- Improving of Anticancer Activity and Solubility of Cisplatin by Methylglycine and Methyl Amine Ligands Against Human Breast Adenocarcinoma Cell Line
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Methylglycine, also known sarcosine, is dramatically used in drug molecules and its metal complexes can interact to DNA and also do cleavage. Hence, to study the influence of methylglycine ligand on biological behavior of metal complexes, two water-solubl
- Shams Abyaneh, Fatemeh Safa,Eslami Moghadam, Mahboube,Divsalar, Adeleh,Ajloo, Davood,Hosaini Sadr, Moyaed
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- Biodegradable block copolymer scaffolds for loading and delivering cisplatin anticancer drug
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A carboxylic acid substituted amphiphilic diblock copolymer scaffold with a hydrophilic PEG-chain and hydrophobic biodegradable poly(caprolactone) (PCL), which forms a cisplatin anticancer drug is reported herein. Cisplatin [cis-dichloro-diammine platinum(II), CDDP] was anchored on the polymer backbone through Pt-OOC-PCL chemical linkage that enabled self-assembly of the prodrug to produce 110±10 nm nanoparticles in water. These drug loaded nanoparticles were characterized by dynamic light scattering, electron microscopy, and X-ray diffraction. The polymer-drug conjugate burst instantaneously in saline and PBS to release 35% of the cisplatin drug for immediate administration. The remaining drug that retained in the polymer scaffold underwent slow and controlled release to deliver the drug over a period of 6-7 d. In the presence of esterase enzyme; the biodegradable PCL aliphatic ester backbone broke completely to release 100% loaded drugs within a few hours. This biodegradable diblock copolymer design strategy opens up new platform for cisplatin-polymer drug delivery approach. Copyright
- Surnar, Bapurao,Subash, Pramod P.,Jayakannan, Manickam
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- Kinetic and Thermodynamic Investigation of Human Serum Albumin Interaction with Anticancer Glycine Derivative of Platinum Complex by Using Spectroscopic Methods and Molecular Docking
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In this paper, a new anticancer Pt (II) complex, cis-[Pt (NH3)2(tertpentylgly)]NO3, was synthesized with glycine-derivative ligand and characterized. Cytotoxicity of this water-soluble Pt complex was studied against human cancer breast cell line of MCF-7. The interaction of human serum albumin (HSA) with Pt complex was studied by using UV-Vis, fluorescence spectroscopy methods, and molecular docking at 27 and 37?°C in the physiological situation (I = 10?mM, pH = 7.4). The negative ΔHb0 and positive ΔSb0 indicated that electrostatic force may be a major mode in the binding between Pt complex and HSA. Binding constant values were obtained through UV-Vis and fluorescence spectroscopy that reveal strong interaction. The negative Gibbs free energy that was obtained by using the UV-Vis method offers spontaneous interaction. Fluorescence quenching the intensity of HSA by adding Pt complex confirms the static mode of interaction is effective for this binding process. Hill coefficients, nH, Hill constant, kH, complex aggregation number around HSA, , number of binding sites, g, HSA melting temperature, Tm, and Stern-Volmer constant, kSV, were also obtained. The kinetics of the interaction was studied, which showed a second-order kinetic. The results of molecular docking demonstrate the position of binding of Pt complex on HSA is the site I in the subdomain IIA.
- Shiekhzadeh, Afrooz,Sohrabi, Nasrin,Moghadam, Mahboube Eslami,Oftadeh, Mohsen
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- Ferrocenyl-bipyridinium cations and their platinum complexes related to viologens - Preparation, redox properties, and crystal structures
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N-R1-N-R2-4,4'-Bipyridinium and N-R1-4,4'-bipyridinium salts containing ferrocenyl substituents were prepared as donor-acceptor compounds (R1 = ferrocenyl, ferrocenylphenyl; R2 = ferrocenyl, ferroceny
- Mochida, Tomoyuki,Funasako, Yusuke,Nezu, Yukiko,Hagiwara, Koji,Horikoshi, Ryo
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- Palladium and platinum complexes of folic acid as new drug delivery systems for treatment of breast cancer cells
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Cisplatin is administrated as an agent in treatment of various cancers by intercalation between DNA strands and inhibition of DNA replication. Among the various factors, two important reasons like inhibition of apoptosis by anti-apoptotic mechanisms and i
- He, Chenyang,Heidari Majd, Mostafa,Shiri, Fereshteh,Shahraki, Somaye
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- Cisplatin-Stitched Polysaccharide Vesicles for Synergistic Cancer Therapy of Triple Antagonistic Drugs
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New cisplatin-stitched polysaccharide vesicular nanocarrier is developed for combination therapy of three clinical important antagonistic drugs together to accomplish synergistic cancer therapy in breast cancer treatment. Carboxylic functionalized dextran was tailor-made for the chemical conjugation of cisplatin, and a renewable hydrophobic unit was anchored in the backbone to interdigitize the chains to self-assemble as cisplatin-stitched polysaccharide nanovesicles. Water-soluble DNA-intercalating drug doxorubicin·HCl (DOX) and water insoluble topoisomerase type I inhibitor drug camptothecin (CPT) were encapsulated in these vesicles to produce dual or triple drug-loaded vesicular nanocarrier. This unique cisplatin, DOX and CPT triple drug-loaded dextran vesicles were stable in aqueous medium, and the vesicular geometry acted as a shield for Pt-polymer drug conjugate against glutathione (GSH) detoxification under physiological conditions. Lysosomal enzymes ruptured the nanovesicle exclusively at the intracellular compartments to deliver the combination of all three drugs simultaneously to maximize the therapeutic efficacies. In vitro cytotoxicity studies revealed that free cisplatin was highly detoxified by the GSH in breast cancer cells, whereas the enhanced stability of Pt-stitched dextran vesicle against GSH facilitated ~99% cell killing in breast cancer cells. Combination therapy studies revealed that the free cisplatin, DOX, and CPT were found to be antagonistic to each other. Dual drug-loaded vesicles exhibited synergistic cancer cell killing while delivering these antagonistic drugs from a dextran vesicular platform. Remarkable synergistic cell killing was accomplished in cisplatin, DOX, and CPT triple drug-loaded vesicles at nanogram concentrations in breast cancer cells. The internalization of drugs and cellular uptake were confirmed by confocal microscope and flow cytometry analysis. The drugs were taken by the cancer cells in large amounts while delivering them from dextran vesicles compared to their free form. These spectacular results opened new opportunities for synergistic cancer therapy for GSH-overexpressed breast cancer using triple drug-loaded polysaccharide vesicular nanocarriers.
- Deshpande, Nilesh Umakant,Jayakannan, Manickam
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- Synthesis, characterization and anticancer evaluation of transplatin derivatives with heterocyclic thiones
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Platinum(II) complexes of heterocyclic thiones (L) based on transplatin having the general formula, trans-[Pt(NH3)2(Thione)2](NO3)2 have been synthesized and characterized using elemental analysis, IR, and NMR (1H & 13C) spectroscopy. The crystal structures of two of them, trans-[Pt(NH3)2(Imt)2](NO3)2 (1) and trans-[Pt(NH3)2(Me2Imt)2](NO3)2 (3) were determined by X-ray crystallography. The structures of 1 and 3 consist of trans-[Pt(NH3)2L2]2+ complex ions and nitrate counter ions. The platinum atom in both the complex ions adopts a distorted square planar geometry. The spectroscopic data indicated the coordination of thione ligands to platinum(II). The in vitro cytotoxicity of these compounds as well as of cisplatin and carboplatin was investigated using MTT assay against three human cancer cell lines, which are; A549 (lung carcinoma), MCF-7 (breast carcinoma) and HTC15 (colon cancer). The in vitro cytotoxicity in several cases is comparable or even higher, than carboplatin and in two cases than cisplatin.
- Jomaa, Mohammed Y.,Altaf, Muhammad,Ahmad, Saeed,Alhoshani, Ali,Baig, Nadeem,Kawde, Abdel-Nasser,Bhatia, Gaurav,Singh, Jatinder,Isab, Anvarhusein A.
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- Novel antitumor cisplatin and transplatin derivatives containing 1-methyl-7-azaindole: Synthesis, characterization, and cellular responses
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The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of huma
- Pracharova, Jitka,Saltarella, Teresa,Radosova Muchova, Tereza,Scintilla, Simone,Novohradsky, Vojtech,Novakova, Olga,Intini, Francesco P.,Pacifico, Concetta,Natile, Giovanni,Ilik, Petr,Brabec, Viktor,Kasparkova, Jana
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- Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes
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Several chlorido and amino Pt2 + complexes of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases HL exhibiting moderate to high cytotoxicity against cancer cell lines were studied in order to investigate their modes of DNA binding, in vitro DNA strand breaks, mechanism of topoisomerase (Topo I) inhibition and cellular accumulation. DNA model base studies have shown that complex 1a [Pt(HL1)Cl2] was capable of binding covalently to 9-ethylguanine (9-EtG) and 5′-GMP. 1H NMR and mass spectrometry studies have shown that both chlorides were substituted by 9-EtG ligands, whereas 5′-GMP was able to replace only one chlorido ligand, due to steric hindrance. The chlorido Pt2 + complexes [Pt(HL)Cl2] highly accumulate in prostate (PC-3) and melanoma (MDA-MB-435) cell lines, being able to induce DNA strand breaks in vitro and inhibit Topo I by a catalytic mode. On the other hand, the free 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones HL and the amino Pt2 + complexes [Pt(L-)(NH3)2]NO3 neither cause DNA strand breakage nor exhibit strong DNA interaction, nevertheless the latter were also found to be catalytic inhibitors of Topo I at 100 μM. Thus, coordination of the Mannich bases HL to the PtCl2 fragment substantially affects the chemical and biophysical properties of the pro-ligands, leading to an improvement of their DNA binding properties and generating compounds that cleave DNA and catalytically inhibit Topo I. Finally, the high cytotoxicity exhibited by the free (uncomplexed) 2-hydroxy-3- (aminomethyl)-1,4-naphthoquinones might be associated with their decomposition in solution, which is not observed for the Pt2 + complexes.
- Neves, Amanda P.,Pereira, Michelle X.G.,Peterson, Erica J.,Kipping, Ralph,Vargas, Maria D.,Silva-Jr, Floriano P.,Carneiro, J. Walkimar M.,Farrell, Nicholas P.
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- Effect of Presence of Aliphatic Glycine in the Anti-cancer Platinum Complex Structure on Human Serum Albumin Binding
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Purpose: In this work, a new water-soluble Pt(II) complex was synthesized with aliphatic glycine ligand with a formula of cis-[Pt(NH3)2(isopentylgly)]NO3,?as an anti-cancer drug, and characterized. To determine the binding constant of the human serum albumin (HSA, the most abundant carrier proteins in the?human circulatory system) to this complex and the binding site of the complex on HSA, the melting point of HSA and the kinetics of this interaction were?investigated to introduce an anti-breast cancer drug with fewer side effects. Methods: HSA interaction with the complex was studied via a spectroscopic method at 27 and 37?°C and physiological situation (I = 10?mM, pH = 7.4) and molecular docking. Results: The toxicity value of this complex was obtained against the human cancer breast cell line of MCF-7. The thermodynamic parameters of enthalpy and entropy were also achieved in the empirical procedure. Due to the spontaneity of the interaction, Gibbs free energy variation was obtained negative. The binding constant of this complex to HSA was 3.9 × 105 (M?1). Empirical results showed that the quenching mechanism was static. Hill coefficients, Hill constant, complex aggregation number around protein, number of binding sites, and protein melting temperature with complex were obtained. The kinetics of this interaction was also investigated, which showed that this interaction follows a second-order kinetic. The molecular docking data indicated that the position of the interaction of complex on the protein was the site I in the sub-second IIA. Also, the hydrogen bonding and the hydrophobic interaction as the dominant binding forces were seen in complex–HSA formation. Conclusion: This interaction with positive cooperativity was recognized via a superior hydrogen bond. The reasonable binding constant was also obtained, which could ultimately be a good option as an anti–breast cancer drug.
- Shiekhzadeh, Afrooz,Sohrabi, Nasrin,Eslami Moghadam, Mahboube,Oftadeh, Mohsen,Divsalar, Adeleh
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- Design, synthesis and anticancer activity of diam(m)ine platinum(II) complexes bearing a small-molecular cell apoptosis inducer dichloroacetate
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Four new diam(m)ine platinum complexes containing the dichloroacetate moiety in 3-dichoroacetoxylcyclobutane-1,1-dicarboxylate as the leaving group were synthesized, characterized by elemental analysis as well as by ESI+-MS (electrospray ionization mass spectrometry in positive mode), FT-IR, 1H- and 13C-NMR, and evaluated for their in vitro anticancer activity against human lung cancer cell line (A549) and ovarian cancer cell lines (SK-OV-3, SK-OV-3/DDP). Diam(m)ines used in the present study belong to the carriers of six clinically approved platinum drugs. Among the complexes synthesized, complex 2, cis-[Pt(II)(1R,2R-diaminocyclohexane)·(3-dichoroacetoxylcyclobutane-1,1-dicarboxylate)] is the most promising in terms of water solubility and potential of being totally devoid of cross-drug resistance with cisplatin. Therefore, complex 2 was selected for the dichloroacetate release test. The test shows dichloroacetate can be efficiently released from complex 2 under physiological conditions via the hydrolysis of an ester bond bridging the dichloroacetate moiety and platinum pharmacophores together. Our study supports the further evaluation of this complex as a drug candidate.
- Liu, Weiping,Jiang, Jing,Xu, Yongping,Hou, Shuqian,Sun, Liping,Ye, Qingsong,Lou, Liguang
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- Ortho-(methylsulfanyl)phenylphosphonates and derivatives: Synthesis and applications as mono- or bidentate ligands for the preparation of platinum complexes
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The preparation of six phenylphosphonates (and phosphonic acid derivatives) bearing a sulfur group in ortho position was accomplished via either a [1,3]- or a [1,4]-sigmatropic rearrangement. Their complexation with different platinum sources has been stu
- Hamel, Matthieu,Lecinq, Mathieu,Gulea, Mihaela,Kozelka, Ji?í
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- Unmodified drug used as a material to construct nanoparticles: Delivery of cisplatin for enhanced anti-cancer therapy
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The poor solubility of cisplatin (CDDP) often presents a major obstacle in the formulation of CDDP in nanoparticles (NPs) by traditional methods. We have developed a novel method for synthesizing CDDP NPs taking advantage of its poor solubility. By mixing two reverse microemulsions containing KCl and a highly soluble precursor of CDDP, cis-diaminedihydroplatinum (II), we have successfully formulated CDDP NPs with a controllable size (in the range of 12-75 nm) and high drug loading capacity (approximately 80 wt.%). The formulation was done in two steps. The pure CDDP NPs were first stabilized for dispersion in an organic solvent by coating with 1, 2-dioleoyl-sn-glycero-3-phosphate (DOPA). Both x-ray photoelectron spectroscopy and 1H NMR data confirmed that the major ingredient of the DOPA-coated NPs was CDDP. After purification, additional lipids were added to stabilize the NPs for dispersion in an aqueous solution. The final NPs contain a lipid bilayer coating and are named Lipid-Pt-Cl (LPC) NPs, which showed significant antitumor activity both in vitro and in vivo. Thus, CDDP precipitate serves as the major material for assembling the novel NPs. This unique method of nanoparticle synthesis may be applicable in formulating other insoluble drugs.
- Guo, Shutao,Miao, Lei,Wang, Yuhua,Huang, Leaf
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- Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor
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A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound's efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch-migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin.
- Calderon, Lindsay E.,Keeling, Jonathan K.,Rollins, Joseph,Black, Carrie A.,Collins, Kendall,Arnold, Nova,Vance, Diane E.,Ndinguri, Margaret W.
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- Maloplatin-B, a Cisplatin-Based BODIPY-Tagged Mito-Specific chemo-PDT Agent Active in Red Light
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Maloplatin-B, a cisplatin-based complex, namely [Pt(A-BOD)(NH3)2](NO3) (Pt-A-BOD) with a pendant boron-dipyrromethene (BODIPY) moiety, where HA-BOD is a methyl malonyl chloride derived monostyryl BODIPY ligand, was designed and developed as near-IR light (600-720 nm) organelle-targeting photodynamic therapy agent. The complex [Pt(acac)(NH3)2](NO3) (Pt-Ac) was used as a control. Pt-A-BOD displayed an absorption band at 616 nm (? = 2.9 × 104 M-1 cm-1) in 10% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (DMSO/DMEM, pH 7.2). This complex displayed a broad emission band within 650-850 nm with a λem value of 720 nm in 10% DMSO-DMEM (pH 7.2) upon excitation (λex) at 615 nm with a large Stokes shift. The fluorescence quantum yield (φF) value for Pt-A-BOD is 0.032 and for the ligand HA-BOD is 0.24. The BODIPY complex and ligand showed the formation of singlet oxygen as the ROS (reactive oxygen species) on irradiation with near-IR red light of 660 nm, as evidenced from a 1,3-diphenylisobenzofuran (DPBF) assay. The complex displayed remarkable apoptotic NIR light-induced PDT activity with half-maximum inhibitory concentration values (IC50) of 1.6-2.4 μM in A549 lung and HeLa cervical cancer cells, while it was less active in the dark. The cellular ROS generation by the complex in red light was ascertained by a DCFDA (2′,7′-dichlorofluorescein diacetate) assay. Cellular imaging showed its localization primarily in the mitochondria of A549 cancer cells. The JC1 and Annexin-V FITC/PI assays carried out for A549 cancer cells treated with the BODIPY complex showed the alteration of mitochondrial membrane potential and apoptotic cell death on near-IR red light (600-720 nm) irradiation, respectively.
- Ramu, Vanitha,Kundu, Paramita,Kondaiah, Paturu,Chakravarty, Akhil R.
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supporting information
p. 6410 - 6420
(2021/05/06)
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- PLATINUM COMPLEXES AND METHODS OF USE THEREOF
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Disclosed herein are platinum(II) complexes that can include complexes of the formula, or pharmaceutically acceptable salts thereof, wherein: R1 and R2 are independently selected from the group consisting of an amine, an optionally substituted amine, and an optionally substituted heterocyclic amine; or the pair of R1 and R2 are joined together to form a bidentate ligand containing nitrogen atoms; R3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted, and polyethylene glycol; R4, R5, R6, and R7 are independently selected from the group consisting of H, halide, -OR, alkyl optionally substituted and polyethylene glycol, or each pair of R4 and R5, R5 and R6, R6 and R7 is joined together to form Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR (wherein R is selected from the group consisting of H and alkyl optionally substituted); Z is selected from a group consisting of a carbon atom and a nitrogen atom; and X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate. Also disclosed are methods for using the platinum (II) complexes in the treatment of cancer and in the visualization inside cells.
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(2018/03/28)
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- NANOEMULSIONS OF HYDROPHOBIC PLATINUM DERIVATIVE
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Provided are nanoemulsion formulations useful for the delivery of hydrophobic platinum chemotherapeutic drugs to cancer patients, as well as methods of their preparation and use.
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Paragraph 00190; 00191
(2015/02/19)
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- COMPOSITIONS, METHODS, AND KITS COMPRISING PLATINUM COMPOUNDS ASSOCIATED WITH A LIGAND COMPRISING A TARGETING MOIETY
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Compositions, kits, and methods for treatment of cancers are generally provided. In some embodiments, the compositions, kits, and methods comprise a platinum (e.g., Pt (II) or Pt (IV)) compound associated with a ligand (e.g., a beta-diketonate ligand) com
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Page/Page column 44; 45
(2014/10/18)
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- Multifunctional magnetic calcium phosphate nanoparticles for targeted platin delivery
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Magnetic mesoporous amorphous calcium phosphate nanoparticles with a size of 62 nm and abundant -COOH groups on the surface have been prepared by a simple method. The particles show excellent aqueous dispersion stability in physiological pH without any deterioration in hydrodynamic size and zetapotential. By virtue of the carboxylate groups on the surface, the platinum pharmacophore cis-diaquadiamine platinum(ii), folic acid and rhodamine isothiocyanate were conjugated on these magnetic calcium phosphate nanoparticles. The cytotoxicity and internalization efficiency of these nanocarriers have been evaluated on folate receptor overexpressed HeLa cells. These drug loaded nanoagents exhibit elevated cytotoxicity and induce apoptosis in HeLa cells.
- Rout, Smruti R.,Behera, Birendra,Maiti, Tapas K.,Mohapatra, Sasmita
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supporting information
p. 10777 - 10783
(2013/01/14)
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- Antitumor platinum(II) complexes containing platinum-based moieties of present platinum drugs and furoxan groups as nitric oxide donors: Synthesis, DNA interaction, and cytotoxicity
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Six novel platinum(II) complexes 1-6 bearing different furoxan moieties as nitric oxide (NO) donors have been designed, synthesized, and characterized by elemental analysis and 1H NMR, IR, and ESI-MS spectroscopy. The furoxan groups were introduced to the platinum complexes to release NO, which may take synergic action with the platinum-based moieties on the tumor cells. It was found that all compounds exhibited considerable cytotoxicity against human HCT-116 and SGC-7901 cell lines via DNA binding together with NO-releasing features, especially for compound 3. This finding is in accordance with the previous reports that NO hybrids show higher cytotoxicity against colon cancer cell lines compared with their parent compounds.
- Zhao, Jian,Gou, Shaohua,Sun, Yanyan,Fang, Lei,Wang, Zhimei
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p. 10317 - 10324
(2013/01/15)
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- HPMA POLYMER PLATINUM CHELATES
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Polymeric platinum amidomalonate complexes, where the platinum is in +2 or +4 oxidation state, and where the complexes optionally contain tumor seeking groups, are useful in the treatment of cancer.
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(2011/12/12)
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- Platinum complexes containing chemically modified bile acids, having antitumor activity
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The present invention relates to platinum complexes containing bile acid derivatives having antitumor activity
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Page/Page column 7
(2010/02/11)
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