- Liposomes actively recognizing the glucose transporter GLUT1 and integrin αvβ3 for dual-targeting of glioma
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The treatment of glioma is a great challenge because of the existence of the blood–brain barrier (BBB). In order to develop an efficient glioma-targeting drug delivery system to greatly improve the brain permeability of anti-cancer drugs and target glioma, a novel glioma-targeted glucose-RGD (Glu-RGD) derivative was designed and synthesized as ligand for preparing liposomes to effectively deliver paclitaxel (PTX) to cross the BBB and target glioma. The liposomes were prepared and characterized for particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis, and cell cytotoxicity. Also, the Glu-RGD modified liposomes showed superior targeting ability in in vitro and in vivo evaluation as compared to naked PTX, non-coated, singly modified liposomes and liposomes co-modified by physical blending. The relative uptake efficiency and concentration efficiency were enhanced by 4.41- and 4.72-fold compared to that of naked PTX, respectively. What is more, the Glu-RGD modified liposomes also displayed the maximum accumulation of DiD-loaded liposomes at tumor sites compared to the other groups in in vivo imaging. All the results in vitro and in vivo suggested that Glu-RGD-Lip would be a potential delivery system for PTX to treat integrin αvβ3-overexpressing tumor-bearing mice.
- Fu, Qiuyi,Zhao, Yi,Yang, Zhongzhen,Yue, Qiming,Xiao, Wenjiao,Chen, Yang,Yang, Yang,Guo, Li,Wu, Yong
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- Self-organization of cholesterol-side-chain liquid crystalline polymers by tailoring the main chain structure and flexible spacer length
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Three kinds of side-chain liquid crystalline polymers (SCLCPs), in which cholesteryl mesogens (Chol) were linked to polyacrylate (PCholAC-m), polymethacrylate (PCholMC-m), and poly(2-vinylbenzene-1,4-dioate) (PCholVA-m) backbones through methylene spacers of different lengths (m = 0, 2, 4, 6, 8, and 10), were successfully synthesized using free-radical polymerization. The phase behavior and structure of the polymers were investigated in detail using DSC, POM, and SAXS. The results indicated that the Chol-SCLCPs displayed interesting self-organization by varying the main-chain structure and spacer length. The polymers initially form a smectic A phase, except for PCholAC-0 without a liquid crystalline phase. Next, polymers PCholAC-m (m = 2, 4, 6) formed a two-layer smectic A phase in which the alkyl tail was overlapped (SmA2). Two-phase coexisting structures were observed in PCholAC-m (m = 8, 10), including a bilayer smectic A phase in which the alkyl tail was inserted into the mesogens (SmAd) and a single-layer smectic A phase in which the mesogens were overlapped (SmA1). Similar results were observed for PCholMC-m. Furthermore, PCholMC-0 possessed a stable bilayer SmA2 owing to the methyl steric effect of the main chain. PCholVA-m (m = 0, 2, 4) samples showed a well-defined smectic A phase in which the backbone was squeezed by the parallel side chains on both sides. PCholVA-6 and PCholVA-10 exhibited a SmAd phase. The two-phase coexisting structures were also found in PCholVA-8. Finally, the glass transition temperature of the polymers decreased with increasing flexible spacer length because the flexible spacer acted as an internal plasticizer in the system. However, changes in the polymer clearing points demonstrated the diversity resulting from the different smectic A phase structures.
- Yang, Xiwen,Chen, Shaonan,Luo, Hang,Xu, Haoran,Chen, Sheng
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- The synthesis of cholesterol-based cationic lipids with trimethylamine head and the effect of spacer structures on transfection efficiency
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Five cholesterol-based cationic lipids were newly synthesized based on cholest-5-en-3β-oxyethane-N,N,N-trimethylammonium bromide (Chol-ETA) structure where the cholesterol backbone is linked to cationic head via various lengths of ether-linked carbon spacer. The transfection efficiency of these compounds was increased in order of three (Chol-PRO) four (Chol-BTA) two (Chol-ETA) methylene unit in their spacer, and was decreased by an addition of isomethyl group to Chol-PRO spacer. In case of the presence of multiple bonds in the spacer, it required the more cationic lipids in liposome formulation than single bond in the spacer to present similar transfection efficiency. Crown Copyright
- Kim, Bieong-Kil,Bae, Yun-Ui,Doh, Kyung-Oh,Hwang, Guen-Bae,Lee, Sung-Hye,Kang, Hyungu,Seu, Young-Bae
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- Synergistic targeted delivery of payload into tumor cells by dual-ligand liposomes co-modified with cholesterol anchored transferrin and TAT
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This study was mainly focused on developing a dual-ligand liposomal delivery system to enhance both targeting specificity and cellular uptake. The specific ligand transferrin (TF) and the cationic cell-penetrating peptide TAT were connected with cholesterol via a polyethylene glycol (PEG) spacer to prepare the dualligand liposomes (TAT/TF-PEG-LP). Then the in vitro cellular uptake by three kinds of cells that possessed different expressing levels of transferrin receptor (TFR) and the in vivo delivery efficiency were evaluated. Compared to the single-ligand TAT or TF modified liposomes (TAT-PEG-LP or TF-PEG-LP), TAT/TF-PEG-LP exhibited the enhanced cellular uptake and selectivity via the synergistic effect of both ligands in vitro. The ex vivo fluorescence imaging of tumors, the qualitative observation of tumor frozen section and the quantitative determination of cellular uptake in tumor tissues altogether showed the in vivo delivery efficiency of TAT/TF-PEG-LP was higher than that of other liposomes. In conclusion, the dual-ligand liposomes co-modified with TF and TAT possessed a strong capability for synergistic targeted delivery of payload into tumor cells both in vitro and in vivo.
- Tang, Jie,Zhang, Li,Liu, Yayuan,Zhang, Qianyu,Qin, Yao,Yin, Yujia,Yuan, Wenmin,Yang, Yuting,Xie, Yafei,Zhang, Zhirong,He, Qin
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- Efficacious Doxorubicin Delivery Using Glutathione-Responsive Hollow Non-phospholipid Vesicles Bearing Lipoyl Cholesterols
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In this study, we developed redox-sensitive vesicles using synthesised lipoyl cholesterol derivatives, a non-ionic surfactant and an optimum level of free cholesterol. Interestingly, concentration-dependent self-assembly was observed by scanning electron microscopy, wherein vesicles manifested as hollow spherical (at 0.15 mm) and triangular (0.50 mm). The redoxresponsive characteristics of the vesicles was probed in the presence of dithiothreitol; they underwent a clear increase in size as observed by dynamic light scattering measurements. These vesicles could easily encapsulate an anticancer drug, doxorubicin, and were observed to be stable in the presence of serum. They showed substantial release of the drug in response to biologically relevant stimulus, that is, glutathione. A toxicity assessment on HeLa and HepG2 cancer cells demonstrated activities of the drug-loaded vesicles comparable to that of free drug, whereas significantly enhanced toxicity and apoptotic induction were observed against drug-resistant HeLa cells, which was determined by studying the cellular internalisation of doxorubicin.
- Kumar, Krishan,Yadav, Lalit,Kondaiah, Paturu,Chaudhary, Sandeep
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- Synthesis of photoresponsive cholesterol-based azobenzene organogels: Dependence on different spacer lengths
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A series of azobenzene-cholesterol organogel compounds (M0 -M12 ) with different spacers were designed and synthesized. The molecular structures were confirmed by 1H NMR and 13C NMR spectroscopy. The rapid and reversible photoresponsive properties of the compounds were investigated by UV-vis spectroscopy. Their thermal phase behaviors were studied by DSC. The length of the spacer plays a crucial role in the gelation. Compound M6 is the only one that can gelate in ethanol, isopropanol and 1-butanol and the reversible gel-sol transitions are also investigated. To obtain visual insight into the microstructure of the gels, the typical structures of the xerogels were studied by SEM. Morphologies of the aggregates change from flower-like, network and rod with different sizes. By using IR and XRD characterization, it is found that intermolecular H-bonding, the solvents and van der Waals interaction are the main contributions to the specific superstructure.
- Ren, Yuchun,Wang, Bin,Zhang, Xiuqing
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- Identification and characterization of β-sitosterol target proteins
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β-Sitosterol is the most abundant plant sterol in the human diet. It is also the major component of several traditional medicines, including saw palmetto and devil's claw. Although β-sitosterol is effective against enlarged prostate in human clinical trials and has anti-cancer and anti-inflammatory activities, the mechanisms of action are poorly understood. Here, we report the identification of two new binding proteins for β-sitosterol that may underlie its beneficial effects.
- Lomenick, Brett,Shi, Heping,Huang, Jing,Chen, Chuo
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- Synthesis and characterization of new chiral liquid crystal monomers containing steroid unit
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To reduce the bulky steric hindrance, improve the reactivity of diosgenin and cholesterol, and obtain mesophase of their derivatives, the commercially available cholesterol and diosgenin were allowed to be structurally modified. Four new chiral LC intermediate compounds (c~f) and the corresponding monomers (M1?M4) with different longer spacer were synthesized. The chemical structures, optical texture, thermal behavior and mesophase structure of all the mesogenic compounds obtained in this study were characterized by FT-IR, 1H-NMR, polarizing optical microscopy, differential scanning calorimetry, and X-ray diffraction measurements. The experimental results showed that the intermediate compounds containing diosgenyl groups c and d only showed a mesophase and exhibited fan-shaped texture of a smectic A (SA) phase, while the compounds containing terminal cholesteryl groups e and f showed two mesophases and exhibited fan-shaped texture of a SA phase, and oily streak texture and focal conic texture of cholesteric phase, respectively. The four chiral monomers M1?M4 all revealed cholesteric oily streak texture and focal conic texture. In addition, the melting temperature (Tm) and isotropic temperature (Ti) of the mesogenic compounds decreased with increasing the flexible spacer length. Compared with the intermediate compounds or monomers based on cholesterol, the compounds or monomers based on diosgenin showed higher Tm and Ti.
- Chen, Qifan,Liu, Xiaofeng,Guo, Zhihao,Xu, Xiaoxu,Lu, Yanhua
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- Differential response of cholesterol based pyrimidine systems with oxyethylene type spacers to gelation and mesogen formation in the presence of alkali metal ions
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A new series of lipophilic cholesteryl derivatives of 2,4,6-trichloro-pyrimidine-5-carbaldehyde has been synthesized. Oxyethylene spacers of variable lengths were inserted between the hydrogen bonding promoting pyrimidine core and the cholesteryl tail in order to understand their effect on the self-assembly of these compounds. Only compound 1a with the shortest spacer formed a gel in organic solvents such as n-butanol and n-dodecane. While other members (1b and c) having longer spacers led to sol formation and precipitation in n-butanol and n-dodecane respectively. The self-assembly phenomena associated with the gelation process were investigated using temperature-dependent UV-Vis and CD-spectroscopy. The morphological features of the freeze-dried gels obtained from different organic solvents were examined by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The solid phase behaviours of these molecules and their associated alkali metal ion complexes were explored using polarized optical microscopy (POM) and differential scanning calorimetry (DSC). The molecular arrangements in the xerogel and in the solid state were further probed using a wide-angle X-ray diffraction (WAXD) technique. Analysis of the wide-angle X-ray diffraction data reveals that this class of molecules adopts a hexagonal columnar organization in the gel and in the solid state. Each slice of these hexagonal columnar structures is composed of a dimeric molecular-assembly as a building block. Significant changes in the conformation of the oxyethylene chains could be triggered via the coordination of selected alkali metal ions. This led to the production of interesting metal ion promoted mesogenic behaviour.
- Datta, Sougata,Bhattacharya, Santanu
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- Liquid crystals derived from hydrogen-bonded supramolecular complexes of pyridinylated hyperbranched polyglycerol and cholesterol-based carboxylic acids
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A hyperbranched polyether polyol was reacted with isonicotinoyl chloride hydrochloride for the introduction of the pyridinyl moiety at the external surface. This pyridinylated hyperbranched polymer was subsequently interacted with cholesterol-based carboxylic acids for the formation of the corresponding hydrogen-bonded supramolecular complexes. The materials obtained exhibited smectic A liquid crystalline phases over a broad thermal range from room temperature up to above 170°C. Within this smectic layer the cholesterol moieties are located above and below the hyperbranched scaffold. Increasing the spacer length, located between the carboxylic group and the cholesterol moiety, the temperature range of the liquid crystalline phases of the complexes is lowered.
- Felekis, Theodores,Tziveleka, Leto,Tsiourvas, Dimitris,Paleos, Constantinos M.
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- Synthesis and properties of isocannabinoid and cholesterol derivatized rhamnosurfactants: Application to liposomal targeting of keratinocytes and skin
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The usefulness of vesicles to cargo material depends on the design of new ligands able to incorporate easily inside the bilayer and also to direct the vesicles to the targeted site. Therefore, the synthesis of two new rhamnose-bearing surfactants is described. The hydrophobic part consists of cholesterol (in compound 3) and citrylidene phloroglucinol (in compound 6). The ability of these two rhamnolipids to incorporate into a DPPC membrane and to form aggregates is investigated, respectively, by differential scanning calorimetry and by surface tension measurements. Those two new surfactants were incorporated in fluorescent liposomes to study their interactions with keratinocytes and skin sections. Intraliposomal delivery to keratinocytes was observed in both cases, even if the kinetics of delivery were different according to the rhamnosurfactant used. Skin sections were stained by both liposomal formulations, and different interactions between the liposomes and skin cells according to the surfactant used were noted.
- Barragan-Montero, Veronique,Winum, Jean-Yves,Moles, Jean-Pierre,Juan, Emmanuelle,Clavel, Caroline,Montero, Jean-Louis
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- Chlorin e6-cholesterol conjugate and its copper complex. Simple synthesis and entrapping in phospholipid vesicles
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Synthesis of 13′[(cholest-5-en)-3β-yloxyethoxycarbamoyl]-chlorin e6 starting from methylpheophorbide and 3β(2-hydroxy)-ethoxycholest-5-ene is presented, as well as the preparation of related copper complex. Both conjugates obtained may be simply incorporated in phosphatidyl choline vesicles.
- Nikolaeva, Irina A.,Misharin, Alexander Yu.,Ponomarev, Gelii V.,Timofeev, Vladimir P.,Tkachev, Yaroslav V.
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- Cholesterol derived cationic lipids as potential non-viral gene delivery vectors and their serum compatibility
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Cholesterol derivatives M1-M6 as synthetic cationic lipids were designed and the biological evaluation of the cationic liposomes based on them as non-viral gene delivery vectors were described. Plasmid pEGFP-N1, used as model gene, was transferred into 293T cells by cationic liposomes formed with M1-M6 and transfection efficiency and GFP expression were tested. Cationic liposomes prepared with cationic lipids M1-M6 exhibited good transfection activity, and the transfection activity was parallel (M2 and M4) or superior (M1 and M6) to that of DC-Chol derived from the same backbone. Among them, the transfection efficiency of cationic lipid M6 was parallel to that of the commercially available Lipofectamine2000. The optimal formulation of M1 and M6 were found to be at a mol ratio of 1:0.5 for cationic lipid/DOPE, and at a N/P charge mol ratio of 3:1 for liposome/DNA. Under optimized conditions, the efficiency of M1 and M6 is greater than that of all the tested commercial liposomes DC-Chol and Lipofectamine2000, even in the presence of serum. The results indicated that M1 and M6 exhibited low cytotoxicity, good serum compatibility and efficient transfection performance, having the potential of being excellent non-viral vectors for gene delivery.
- Ju, Jia,Huan, Meng-Lei,Wan, Ning,Hou, Yi-Lin,Ma, Xi-Xi,Jia, Yi-Yang,Li, Chen,Zhou, Si-Yuan,Zhang, Bang-Le
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- Design, synthesis and biological evaluation for docetaxel-loaded brain targeting liposome with "lock-in" function
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Background: Glucose-modified liposome showed a good brain-targeting ability. However, bidirectional transport of glucose transporter-1 (GLUT1) might reversely pump drugs out of the brain before releasing from the liposomes. Purpose: To overcome the bidirectional delivery of GLUT1, the thiamine disulfide system (TDS), with ability of "lock-in", was introduced and a new ligand, L-TDS-G, was designed and synthesized. Methods: The liposome was prepared and characterized for particle size, zeta potential, surface morphological property, encapsulation efficiency and release profile. C6 glioma cells were used as an in vitro model to access the cellular uptake abilities and cytotoxicity of the liposomes. Competition assay was performed to validate the GLUT1-mediated transport mechanism. Furthermore, the brain targeting abilities of the liposomes were evaluated through in vivo. Results: The preliminary evaluation in vivo demonstrated that L-TDS-G-coated liposome has an improved targeting ability and significantly increased the area under the concentration-time of docetaxel in brain as compared to naked docetaxel, non-coated and L-G coated liposomes. The relative uptake efficiency and concentration efficiency were enhanced by 3.82- and 4.99-fold compared to that of naked docetaxel, respectively. Conclusion: The results of this study indicated that L-TDS-G-coated liposome is a promising drug delivery system to enhance the brain concentrations of chemotherapeutic agents.
- Li, Xiaocen,Qu, Boyi,Jin, Xiuxiu,Hai, Li,Wu, Yong
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- Anion-Selective Cholesterol Decorated Macrocyclic Transmembrane Ion Carriers
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Anion transporters play a vital role in cellular processes and their dysregulation leads to a range of diseases such as cystic fibrosis, Bartter's syndrome and epilepsy. Synthetic chloride transporters are known to induce apoptosis in cancer cell lines. Herein, we report triamide macrocycles that are easily synthesized and externally functionalized by pendant membrane-permeable groups. Among a variety of chains appended onto the macrocycle scaffold, cholesterol is found to be the best with an EC50 value of 0.44 μM. The macrocycle is highly anion-selective and transports ions via an OH-/X- antiport mechanism. The macrocycle is an interesting scaffold for ion-Transport as it is able to discriminate between various anions and shows a preference for SCN- and Cl-. Such anion-selective transporters are highly attractive model systems to study ion-Transport mechanisms and could potentially be of high therapeutic value.
- Behera, Harekrushna,Madhavan, Nandita
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- Synthesis of Triaromatic Steroid Hydrocarbons Methylated at Position 2, 3 or 6: Molecular Fossils of Yet Unknown Biological Origin.
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C21-29 triaromatic steroid hydrocarbons bearing a methyl group at unusual positions 2, 3 or 6 have been synthesized from pregnenolone, cholesterol or stigmasterol via stera-3,5-dienes.Their occurence in various sedimentary rocks and petroleums suggests the presence of yet unknown biological precursors.
- Lichtfouse, Eric,Albrecht, Pierre
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- Amphiphilic diblock terpolymer PMAgala-b-P(MAA-co-MAChol)s with attached galactose and cholesterol grafts and their intracellular pH-responsive doxorubicin delivery
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In this work, a series of diblock terpolymer poly(6-O-methacryloyl-d-galactopyranose)-b-poly(methacrylic acid-co-6-cholesteryloxy hexyl methacrylate) amphiphiles bearing attached galactose and cholesterol grafts denoted as the PMAgala-b-P(MAA-co-MAChol)s were designed and prepared, and these terpolymer amphiphiles were further exploited as a platform for intracellular doxorubicin (DOX) delivery. First, employing a sequential RAFT strategy with preliminarily synthesized poly(6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose) (PMAIpGP) macro-RAFT initiator and a successive trifluoroacetic acid (TFA)-mediated deprotection, a series of amphiphilic diblock terpolymer PMAgala-b-P(MAA-co-MAChol)s were prepared, and were further characterized by NMR, Fourier transform infrared spectrometer (FTIR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and a dynamic contact angle testing instrument (DCAT). In aqueous media, spontaneous micellization of the synthesized diblock terpolymer amphiphiles were continuously examined by critical micellization concentration assay, dynamic light scattering (DLS), and transmission electron microscopy (TEM), and the efficacies of DOX loading by these copolymer micelles were investigated along with the complexed nanoparticle stability. Furthermore, in vitro DOX release of the drug-loaded terpolymer micelles were studied at 37 °C in buffer under various pH conditions, and cell toxicities of as-synthesized diblock amphiphiles were examined by MTT assay. Finally, with H1299 cells, intracellular DOX delivery and localization by the block amphiphile vectors were investigated by invert fluorescence microscopy. As a result, it was revealed that the random copolymerization of MAA and MAChol comonomers in the second block limited the formation of cholesterol liquid-crystal phase and enhanced DOX loading efficiency and complex nanoparticle stability, that ionic interactions between the DOX and MAA comonomer could be exploited to trigger efficient DOX release under acidic condition, and that the diblock terpolymer micellular vector could alter the DOX trafficking in cells. Hence, these suggest the pH-sensitive PMAgala-b-P(MAA-co-MAChol)s might be further exploited as a smart nanoplatform toward efficient antitumor drug delivery.
- Wang, Zhao,Luo, Ting,Sheng, Ruilong,Li, Hui,Sun, Jingjing,Cao, Amin
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- In vitro and in vivo investigation of glucose-mediated brain-targeting liposomes
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New glycosyl derivative of cholesterol was synthesized as a material for preparing novel liposome to overcome the ineffective delivery of normal drug formulations to brain by targeting the (glucose transporters) GLUTs on the BBB. Coumarin-6 was used as fluorescent probe. The results have shown that the cytotoxicity for the brain capillary endothelial cells (BCECs) of the glucose-mediated brain targeting liposome containing coumarin-6 was less than that of conventional liposome. The BBB model in vitro was established by coculturing of BCECs and astrocytes (ACs) of rat to test the transendothelial ability crossing the BBB. The transendothelial ability was confirmed strengthen alone with the amount of the new glycosyl derivative of cholesterol used in liposome. After i.v. administration of LIP, control liposome (CLP), and GLP-4, the AUC0t of coumarin-6 for GLP-4 was 2.85 times higher than that of LIP, and 3.33 times higher than that of CLP. The Cmax of CLP-4 was 1.43 times higher than that of LIP, and 3.10 times higher than that of CLP. Both pharmacokinetics and distribution in mice were also investigated to show that this novel brain targeting drug delivery system was promising.
- Qin, Yao,Fan, Wei,Chen, Huali,Yao, Nian,Tang, Wenwei,Tang, Jie,Yuan, Wenmin,Kuai, Rui,Zhang, Zhirong,Wu, Yong,He, Qin
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- Co-liposomes comprising a lipidated multivalent RGD-peptide and a cationic gemini cholesterol induce selective gene transfection in αvβ3 and αvβ5 integrin receptor-rich cancer cells
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The αvβ3 and αvβ5 integrins, transmembrane glycoprotein receptors, are over-expressed in numerous tumors and in endothelial cells that constitute tumor blood vessels. As this protein selectively binds to the Arg-Gly-Asp (RGD) sequence containing peptides, it is an attractive way to target tumors. Herein we have developed novel formulations for integrin mediated selective gene delivery. These formulations are composed of a novel palmitoylated tetrameric RGD containing scaffold (named RAFT-RGD), cationic gemini cholesterol (GL5) and a natural helper lipid 1,2-dioleoyl-l-α- glycero-3-phosphatidylethanolamine (DOPE). We have optimized a co-liposomal formulation to introduce the multivalent RGD-containing macromolecule in GL5: DOPE (GL5D) mixture to produce GL5D-RGD. We have unambiguously shown the selectivity of these formulations towards cancer cells that over express αvβ3 and αvβ5 integrins. Two reporter plasmids, pEGFP-C3 and PGL-3, were employed for the transfection experiments and it was shown that GL5D-RGD liposomes increased exclusively the transfection in αvβ3 and αvβ5-overexpressing HeLa cells. This journal is the Partner Organisations 2014.
- Misra, Santosh K.,Kondaiah, Paturu,Bhattacharya, Santanu,Boturyn, Didier,Dumy, Pascal
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- 2-(2-Cholesteroxyethoxyl)ethyl 3′-S-glutathionylpropionate and its self-assembled micelles for brain delivery: Design, synthesis and evaluation
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The blood–brain barrier (BBB) is a barrier that prevents almost all large and most small exogenous molecules from reaching the brain. The barrier is the major cause of treatment failure for most brain diseases. Extensive efforts have been made to facilitate drug molecules to cross the BBB. One of the approaches is to employ an endogenous ligand or ligand analogue that can enter the brain through its transporter or receptor at the BBB as a brain-targeting agent. Glutathione (GSH) transporters are richly expressed at the BBB with limited presence in other tissues except kidneys. 2-(2-Cholesteroxyethoxyl)ethyl 3′-S-glutathionylpropionate (COXP), formed by connecting GSH with cholesterol through a linker, was designed as a GSH transporter-mediated brain targeting molecule. The amphiphilic nature of COXP enables the molecule to self-assemble to form micelles with a CMC value of 3.9 μM. By using DiR as a fluorescence tracking agent and the whole-body fluorescence imaging technique, the brain distribution of DiR delivered by COXP micelles in mice was 20 folds higher when compared with free DiR. Interestingly, the brain targeting effect was further enhanced by co-administration of GSH. The low CMC value and effective brain targeting make COXP micelles a promising drug delivery system to the brain.
- Najmi, Asim,Wang, Shenggang,Huang, Yue,Seefeldt, Teresa,Alqahtani, Yahya,Guan, Xiangming
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- Syntheses, transfection efficacy and cell toxicity properties of novel cholesterol-based gemini lipids having hydroxyethyl head group
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We have synthesized five new cholesterol based gemini cationic lipids possessing hydroxyethyl (-CH2CH2OH) function on each head group, which differ in the length of the polymethylene spacer chain. These gemini lipids are important for gene delivery processes as they possess pre-optimized molecular features, e.g., cholesterol backbone, ether linkage and a variable spacer chain between both the headgroups of the gemini lipids. Cationic liposomes were prepared from each of these lipids individually and as a mixture of individual cationic gemini lipid and 1,2-dioleoyl phosphatidylethanolamine (DOPE). Each gemini lipid based formulation induced better transfection activity than that of their monomeric counterpart. One such gemini lipid with a -(CH2)12- spacer, HG-12, showed dramatic increase in the mean fluorescence intensity due to the expression of green-fluorescence protein (GFP) in the presence of 10% FBS compared to the conditions where there was no serum. Other gemini lipids retained their gene transfection efficiency without any marked decrease in the presence of serum. The only exception was seen with the gemini with a -(CH2) 3- spacer, HG-3, which on gene transfection in the presence of 10% FBS lost ~70% of its transfection efficiency. Overall the gemini lipid with a -(CH2)5- spacer, HG-5, showed the highest transfection activity at N/P (lipid/DNA) ratio of 0.5 and lipid:DOPE molar ratio of 2. Upon comparison of the relevant parameters, e.g., %-transfected cells, the amount of DNA transfected to each cell and %-cell viability all together against Lipofectamine 2000, one of the best commercial transfecting agents, the optimized lipid formulation based on DOPE/HG-5 was found to be comparable. In terms of its ability to induce gene-transfer in the presence of serum and shelf-life DOPE/HG-5 liposome was found to be superior to its commercial counterpart. Confocal imaging analysis confirmed that in the presence of 10% serum using a Lipid:DOPE of 1:4 and N/P charge ratio of 0.75 with 1.2 μg DNA per well, HG-5 is better than Lipofectamine 2000.
- Biswas, Joydeep,Mishra, Santosh K.,Kondaiah, Paturu,Bhattacharya, Santanu
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- Facile Access to Bridged Ring Systems via Point-to-Planar Chirality Transfer: Unified Synthesis of Ten Cyclocitrinols
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Bridged ring systems are found in a wide variety of biologically active molecules including pharmaceuticals and natural products. However, the development of practical methods to access such systems with precise control of the planar chirality presents considerable challenges to synthetic chemists. In the context of our work on the synthesis of cyclocitrinols, a family of steroidal natural products, we herein report the development of a point-to-planar chirality transfer strategy for preparing bridged ring systems from readily accessible fused ring systems. Inspired by the proposed pathway for biosynthesis of cyclocitrinols from ergosterol, our strategy involves a bioinspired cascade rearrangement, which enabled the gram-scale synthesis of a common intermediate in nine steps and subsequent unified synthesis of 10 cyclocitrinols in an additional one to three steps. Our work provides experimental support for the proposed biosynthetic pathway and for the possible interrelationships between members of the cyclocitrinol family. In addition to being a convenient route to 5(10→19)abeo-steroids, our strategy also offers a generalized approach to bridged ring systems via point-to-planar chirality transfer. Mechanistic investigations suggest that the key cascade rearrangement involves a regioselective ring scission of a cyclopropylcarbinyl cation rather than a direct Wagner-Meerwein rearrangement.
- Wang, Yu,Ju, Wei,Tian, Hailong,Sun, Suyun,Li, Xinghui,Tian, Weisheng,Gui, Jinghan
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- Liposomes modified with double-branched biotin: A novel and effective way to promote breast cancer targeting
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Although active targeting liposomes with cancer-specific ligands can bind and internalize into cancer cells, only a few high-efficiency liposomes have been developed so far because traditional single branched ligand modified liposomes generally failed to deliver adequate therapeutic payload. In this paper, we broke the traditional design concept and synthesized the double branched biotin modified cholesterol (Bio2-Chol) for the first time. On this basis, different biotin density modified liposomes ((Bio-Chol)Lip, (Bio-Chol)2Lip and (Bio2-Chol)Lip) were successfully prepared and used as active targeting drug delivery systems for the treatment of breast cancer. The in vitro and in vivo breast cancer-targeting ability of these liposomes were systemically studied using paclitaxel (PTX) as the model drug. And the uptake mechanism of (Bio2-Chol)Lip was investigated. The results showed that (Bio2-Chol)Lip had the best breast cancer-targeting ability compared with naked paclitaxel, unmodified Lip, (Bio-Chol)Lip and (Bio-Chol)2Lip. In particular, the relative uptake efficiency (RE) and concentration efficiency (CE) of (Bio2-Chol)Lip were respectively enhanced by 5.61- and 5.06-fold compared to that of naked paclitaxel. Both distribution data and pharmacokinetic parameters suggested that the double branched biotin modified liposome ((Bio2-Chol)Lip) is a very promising drug delivery carrier for breast cancer.
- Lu, Runxin,Zhou, Lin,Yue, Qiming,Liu,Cai, Xiaojing,Xiao, Wenjiao,Hai, Li,Guo, Li,Wu, Yong
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- Design, synthesis and biological evaluation of multivalent glucosides with high affinity as ligands for brain targeting liposomes
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The new bifunctional cluster glucosides were designed and synthesized as liposome ligands for preparing novel liposome to achieve the effective delivery of drug formulations to brain by GLUT1. Docetaxel-loaded five liposomes were prepared successfully and tested in the animals. Results from the in vivo distribution study after i.v. administration of these five liposomes and blank-docetaxel indicated that the coupled liposomes Lip-1, Lip-2, Lip-3, Lip-5 exhibited excellent transport ability across the BBB. In particular, they significantly increased the level of docetaxel in brain compared to blank-docetaxel and Lip. Among them, Lip-5 showed higher brain concentration. Both pharmacokinetics and distribution study in mice confirmed that this novel brain targeting drug delivery system was a promising carrier to enhance brain delivery capacity for CNS drugs.
- Qu, Boyi,Li, Xiaocen,Guan, Mei,Li, Xun,Hai, Li,Wu, Yong
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- Novel galactosylated poly(ethylene glycol)-cholesterol for liposomes as a drug carrier for hepatocyte-targeting
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In this study, three types of galactosylated cholesterol (i.e., gal-PEG194-chol, gal-PEG1000-chol and gal-PEG2000-chol) were synthesized with one terminal of polyethylene glycol of various chain lengths conjugated to the galactoside moiety, and the other terminal conjugated to the cholesterol. The galactose-modified liposomes were prepared by thin film-hydration method and doxorubicin (DOX) was loaded to the liposomes by using a ammonium sulfate gradient procedure. The liposomal formulations with galactosylated cholesterol were characterized. Flow cytometry and laser confocal scanning microscopy analyses showed that the galactose-modified liposomes facilitated the intracellular uptake of liposomes into HepG2 via asialoglycoprotein receptor (ASGP-R) mediated endocytosis. Cytotoxicity assay showed that the cell proliferation inhibition effect of galactosemodified liposomes was higher than that of the unmodified liposomes. Additionally, the study on frozen section of liver showed that the galactose-modified liposomes enhanced the intracellular uptake of liposomes into hepatocytes. Taken together, these results suggested that liposomes containing such galactosylated cholesterol (i.e., gal-PEG-chol), had a great potential as drug delivery carriers for hepatocyte-selective targeting.
- Zhang, Huafang,Xiao, Yan,Cui, Shengmiao,Zhou, Yuefang,Zeng, Ke,Yan, Mina,Zhao, Chunshun
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Read Online
- Non-Covalent Assembly Method that Simultaneously Endows a Liposome Surface with Targeting Ligands, Protective PEG Chains, and Deep-Red Fluorescence Reporter Groups
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A new self-assembly method is used to rapidly functionalize the surface of liposomes without perturbing the membrane integrity or causing leakage of the aqueous contents. The key molecule is a cholesterol-squaraine-PEG conjugate with three important structural elements: a cholesterol membrane anchor, a fluorescent squaraine docking station that allows rapid and high-affinity macrocycle threading, and a long PEG-2000 chain to provide steric shielding of the decorated liposome. The two-step method involves spontaneous insertion of the conjugate into the outer leaflet of pre-formed liposomes followed by squaraine threading with a tetralactam macrocycle that has appended targeting ligands. A macrocycle with six carboxylates permitted immobilization of intact fluorescent liposomes on the surface of cationic polymer beads, whereas a macrocycle with six zinc(II)-dipicolylamine units enabled selective targeting of anionic membranes, including agglutination of bacteria in the presence of human cells.
- Shaw, Scott K.,Liu, Wenqi,Brennan, Seamus P.,de Lourdes Betancourt-Mendiola, María,Smith, Bradley D.
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Read Online
- Preparation and application of brain glioma targeting berberine and folic acid modified lipid material
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The invention discloses preparation and application of a brain glioma targeting berberine and folic acid modified lipid material, and can be used for preparing lipidosome modified by brain glioma targeting Tween 80 coated berberine and folic acid. The liposome surface is coated with Tween 80 and can pass through the blood-brain barrier effectively through receptor-mediated endocytosis after binding with low density lipoprotein receptors to deliver the drug to the brain. In addition, the liposome uses folic acid and berberine to modify brain glioma targeting and mitochondrial targeting capacity of the liposome, and the long chain of polyethylene glycol is introduced to stabilize the liposome. A new thought and a method can be provided for targeted therapy of glioma, and a wide application prospect is provided. pH MDR. The utility model can provide a new idea and a method for targeted therapy of brain glioma.
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Paragraph 0010; 0027
(2021/09/21)
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- Preparation and application of three-branch RGD modified brain glioma targeting lipid material
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The invention discloses a three-branch RGD-modified glioma targeting lipid material which is used for targeted delivery of brain glioma treatment drugs. One end of the novel lipid material is connected with cholesterol extending through polyethylene glycol, and the other end of the novel lipid material is connected with RGD peptide with brain glioma targeting function, and the novel lipid material can be used for integrin receptor α which is highly expressed on the surface of brain capillary endothelial cells and brain glioma cells. v β3 The affinity between the brain glioma is achieved through the affinity between the brain glioma, and the effective concentration of the therapeutic drug to the brain tumor is improved. The novel lipid lipid material can be used for liposome. The prepared paclitaxel liposome has obvious brain targeting property and tumor targeting property, and has wide application prospects.
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Paragraph 0028
(2021/11/03)
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- GLUTATHIONE-CHOLESTEROL DERIVATIVES AS BRAIN TARGETING AGENTS
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The present invention describes compositions containing cholesterol-linker-glutathione conjugates for targeting the brain by overcoming barrier entry to the CNS through the blood brain barrier (BBB), including micelle and liposome forms of such compositions. In addition, methods for treating subjects by administering such compositions are also disclosed.
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Paragraph 0108-0112
(2020/02/27)
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- Preparation and application of multi-branch biotin modified breast cancer targeted liposomes
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The invention discloses novel lipid materials for realizing the delivery of breast cancer targeted drugs. According to the novel lipid materials, through a branch framework, one end is connected to cholesterol extended by polyethylene glycol, and the other end is connected to a different number of biotins with a breast cancer targeting function; and affinity between the novel lipid materials and areceptor can be used to realize stronger tumor targeting and play a more effective role in breast cancer treatment. The novel lipid materials can be used in different dosage forms such as liposomes,nanoparticles and micelles, and the prepared paclitaxel-loaded liposomes have obvious breast cancer targeting and broad application prospects.
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Paragraph 0026
(2020/04/09)
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- Biotin and membrane-penetrating peptide CO-mediated intelligent liposome material for breast cancer targeting (by machine translation)
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The invention discloses a breast cancer targeting intelligent liposome material which is jointly mediated by biotin and a membrane penetrating peptide. After the liposome reaches the breast tumor part, PEG long-chain rupture of the hydrazone key is removed, and the short-chain-connected R8-mediated transmembrane is exposed, so that the effect of effectively treating the breast cancer is achieved through Michahael adducts. R8; 2; after the liposome reaches the mammary gland tumor site, the liposome is exposed out of the short-chain-linked immunostimulatory SMVT transposon. The novel intelligent lipid material can be used for different dosage forms including liposomes, nanoparticles, micelles and the like, and the prepared paclitaxel liposome has strong breast cancer penetration and treatment effects and has a wide application prospect. (by machine translation)
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Paragraph 0024
(2020/06/16)
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- Preparation and application of breast cancer targeted liposome modified by biotin and glucose
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The invention discloses a novel lipid material for realizing the delivery of a breast cancer targeted drug. The novel lipid material takes lysine as a connecting group and is connected with a cholesteric part, a biotin part and a glucose part. The affinity between biotin and glucose in the novel lipid material and biotin transporter (SMVT) and glucose transporter (GLUT1) can be utilized to realizethe double targeting function to breast cancer and play a stronger breast cancer targeting therapeutic role, wherein the biotin transporter (SMVT) and the glucose transporter (GLUT1) are highly expressed on the surface of breast cancer cells. The novel lipid material can be used in different dosage forms comprising liposomes, nanoparticles, micelles and the like, and the prepared paclitaxel-loaded liposome has obvious breast cancer targeting property and a wide application prospect.
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Paragraph 0028
(2020/03/11)
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- Biotin and glucose dual-targeting, ligand-modified liposomes promote breast tumor-specific drug delivery
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Breast cancer is the second leading cause of cancer-related deaths in women. Ligand-modified liposomes are used for breast tumor-specific drug delivery to improve the efficacy and reduce the side effects of chemotherapy; however, only a few liposomes with high targeting efficiency have been developed because the mono-targeting, ligand-modified liposomes are generally unable to deliver an adequate therapeutic dose. In this study, we designed biotin-glucose branched ligand-modified, dual-targeting liposomes (Bio-Glu-Lip) and evaluated their potential as a targeted chemotherapy delivery system in vitro and in vivo. When compared with the non-targeting liposome (Lip), Bio-Lip, and Glu-Lip, Bio-Glu-Lip had the highest cell uptake in 4T1 cells (3.00-fold, 1.60-fold, and 1.95-fold higher, respectively) and in MCF-7 cells (2.63-fold, 1.63-fold, and 1.85-fold higher, respectively). The subsequent cytotoxicity and in vivo assays further supported the dual-targeting liposome is a promising drug delivery carrier for the treatment of breast cancer.
- Fu, Qiuyi,Guo, Li,Huang, Mengyi,Peng, Yao,Pu, Yanchi,Wu, Yong,Zheng, Yongxiang
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supporting information
(2020/04/21)
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- Deep-Red-Fluorescent Zinc Probe with a Membrane-Targeting Cholesterol Unit
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Organelle-targeting fluorescence probes are valuable because they can provide spatiotemporal information about the trafficking of analytes of interest. The spatiotemporal resolution can be improved by using low-energy emission signals because they are barely contaminated by autofluorescence noises. In this study, we designed and synthesized a deep-red-fluorescent zinc probe (JJ) with a membrane-targeting cholesterol unit. This zinc probe consists of a boron-azadipyrromethene (aza-BODIPY) fluorophore and a zinc receptor that is tethered to a tri(ethylene glycol)-cholesterol chain. In aqueous solutions buffered to pH 7.4, JJ exhibits weak fluorescence with a peak wavelength of 663 nm upon excitation at 622 nm. The addition of ZnCl2 elicits an approximately 5-fold enhancement of the fluorescence emission with a fluorescence dynamic range of 141000. Our electrochemical and picosecond transient photoluminescence investigations indicate that the fluorescence turn-on response is due to the zinc-induced abrogation of the formation of a nonemissive intramolecularly charge-separated species, which occurs with a driving force of 0.98 eV. The fluorescence zinc response was found to be fully reversible and to be unaffected by pH changes or the presence of biological metal ions. These properties are due to tight zinc binding with a dissociation constant of 4 pM. JJ was found to be nontoxic to HeLa cells up to submicromolar concentrations, which enables cellular imaging. Colocalization experiments were performed with organelle-specific stains and revealed that JJ is rapidly internalized into intracellular organelles, including lysosomes and endoplasmic reticula. Unexpectedly, probe internalization was found to permeabilize the cell membrane, which facilitates the influx of exogens such as zinc ions. Such permeabilization does not arise for a control probe without the tri(ethylene glycol)-cholesterol chain (JJC). Our results show that the membrane-targeting cholesterol unit can disrupt membrane integrity.
- Hong, Jayeon,Kim, Jin Ju,You, Youngmin,Yu, Seungyeon
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p. 11562 - 11576
(2020/09/09)
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- Dual-targeting liposome modified by glutamic hexapeptide and folic acid for bone metastatic breast cancer
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Bone is the most common organ affected by metastatic breast cancer. Targeting delivery of drugs to bone may not only enhance the treatment efficacy, but also reduce the quantity of drug administered. In order to increase the distribution of paclitaxel (PTX) in bone, herein, a novel bone metastasis-targeted glutamic hexapeptide-folic acid (Glu6-FA) derivative was designed and synthesized as liposome ligand to deliver PTX to bone metastasis effectively. The liposomes were prepared by thin film hydration method and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis were also characterized. What's more, the anti-tumor effects of PTX-Glu6-FA-Lip were confirmed by the detection of cell cycle, migration, and further measurement of microtubule stabilization. In addition, the PTX-Glu6-FA-Lip showed superior targeting ability in vitro and in vivo evaluation as compared to naked PTX, non-coated, singly-modified and co-modified by physical blending liposomes. All the results suggested that Glu6-FA-modified liposome showed excellent targeting activity to metastatic bone cancer. These findings suggested that Glu6-FA-Lip was a promising bone metastasis-targeting carrier for the delivery of PTX. This study may therefore be conducive to the field of bone-targeting drugs delivery.
- Xie, Changwei,Yang, Yang,Zhao, Yi,Zhao, Ze
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- Design, preparation and evaluation of different branched biotin modified liposomes for targeting breast cancer
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A series of liposome ligands (Bio-Chol, Bio-Bio-Chol, tri-Bio-Chol and tetra-Bio-Chol) modified by different branched biotins that can recognize the SMVT receptors over-expressed in breast cancer cells were synthesized. And four liposomes (Bio-Lip, Bio-Bio-Lip, tri-Bio-Lip and tetra-Bio-Lip) modified by above mentioned ligands as well as the unmodified liposome (Lip) were prepared to study the targeting ability for breast cancer. The cytotoxicity study and apoptosis assay of paclitaxel-loaded liposomes showed that tri-Bio-Lip had the strongest anti-proliferative effect on breast cancer cells. The cellular uptake studies on mice breast cancer cells (4T1) and human breast cancer cells (MCF-7) indicated tri-Bio-Lip possessed the strongest internalization ability, which was 5.21 times of Lip, 2.60 times of Bio-Lip, 1.67 times of Bio-Bio-Lip and 1.17 times of tetra-Bio-Lip, respectively. Moreover, the 4T1 tumor-bearing BALB/c mice were used to evaluate the in vivo targeting ability. The data showed the enrichment of liposomes at tumor sites were tri-Bio-Lip > tetra-Bio-Lip > Bio-Bio-Lip > Bio-Lip > Lip, which were consistent with the results of in vitro targeting studies. In conclusion, increasing the density of targeting molecules on the surface of liposomes can effectively enhance the breast cancer targeting ability, and the branching structure and spatial distance of biotin residues may also have an important influence on the affinity to SMVT receptors. Therefore, tri-Bio-Lip could be a promising drug delivery system for targeting breast cancer.
- Guo, Li,Hai, Li,Li, Ru,Peng, Yao,Pu, Yanchi,Tang, Baolan,Wu, Yong,Yue, Qiming,Zhao, Yi
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- LIPIDIC ANALOGS OF ANTI-CANCER STEM CELL AGENT
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A group of specific sulfated flavonoid agents carrying cholesterol modification display promising in vivo anti-cancer activity through selective inhibition of cancer stem cells, and not of adult or hematopoietic stem cells. The compounds exhibit high potency, excellent oral bioavailability and a physiologically relevant therapeutic window.
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Page/Page column 12; 34
(2020/09/19)
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- Dual-active targeting liposomes drug delivery system for bone metastatic breast cancer: Synthesis and biological evaluation
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Bone is the most common organ affected by metastatic breast cancer. Targeting cancers within the bone remains a great challenge due to the inefficient delivery of therapeutic to bone. In order to increase the distribution of paclitaxel (PTX) in bone metastases, in this study, a novel bone-targeted glutamic oligopeptides-RGD peptide (Glu6-RGD) derivative was designed and synthesized as liposome ligand for preparing liposome to effectively deliver PTX to bone metastases. The liposome was prepared and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis and cytotoxicity were also characterized. What's more, the Glu6-RGD-Lip showed superior targeting ability in vitro and in vivo evaluation as compared to naked PTX, non-coated, singly-modified and co-modified by physical blending liposomes. All the results suggested that Glu6-RGD-modified liposome showed excellent targeting activity to metastatic bone cancer. This study may be conducive to the field of bone-targeting drugs delivery.
- Zhao, Ze,Zhao, Yi,Xie, Changwei,Chen, Changqing,Lin, Dong,Wang, Sheng,Cui, Xinhua,Guo, Zhongshuai,Zhou, Junfeng
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- Fructose and RGD peptide co-modified dual-targeting triple-negative breast cancer lipid material
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The present invention discloses a novel lipid material for realizing transfer of triple negative breast cancer targeted drugs. The novel lipid material takes lysine as a connecting group to respectively connect a cholesteric part, a fructose part and an RGD part. Affinities between fructose in the novel lipid material and a fructose transporter GLUT5, and between RGD in the novel lipid material and an integrin receptor alpha v beta 3 are respectively utilized to realize double targeting functions of the triple negative breast cancer and exert stronger targeted treatment effects on the triple negative breast cancer. The novel liquid material can be sued for different dosages of liposomes, nanoparticles, micelle, etc. A prepared paclitaxel-loaded liposome has obvious triple negative breast cancer targeting property and a wide application prospect.
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Paragraph 0026
(2019/12/15)
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- Dual-targeting liposomes with active recognition of GLUT5 and αvβ3 for triple-negative breast cancer
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At present, chemo- and radiotherapies remain to be the mainstream methods for treating triple-negative breast cancer (TNBC), which is known for poor prognosis and high rate of mortality. Two types of novel dual-targeting TNBC liposomes (Fru-RGD-Lip and Fru+RGD-Lip) that actively recognize both fructose transporter GLUT5 and integrin αvβ3 were designed and prepared in this work. Firstly, a Y-shaped Fru-RGD-chol ligand, where a fructose and peptide Arg-Gly-Asp (RGD) were covalently attached to cholesterol, was designed and synthesized. Then, the Fru-RGD-Lip was constructed by inserting Fru-RGD-chol into liposomes, while Fru+RGD-Lip was obtained by inserting both Fru-chol and RGD-chol (with the molar ratio of 1:1) into liposomes. The particle size, zeta potential, encapsulation efficiency and serum stability of the paclitaxel-loaded liposomes were characterized. The results indicated that the paclitaxel-loaded Fru-RGD-Lip had the strongest growth inhibition against GLUT5 and αvβ3 overexpressed MDA-MB-231 and 4T1 cells. The cellular uptake of Fru-RGD-Lip on MDA-MB-231 cells and 4T1 cells was 3.19- and 3.23-fold more than that of the uncoated liposomes (Lip). The uptake of Fru+RGD-Lip was slightly lower, giving a 2.81- and 2.90-fold increase than that of Lip in two cell lines, respectively. The mechanism study demonstrated that the cellular uptake of both dual-targeting liposomes was likely to be recognized and mediated by GLUT5 and αvβ3 firstly, then endocytosed through comprehensive pathways in an energy-dependent manner. Moreover, Fru-RGD-Lip displayed the maximum accumulation, which was 2.62-fold higher than that of Lip for instance, at the tumor sites compared to other liposomes using in vivo imaging. Collectively, the liposomes co-modified by fructose and RGD have enormous potential in the development of targeted TNBC treatment, especially the covalently modified Fru-RGD-Lip, making it a promising multifunctional liposome.
- Pu, Yanchi,Zhang, Hao,Peng, Yao,Fu, Qiuyi,Yue, Qiming,Zhao, Yi,Guo, Li,Wu, Yong
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- Novel double brain tumor-targeted lipid material and application thereof
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The invention discloses a novel lipid material. The novel lipid material is used for prolonging the circulating time and increasing the transfer amount of medicine to brain tumor tissues in a target way. The novel lipid material is characterized in that polyethylene glycol is used as a bridge, one side of the bridge is connected with cholesterol, and one side of the bridge is connected with glucose and RGD (arginine-glycine-aspartic acid) peptide, so that the lack of brain tumor targeting ability by the lipid modified by the single glucose or the RGD peptide is overcome, and the brain tumor can be effectively targeted after blood brain barrier crossing. The novel lipid material can be used for different preparation types of lipids, nanoparticles, micelles and the like; the prepared paclitaxel-carrying lipid has obvious brain tumor targeting function, and broad application prospect.
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Paragraph 0031
(2018/12/02)
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- Cholesterol pyrophosphate, and preparation method and use thereof
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The invention discloses a cholesterol pyrophosphate, and a preparation method and a use thereof. Cholesterol and pyrophosphate are connected through click chemistry, and the targeting auxiliary material cholesterol pyrophosphate (PPi-Chol) having strong affinity to bones is prepared through combining the wide application of the cholesterol in a medicinal preparation with the bone targeting property of the pyrophosphate, so the studying process of the bone targeting dosage form is greatly improved, and the therapy effect of bone related diseases is improved.
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Paragraph 0024; 0039
(2018/03/26)
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- Catalytic cyclometallation in steroid chemistry VI: Targeted synthesis of hybrid molecules based on steroids and tetradeca-5Z,9Z-diene-1,14-dicarboxylic acid and study of their antitumor activity
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Hybrid molecules based on a number of steroids (cholesterol, pregnenolone, androsterone) and 1,14-tetradeca-5Z,9Z-dienedicarboxylic acid linked via mono- and diethylene glycol spacers were synthesized for the first time and studied for antitumor activity in vitro. The acid was prepared using catalytic cyclomagnesiation of oxygenated 1,2-dienes with Grignard reagent in the presence of Cp2TiCl2 as the key synthetic step. Using flow cytometry, the new molecules were shown for the first time to be efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562 cell cultures and to have dose-dependent effect on the S and G2 phases of the cell cycle.
- D'yakonov, Vladimir A.,Tuktarova, Regina A.,Dzhemileva, Lilya U.,Ishmukhametova, Svetlana R.,Yunusbaeva, Milyausha M.,Dzhemilev, Usein M.
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- FLUORESCENT ANTICANCER PLATINUM DRUGS
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The present disclosure is in relation to the field of nanotechnology and cancer therapeutics. In particular, the present disclosure relates to fluorescent platinum based compounds. The disclosure further relates to synthesis of said fluorescent platinum based compounds, nanoparticles and compositions comprising said fluorescent platinum based compounds/nanoparticles. The disclosure also relates to methods of managing cancer by the fluorescence changes between aforesaid platinum based compounds and corresponding free ligands, nanoparticles and compositions.
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Paragraph 0463; 0475
(2018/11/21)
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- A doxorubicin altogether carries the medicine system, preparation method and application thereof
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The invention discloses an adriamycin co-drug-loading system and a preparing method and application thereof. The adriamycin co-drug-loading system comprises an adriamycin active ingredient and a targeting vector. A targeting ligand is in covalent binding with the surface of the targeting vector, small interfering RNA is carried on the targeting vector, and the targeting vector is used for inhibiting cancer gene expression. The adriamycin active ingredient accounts for 4%-8% of the co-drug-loading system by mass, the targeting ligand accounts for 1%-10% of the co-drug-loading system by mass, and the small interfering RNA accounts for 0.5%-2% of the co-drug-loading system by mass. The preparing method of the adriamycin co-drug-loading system comprises the following steps that firstly, a targeting conjugate of a folic acid ligand is prepared; secondly, a precursor of the adriamycin co-drug-loading system is prepared; thirdly, the adriamycin co-drug-loading system is prepared. The adriamycin co-drug-loading system is good in targeting performance, high in anti-cancer activity, low in toxicity, not likely to cause drug resistance and especially suitable for preparing targeting solid tumor resisting drugs.
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Paragraph 0025; 0070; 0071; 0097; 0098; 0124; 0125
(2018/11/04)
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- Dual-targeting for brain-specific liposomes drug delivery system: Synthesis and preliminary evaluation
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The treatment of glioma has become a great challenge because of the existence of brain barrier (BB). In order to develop an efficient brain targeting drug delivery system to greatly improve the brain permeability of anti-cancer drugs, a novel brain-targeted glucose-vitamin C (Glu-Vc) derivative was designed and synthesized as liposome ligand for preparing liposome to effectively deliver paclitaxel (PTX). The liposome was prepared and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis and cytotoxicity were also characterized. What's more, the cellular uptake of CFPE-labeled Glu-Vc-Lip on GLUT1- and SVCT2-overexpressed C6 cells was 4.79-, 1.95-, 4.00- and 1.53-fold higher than that of Lip, Glu-Lip, Vc-Lip and Glu + Vc-Lip. Also, the Glu-Vc modified liposomes showed superior targeting ability in vivo evaluation compared with naked paclitaxel, non-coated, singly-modified and co-modified by physical blending liposomes. The relative uptake efficiency was enhanced by 7.53 fold to that of naked paclitaxel, while the concentration efficiency was up to 7.89 times. What's more, the Glu-Vc modified liposomes also displayed the maximum accumulation of DiD-loaded liposomes at tumor sites with the strongest fluorescence in the brain in vivo imaging. Our results suggest that chemical modification of liposomes with warheads of glucose and vitamin C represents a promising and efficient strategy for the development of brain-specific liposomes drug delivery system by utilizing the endogenous transportation mechanism of the warheads.
- Peng, Yao,Zhao, Yi,Chen, Yang,Yang, Zhongzhen,Zhang, Li,Xiao, Wenjiao,Yang, Jincheng,Guo, Li,Wu, Yong
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p. 4677 - 4686
(2018/08/11)
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- NOVEL INHIBITORS OF CELLULAR SIGNALLING
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The present disclosure relates generally to Cellular Signalling inhibitors of compound of Formula I, compositions and formulations comprising the same, methods, processes, and uses thereof. In particular, the present disclosure provides CSF-1R inhibitors of BLZ-945-lipids conjugates, GW2580-lipid conjugates and PLX-3397-lipid conjugates demonstrating sustained inhibition of CSF/CSF1R signalling pathway with decreased toxicity. The present disclosure also provides supramolecular combinatorial therapeutics, wherein a CSF-1R inhibitor is combined with one or more of a chemotherapeutic agent, a kinase inhibitor, and an immunoregulator, each of which is optionally conjugated with a lipid. The present disclosure also provides a method for treating cancer, allergy, Systemic lupus erythematosus, nephritis, Chronic Obstructive Pulmonary Disease, and abnormal macrophage functions or any combinations thereof.
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Page/Page column 40; 53
(2018/09/08)
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- CELLULAR SIGNALLING INHIBITORS, THEIR FORMULATIONS AND METHODS THEREOF
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The present disclosure relates generally to Cellular Signalling inhibitors of compound of Formula (I), compositions and formulations comprising the same, methods, processes, and uses thereof. In particular, the present disclosure provides CSF-1R inhibitors demonstrating sustained inhibition of CSF/CSF1R signalling pathway with decreased toxicity. The present disclosure also provides supramolecular combinatorial therapeutics, wherein a CSF-1R inhibitor is combined with one or more of a chemotherapeutic agent, a kinase inhibitor, and an immunoregulator, each of which is optionally conjugated with a lipid. The present disclosure also provides a method for treating cancer, allergy, Systemic lupus erythematosus, nephritis, Chronic Obstructive Pulmonary Disease, and abnormal macrophage functions or any combinations thereof.
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Paragraph 00182
(2017/09/05)
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- Bone targeted liposome, drugs and preparations thereof, and preparation method and application thereof
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The invention discloses a bone targeted liposome containing a compound of a structure in Formula 5, wherein n is selected from integers from 1 to 100, and the invention also discloses a bone targeted liposome drug containing the liposome and active drug molecules wrapped therein and preparations of the bone targeted liposome drug and a preparation method and application thereof. The bone targeted liposome uses pyrophosphoric acid to modify the liposome surface, has good bone affinity and good targeting, solves the problem that bonding between existing bone targeted drugs and a bone surface is insufficient, and can be targeted to various surfaces of bones: a bone absorption surface, a bone forming surface, a bone growth plate, the interior of cortical bone and a bone concave cavity, a bone targeting characteristic range is wider, and requirements for loading various drugs for treating bone diseases can be fully satisfied. The invention also discloses a tanshinol bone targeted liposome drug and application thereof in fracture healing disorders, and the drugs can promote formation of callus in an early stage, and promote transformation of the callus to normal bone in a later stage, thereby remarkably shortening fracture healing time and enhancing the mechanical property of bone after fracture healing.
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Paragraph 0062-0063
(2017/11/16)
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- Biomineral and metal binding liposomes, their synthesis, and methods of use thereof
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Drug carriers, methods of synthesizing, and methods of use thereof are provided. The drug carriers are liposomes comprising at least one functionalized cholesterol of the formula: Chol-X-T, wherein X is a linker domain, T is at least one targeting moiety which binds hard tissue and/or medical implants, and Chol is cholesterol or a derivative or analog thereof. The liposomes may encapsulate at least one therapeutic agent for the treatment of an oral disease or disorder.
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Page/Page column 12
(2017/02/09)
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- Liphophilic polynucleotide assembly (by machine translation)
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Disclosed are lipophilic polynucleotide conjugates including polynucleotide-cholesterol conjugates and methods of delivering therapeutic polynucleotides to a mammalian cell or patient in need of treatment using said conjugates. The disclosure further provides methods of synthesizing the lipophilic polynucleotide conjugates. The conjugates are designed to mimic or target cellular miRNAs. The lipophilic moiety, such as cholesterol or cholesterol derivative, is spaced from the polynucleotide by a substantially linear hydrocarbon group. Due to an absence of significantly polar groups and/or exchangeable protons in the vicinity of the lipophilic moiety, the interaction between the lipophilic moiety and cell membranes is enhanced to provide for efficient entry into cells.
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Page/Page column 26; 36
(2016/10/09)
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- SILENCING OF POLO-LIKE KINASE EXPRESSION USING INTERFERING RNA
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The present invention provides compositions comprising interfering RNA (e.g., siRNA, aiRNA, miRNA) that target polo-like kinase 1 (PLK-1) expression and methods of using such compositions to silence PLK-1 expression. More particularly, the present invention provides unmodified and chemically modified interfering RNA molecules which silence PLK-1 expression and methods of use thereof. The present invention also provides serum-stable nucleic acid-lipid particles (e.g., SNALP) comprising an interfering RNA molecule described herein, a cationic lipid, and a non-cationic lipid, which can further comprise a conjugated lipid that inhibits aggregation of particles. The present invention further provides methods of silencing PLK-1 gene expression by administering an interfering RNA molecule described herein to a mammalian subject. The present invention additionally provides methods of identifying and/or modifying PLK-1 interfering RNA having immunostimulatory properties. Methods for sensitizing a cell such as a cancer cell to the effects of a chemotherapy drug comprising sequentially delivering PLK-1 interfering RNA followed by the chemotherapy drug are also provided.
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Paragraph 0687; 0688
(2016/05/19)
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- MODIFIED THERAPEUTIC AGENTS AND COMPOSITIONS THEREOF
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Methods and compositions are provided for extending the half-life of a therapeutic agent. One half-life extending moieties may be attached to a therapeutic agent, thereby extending the half life of the therapeutic agent. The modified therapeutic agents comprising a half-life extending moieties attached to a therapeutic agent may be used to treat a disease or condition in a subject in need thereof.
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Paragraph 0318
(2016/10/04)
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- LIGAND-MODIFIED DOUBLE-STRANDED NUCLEIC ACIDS
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The invention provides for double stranded nucleic acid molecules comprising a 5 'extension of the sense or antisense strand and further comprising a plurality of nucleotides that are conjugated to a ligand and methods of using the double-stranded nucleic acid molecules. Ligand-modified oligomers where the sense stands form a tetraloop provide new potent and stable RNA interference agents. These dsNA molecules are synthesized using a plurality of nucleotides that include ligand-modified monomers, nucleotide analog monomers, modified nucleotide monomers and the like, using standard nucleotide synthetic methods and systems.
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Paragraph 00663
(2016/07/05)
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- Lipids, lipid compositions, and methods of using them
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Disclosed are formulation and optimization protocols for delivery of therapeutically effective amounts of biologically active agents to liver, tumors, and/or other cells or tissues. Also provided are compositions and uses for cationic lipid compounds of formula (I). The invention also relates to compositions and uses for stealth lipids of formula (XI). Also provided are processes for making such compounds, compositions, and formulations, plus methods and uses of such compounds, compositions, and formulations to deliver biologically active agents to cells and/or tissues.
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Page/Page column 75
(2016/05/02)
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- MODIFIED THERAPEUTIC AGENTS AND COMPOSITIONS THEREOF
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Methods and compositions are provided for extending the half-life of a therapeutic agent. One or more half-life extending moieties may be attached to a therapeutic agent, thereby extending the half life of the therapeutic agent. The modified therapeutic agents (mTAs) comprising one or more half-life extending moieties attached to a therapeutic agent may be used to treat a disease or condition in a subject in need thereof.
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Paragraph 0466; 0472
(2015/03/28)
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- A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane
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A non-symmetrical pH-sensitive bistable [2]rotaxane that bears a cholesterol unit and a tetraphenylmethane group as stopper groups was designed and synthesized in 18 steps. The successful formation of the rotaxane was proven by NMR spectroscopy and MS/MS. Besides a permanent cationic alkylated triazolium unit, the axle contains a secondary amine that can act as a second pH-sensitive binding site for a crown ether. Depending on the protonation state of this amine function, the crown ether reversibly changes its position by moving between the two binding sites along the axle, as revealed by NMR spectroscopy. A pH-sensitive bistable [2]rotaxane was synthesized and characterized by NMR spectroscopy and MS/MS. Besides an alkylated triazolium ion, the axle contains a secondary amine that acts as a second pH-sensitive binding site for a crown ether. Depending on the protonation state of this amine function, the crown ether reversibly changes its position by moving between two binding sites on the axles.
- Berg, Martin,Nozinovic, Senada,Engeser, Marianne,Lützen, Arne
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p. 5966 - 5978
(2015/09/22)
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- FUNCTIONALIZED LIPOSOMES USEFUL FOR THE DELIVERY OF BIOACTIVE COMPOUNDS
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The invention relates to conjugates in which a sterol is functionalized by an ether bond with a water-soluble polymer to which a guiding ligand is bound. These conjugates improve the physico-chemical and delivery properties of their carrying vesicles, making these more stable, homogeneous and effective. A method for their preparation, a pharmaceutical composition containing said liposomes, and their therapeutic use are described as well.
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Paragraph 0048; 0049
(2015/07/15)
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- TARGETED DRUG DELIVERY THROUGH AFFINITY BASED LINKERS
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The current invention discloses targeted drug delivery conjugates comprising a targeting moiety linked to a drug via a molecule having an affinity for the targeting moiety. Typically, the conjugate comprises a targeting ligand and a molecule of interest, e.g., a therapeutic agent. The targeting ligand and the molecule of interest are linked to each other via an affinity ligand. The affinity ligand is further covalently or non-covalently linked to a drug or therapeutic agent. The drug can be modified to make it more soluble and so that it cleaves from the linking molecule at the target site.
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Paragraph 00252
(2015/12/08)
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