on improving antitumor activity of nanoparticles in vitro and in vivo, using block copolymer micelles as drug carriers. Micelles were prepared from poly(ethylene glycol)-poly(aspartate) block copolymers modified with hydrazide (HYD), aminobenzoate hydrazide (ABZ) and glycine hydrazide (GLY) linkers to achieve a pH-dependent, tunable release of doxorubicin (DOX), a model anticancer drug. Regardless of the drug-release profile, all three micelles showed similar properties in vitro, such as pH-dependent drug release, intracellular drug delivery and cancer cell growth inhibition. However, micelles releasing DOX slowly in vitro showed that the most effective antitumor activity in vivo, compared to the micelles releasing drugs faster. These results demonstrate that tumor-preferential sustained drug release can enhance the antitumor activity of the micelles.
- Ponta, Andrei,Bae, Younsoo
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p. 619 - 628
(2014/08/05)
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- Multifunctional envelope-type mesoporous silica nanoparticles for tumor-triggered targeting drug delivery
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A novel type of cellular-uptake-shielding multifunctional envelope-type mesoporous silica nanoparticle (MEMSN) was designed for tumor-triggered targeting drug delivery to cancerous cells. β-Cyclodextrin (β-CD) was anchored on the surface of mesoporous silica nanoparticles via disulfide linking for glutathione-induced intracellular drug release. Then a peptide sequence containing Arg-Gly-Asp (RGD) motif and matrix metalloproteinase (MMP) substrate peptide Pro-Leu-Gly-Val-Arg (PLGVR) was introduced onto the surface of the nanoparticles via host-guest interaction. To protect the targeting ligand and prevent the nanoparticles from being uptaken by normal cells, the nanoparticles were further decorated with poly(aspartic acid) (PASP) to obtain MEMSN. In vitro study demonstrated that MEMSN was shielded against normal cells. After reaching the tumor cells, the targeting property could be switched on by removing the PASP protection layer via hydrolyzation of PLGVR at the MMP-rich tumor cells, which enabled the easy uptake of drug-loaded nanoparticles by tumor cells and subsequent glutathione-induced drug release intracellularly.
- Zhang, Jing,Yuan, Zhe-Fan,Wang, Ya,Chen, Wei-Hai,Luo, Guo-Feng,Cheng, Si-Xue,Zhuo, Ren-Xi,Zhang, Xian-Zheng
-
supporting information
p. 5068 - 5073
(2013/06/04)
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- BLOCK COPOLYMER CROSS-LINKED NANOASSEMBLIES AS MODULAR DELIVERY VEHICLES
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A nanoassembly includes a core protected by a biocompatible shell. The nanoassembly includes a plurality of block copolymers including drug-binding linkers and block copolymer cross-linkers. A first active agent is covalently conjugated to the plurality of block copolymers and a second active agent is physically entrapped in the core.
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Paragraph 0086
(2013/03/28)
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- Highly efficient theranostics system based on surface-modified gold nanocarriers for imaging and photodynamic therapy of cancer
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Nanoparticle technologies are significantly impacting the development of both therapeutic and diagnostic agents. At the intersection between treatment and diagnosis, interest has grown for combining both paradigms into clinically effective formulations. In this study we describe a highly efficient drug vector for photodynamic therapy (PDT) and cell imaging developed by designing multifunctional and biodegradable block copolymer-gold nanoparticle (AuNP) conjugates. These conjugates act as water-soluble and biocompatible carriers that allow the delivery of a hydrophobic photosensitizer to a tumor site for PDT action. The 17.6 nm citrate-stabilized AuNPs used herein were modified with folic acid (FA)-conjugated biocompatible block copolymers through a bidentate dihydrolipoic acid (DHLA) linker. The FA-PEG-P(Asp-Hyd)-DHLA-modified AuNPs (FA-PEG-P(Asp-Hyd)-DHLA-AuNPs) were sufficiently stable that their optical properties were not changed under very harsh conditions. Then, the hydrophobic photosensitizer, pheophorbide a (Pheo), was conjugated to the stable vectors through a pH-sensitive linkage. The synthesis and composition of all copolymers were confirmed by 1H NMR measurement. The size of Pheo-conjugated FA-PEG-P(Asp-Hyd)-DHLA-AuNPs-Pheo determined by light-scattering measurements was about 54.7 nm. FE-SEM and FE-TEM images showed that these nanoparticles have a spherical shape and adequate dispersivity after modification. Confocal microscopy, flow cytometry assay, and bio-TEM measurements were used for determining the cellular uptake of Pheo and AuNPs in HeLa cells. The FA-PEG-P(Asp-Hyd)-DHLA-AuNPs-Pheo showed 99.16% cellular uptake and exhibited an excellent phototoxicity compared to free Pheo and FA-unconjugated nanoparticles at pH 6.4.
- Zhao, Linlin,Kim, Tae-Hyun,Ahn, Jin-Chul,Kim, Hae-Won,Kim, So Yeon
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p. 5806 - 5817
(2013/10/22)
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- Thermosensitive hydrogel from oligopeptide-containing amphiphilic block copolymer: Effect of peptide functional group on self-assembly and gelation behavior
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We reveal that a slight change in the functional group of the oligopeptide block incorporated into the poloxamer led to drastically different hierarchical assembly behavior and rheological properties in aqueous media. An oligo(l-Ala-co-l-Phe-co-β-benzyl l-Asp)-poloxamer-oligo(β-benzyl-l- Asp-co-l-Phe-co-l-Ala) block copolymer (OAF-(OAsp(Bzyl))-PLX-(OAsp(Bzyl))-OAF, denoted as polymer 1), which possessed benzyl group on the aspartate moiety of the peptide block, was synthesized through ring-opening polymerization. The benzyl group on aspartate was then converted to carboxylic acid to yield oligo(l-Ala-co-l-Phe-co-l-Asp)-poloxamer-oligo(l-Asp-co-l-Phe-co-l-Ala) (OAF-(OAsp)-PLX-(OAsp)-OAF, denoted as polymer 2). Characterization of the peptide secondary structure in aqueous media by circular dichroism revealed that the oligopeptide block in polymer 1 exhibited mainly an α-helix conformation, whereas that in polymer 2 adopted predominantly a β-sheet conformation at room temperature. The segmental dynamics of the PEG in polymer 1 remained essentially unperturbed upon heating from 10 to 50 C; by contrast, the PEG segmental motion in polymer 2 became more constrained above ca. 35 C, indicating an obvious change in the chemical environment of the block chains. Meanwhile, the storage modulus of the polymer 2 solution underwent an abrupt increase across this temperature, and the solution turned into a gel. Wet-cell TEM observation revealed that polymer 1 self-organized to form microgel particles of several hundred nanometers in size. The microgel particle was retained as the characteristic morphological entity such that the PEG chains did not experience a significant change of their chemical environment upon heating. The hydrogel formed by polymer 2 was found to contain networks of nanofibrils, suggesting that the hydrogen bonding between the carboxylic acid groups led to an extensive stacking of the β sheets along the fibril axis at elevated temperature. The in vitro cytotoxicity of the polymer 2 aqueous solution was found to be low in human retinal pigment epithelial cells. The low cytotoxicity coupled with the sol-gel transition makes the corresponding hydrogel a good candidate for biomedical applications.
- Chiang, Ping-Ray,Lin, Tsai-Yu,Tsai, Hsieh-Chih,Chen, Hsin-Lung,Liu, Shih-Yi,Chen, Fu-Rong,Hwang, Yih-Shiou,Chu, I-Ming
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p. 15981 - 15991
(2014/04/03)
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- Pharmaceutical differences between block copolymer self-assembled and cross-linked nanoassemblies as carriers for tunable drug release
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Purpose: To identify the effects of cross-linkers and drug-binding linkers on physicochemical and biological properties of polymer nanoassembly drug carriers. Methods: Four types of polymer nanoassemblies were synthesized from poly(ethylene glycol)-poly(aspartate) [PEG-p(Asp)] block copolymers: self-assembled nanoassemblies (SNAs) and cross-linked nanoassemblies (CNAs) to each of which an anticancer drug doxorubicin (DOX) was loaded by either physical entrapment or chemical conjugation (through acid-sensitive hydrazone linkers). Results: Drug loading in nanoassemblies was 27 ~ 56% by weight. The particle size of SNA changed after drug and drug-binding linker entrapment (20 ~ 100 nm), whereas CNAs remained 30 ~ 40 nm. Drug release rates were fine-tunable by using amide cross-linkers and hydrazone drug-binding linkers in combination. In vitro cytotoxicity assays using a human lung cancer A549 cell line revealed that DOX-loaded nanoassemblies were equally potent as free DOX with a wide range of drug release half-life (t1/2 = 3.24 ~ 18.48 h, at pH 5.0), but 5 times less effective when t1/2 = 44.52 h. Conclusion: Nanoassemblies that incorporate cross-linkers and drug-binding linkers in combination have pharmaceutical advantages such as uniform particle size, physicochemical stability, fine-tunable drug release rates, and maximum cytotoxicity of entrapped drug payloads.
- Lee, Hyun Jin,Bae, Younsoo
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p. 478 - 488
(2013/08/24)
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- Synthesis of polypeptide conjugated with near infrared fluorescence probe and doxorubicin for pH-responsive and image-guided drug delivery
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A near infrared fluorescent polymeric drug delivery system (NIRF DDS) with pH-responsive drug release properties has been designed and developed. This material was prepared by chemical conjugation of the anticancer drug doxorubicin and hydrophobic aminocyanine dye to triblock copolypeptide via hydrazone and amide bonds, respectively. Conjugation with aminocyanine shows almost no toxicity of the material, while conjugation with doxorubicin induces pronounced toxicity on the original biocompatible material. The pH sensitive drug release nature of the near infrared fluorescent polymeric drug (NIRF prodrug) was confirmed by accelerated drug release at pH of 5.0 via an in vitro drug release experiment and gradual drug cleavage from the NIRF prodrug during a confocal laser scanning microscopic (CLSM) experiment. The CLSM experiment also reveals that the released drug subsequently migrated to the nucleus, while the polymeric residue still remained in cytoplasm, indicating that the as-prepared polymer can be a promising candidate for theranosis of cancer.
- Xing, Tao,Lai, Bin,Yan, Lifeng,Yang, Xianzhu,Wang, Feng
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p. 22290 - 22300,11
(2020/09/02)
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- Block copolymer micelles for controlled delivery of glycolytic enzyme inhibitors
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Purpose: To develop block copolymer micelles as an aqueous dosage form for a potent glycolytic enzyme inhibitor, 3-(3- pyridinyl)-1-(4-pyridinyl)-2-propen- 1-one (3PO). Methods: The micelles were prepared from poly(ethylene glycol)-poly(aspartate hydrazide) [PEG-p(HYD)] block copolymers to which 3PO was conjugated through an acid-labile hydrazone bond. The optimal micelle formulation was determined following the screening of block copolymer library modified with various aromatic and aliphatic pendant groups. Both physical drug entrapment and chemical drug conjugation methods were tested to maximize 3PO loading in the micelles during the screening. Results: Particulate characterization showed that the PEG-p (HYD) block copolymers conjugated with 3PO (2.08~2.21 wt. %) appeared the optimal polymer micelles. Block copolymer compositions greatly affected the micelle size, which was 38 nm and 259 nm when 5 kDa and 12 kDa PEG chains were used, respectively. 3PO release from the micelles was accelerated at pH 5.0, potentiating effective drug release in acidic tumor environments. The micelles retained biological activity of 3PO, inhibiting various cancer cells (Jurkat, He-La and LLC) in concentration ranges similar to free 3PO. Conclusion: A novel micelle formulation for controlled delivery of 3PO was successfully prepared. Springer Science+Business Media, LLC 2011.
- Akter, Shanjida,Clem, Brian F.,Lee, Hyun Jin,Chesney, Jason,Bae, Younsoo
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experimental part
p. 847 - 855
(2012/08/08)
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- PEG-poly(amino acid) block copolymer micelles for tunable drug release
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Purpose: To achieve tunable pH-dependent drug release in tumor tissues. Methods: Poly(ethylene glycol)-poly(aspartic acid) [PEG-p(Asp)] containing 12 kDa PEG and pAsp (5, 15, and 35 repeating units) were prepared. Hydrazide linkers with spacers [glycine (Gly) and 4-aminobenzoate (Abz)] were introduced to PEG-p(Asp), followed by drug conjugation [doxorubicin (DOX)]. The block copolymer-drug conjugates were either reconstituted or dialyzed in aqueous solutions to prepare micelles. Drug release patterns were observed under sink conditions at pH 5.0 and 7.4, 37°C, for 48 h. Results: A collection of six block copolymers with different chain lengths and spacers was synthesized. Drug binding yields were 13-43.6%. The polymer-drug conjugates formed a crucial role in controlling drug release and stability of polymer micelles in combination with block copolymer chain lengths. Conclusion: A drug delivery platform for tunable drug release was successfully developed with polymer micelles possessing spacer-modified hydrazone drug-binding linkers.
- Ponta, Andrei,Bae, Younsoo
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experimental part
p. 2330 - 2342
(2011/08/06)
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- Mixed pH-sensitive polymeric micelles for combination drug delivery
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Purpose: To prepare mixed polymeric micelles that can carry two different drugs, doxorubicin (DOX) and 17-hydroxyethylamino-17-demethoxygeldanamycin (GDM-OH), for combination cancer chemotherapy. Methods: The pH-sensitive micelles were prepared from poly(ethylene glycol)-poly(aspartate hydrazide) block copolymers to which either DOX or GDM-OH is conjugated through acid-labile hydrazone bond (individual micelles). Mixed micelles were formed not only by simply mixing two different individual micelles in aqueous solutions (aqueous mixed micelles) but also by evaporating organic solvents from the organic/aqueous mixed solvents in which two block copolymers possessing different drugs were dissolved homogeneously (organic mixed micelles). Particle size measurements, pH-dependent drug release tests, cytotoxicity assays and western blot analysis were subsequently conducted. Results: Individual and aqueous/organic mixed micelles showed clinically relevant particle size (a drug concentration, mixing method and schedule-dependent way. Conclusion: Combination chemotherapy using polymeric micelles seems to minimize a schedule-dependent change in combination drug efficacy in comparison to drug combination using DMSO formulations.
- Bae, Younsoo,Alani, Adam W.G.,Rockich, Nicole C.,Lai, T.S.Z. Chung,Kwon, Glen S.
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experimental part
p. 2421 - 2432
(2011/09/12)
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- POLYMERIC MICELLES FOR COMBINATION DRUG DELIVERY
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The invention provides block polymers, micelles, and micelle formulations for combination drug therapy. Polyamide block polymers, such as those of formulas I and II are useful, for example, for preparation of mixed drug micelles, including simply mixed micelles, physically mixed micelles, and chemically mixed micelles. The invention further provides methods of treating cancer, and inhibiting and killing cancer cells. Also provided are methods for the preparation of polymer drug conjugates and intermediates for their synthesis.
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Page/Page column 34
(2008/12/07)
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- Potential tuberculostatic agent: Micelle-forming pyrazinamide prodrug
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Pyrazinamide was condensed with the poly(ethylene glycol)-poly(aspartic acid) copolymer (PEG-PASP), a micelle-forming derivative was obtained that was characterized in terms of its critical micelle concentration (CMC) and micelle diameter. The CMC was found by observing the solubility of Sudan III in Poly(ethylene glycol)-poly(pyrazinamidomethyl aspartate) copolymer (PEG-PASP-PZA) solutions. The mean diameter of PEG-PASP-PZA micelles, obtained by analyzing the dynamic light-scattering data, was 78.2 nm. The PEG-PASP-PZA derivative, when assayed for anti-Mycobacterium activity, exhibited stronger activity than the simple drug.
- Silva, Marcia,Ricelli, Nara L.,Seoud, Omar El,Valentim, Celso S.,Ferreira, Antonio G.,Sato, Daisy N.,Leite, Clarice Q. F.,Ferreira, Elizabeth I.
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p. 283 - 290
(2007/10/03)
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- N-Carboxy-L-aspartic anhydride benzyl ester
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The structure of the title compound, benzyl (1,2,3,4-tetrahydro-2,5-dioxo-1,3-oxazol-4-yl)acetate, C12H11NO5, has been determined in an attempt to explain the polymerization observed in the solid state. The molecules are linked by intermolecular hydrogen bonds between the imino group of the five-membered ring and an adjacent carbonyl O atom, along the c axis. Intramolecular hydrogen bonds are also formed, between the imino group and the carbonyl O atom of the ester group. The five-membered rings are arranged in a layer, sandwiched by layers incorporating the benzyl groups. This structure is thought to be preferable for the polymerization of the compound in the solid state, because the five-membered rings can react with each other in the layer.
- Kanazawa, Hitoshi,Magoshi, Jun
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p. o159-o161
(2007/10/03)
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- Potential tuberculostatic agents: Micelle-forming copolymer poly(ethylene glycol)-poly(aspartic acid) prodrug with isoniazid
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With the objective of obtaining slow-acting isoniazid derivatives, of potential use as chemoprophylactics or chemotherapeutics in tuberculosis, the micelle-forming copolymer of poly(ethylene glycol)-poly(aspartic acid) prodrug with isoniazid was synthesized. The derivative obtained was found to be active in Mycobacterium tuberculosis culture, with a minimal inhibitory concentration (MIC) 5.6 times lower than that of the tuberculostatic drug.
- Silva,Lara,Leite,Ferreira
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p. 189 - 193
(2007/10/03)
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- SYNTHETIC ENZYMES-4. HIGHLY ENANTIOSELECTIVE EPOXIDATION BY MEANS OF POLYAMINOACIDS IN A TRIPHASE SYSTEM: INFLUENCE OF STRUCTURAL VARIATIONS WITHIN THE CATALYSTS.
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The asymmetric epoxidation of chalcone and other electron-poor olefins in a triphase system (water-organic solvent-polyaminoacid) affords optically active oxiranes.The influence of the molecular structure of catalysts and of their secondary conformation on the enantioselectivity of the reaction has also been examined.
- Colonna, Stefano,Molinari, Henriette,Banfi, Stefano,Julia, Sebastian,Masana, Jaume,Alvarez, Angel
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p. 1635 - 1642
(2007/10/02)
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