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Targeting Ligands (targeting + ligand)
Selected AbstractsAn HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate-specific membrane antigen small molecule derivativesCONTRAST MEDIA & MOLECULAR IMAGING, Issue 5 2006Valerie Humblet Abstract The production of disease-targeted agents requires the covalent conjugation of a targeting molecule with a contrast agent or therapeutic, followed by purification of the product to homogeneity. Typical targeting molecules, such as small molecules and peptides, often have high charge-to-mass ratios and/or hydrophobicity. Contrast agents and therapeutics themselves are also diverse, and include lanthanide chelates for MRI, 99mTc chelates for SPECT, 90Y chelates for radiotherapy, 18F derivatives for PET, and heptamethine indocyanines for near-infrared fluorescent optical imaging. We have constructed a general-purpose HPLC/mass spectrometry platform capable of purifying virtually any targeted agent for any modality. The analytical sub-system is composed of a single dual-head pump that directs mobile phase to either a hot cell for the purification of radioactive agents or to an ES-TOF MS for the purification of nonradioactive agents. Nonradioactive agents are also monitored during purification by ELSD, absorbance and fluorescence. The preparative sub-system is composed of columns and procedures that permit rapid scaling from the analytical system. To demonstrate the platform's utility, we describe the preparation of five small molecule derivatives specific for prostate-specific membrane antigen (PSMA): a gadolinium derivative for MRI, indium, rhenium and technetium derivatives for SPECT, and an yttrium derivative for radiotherapy. All five compounds are derived from a highly anionic targeting ligand engineered to have a single nucleophile for N -hydroxysuccinimide-based conjugation. We also describe optimized column/mobile phase combinations and mass spectrometry settings for each class of agent, and discuss strategies for purifying molecules with extreme charge and/or hydrophobicity. Taken together, our study should expedite the development of disease-targeted, multimodality diagnostic and therapeutic agents. Copyright © 2006 John Wiley & Sons, Ltd. [source] Doxorubicin-Conjugated Immuno-Nanoparticles for Intracellular Anticancer Drug DeliveryADVANCED FUNCTIONAL MATERIALS, Issue 11 2009Meng Shi Abstract A polymeric nanoparticle comprised of surface furan groups is used to bind, by Diels,Alder (DA) coupling chemistry, both targeting anti-human epidermal growth factor receptor 2 (anti-HER2) antibodies and chemotherapeutic doxorubicin (DOX) for targeted, intracellular delivery of DOX. In this new approach for delivery, where both chemotherapeutic and targeting ligand are attached, for the first time, to the surface of the delivery vehicle, the nuclear localization of DOX in HER2-overexpressing breast cancer SKBR-3 cells is demonstrated, as determined by confocal laser scanning microscopy. Flow cytometric analysis shows that the conjugated DOX maintains its biological function and induces similar apoptotic progression in SKBR-3 cells as free DOX. The viable cell counts of SKBR-3 cancer cells following incubation with different nanoparticle formulations demonstrates that the combined DOX and anti-HER2 nanoparticle is more efficacious than the nanoparticle formulation with either DOX or anti-HER2 alone. While free DOX shows similar cytotoxicity against both cancerous SKBR-3 cells and healthy HMEC-1 cells, the combined DOX-anti-HER2 nanoparticle is significantly more cytotoxic against SKBR-3 cells than HMEC-1 cells, suggesting the benefit of nanoparticle-conjugated DOX for cell type-specific targeting. The DOX-conjugated immuno-nanoparticle represents an entirely new method for localized co-delivery of chemotherapeutics and antibodies. [source] Synthesis of Folic Acid Functionalized PLLA- b -PPEGMA Nanoparticles for Cancer Cell TargetingMACROMOLECULAR RAPID COMMUNICATIONS, Issue 8 2009Feixiong Hu Abstract Poly(L -lactic acid)- block -poly(poly(ethylene glycol) monomethacrylate) (PLLA- b -PPEGMA) has been prepared by the ring-opening polymerization of lactide with a double-headed initiator, 2-hydroxyethyl 2,-methyl-2,-bromopropionate (HMBP), followed by atom transfer radical polymerization (ATRP) of poly(ethylene glycol) monomethacrylate (PEGMA). PLLA- b -PPEGMA nanoparticles with encapsulated Fe3O4 are prepared by a solvent evaporation/extraction technique, and then further functionalized with folic acid, a cancer targeting ligand. Our results show that such functionalized PLLA- b -PPEGMA nanoparticles have good potential as carriers for targeted drug delivery in cancer treatment. [source] Recent developments in carbohydrate-decorated targeted drug/gene deliveryMEDICINAL RESEARCH REVIEWS, Issue 2 2010Hailong Zhang Abstract Targeted delivery of a drug or gene to its site of action has clear therapeutic advantages by maximizing its therapeutic efficiency and minimizing its systemic toxicity. Generally, targeted drug or gene delivery is performed by loading a macromolecular carrier with an appropriate drug or gene, and by targeting the drug/gene carrier to specific cell or tissue with the help of specific targeting ligand. The emergence of glycobiology, glycotechnology, and glycomics and their continual adaptation by pharmaceutical scientists have opened exciting avenue of medicinal applications of carbohydrates. Among them, the biocompatibility and specific receptor recognition ability confer the ability of carbohydrates as potential targeting ligands for targeted drug and gene delivery applications. This review summarizes recent progress of carbohydrate-decorated targeted drug/gene delivery applications. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 2, 270,289, 2010 [source] Identification of oligopeptides binding to peritoneal tumors of gastric cancerCANCER SCIENCE, Issue 10 2006Noriyuki Akita This is a report of in vivo intraperitoneal biopanning, and we successfully identified a novel peptide to target the multiple peritoneal tumors of gastric cancer. A phage display library was injected directly into the abdominal cavity of mice bearing peritoneal tumors of human gastric cancer, and phages associated with the tumors were subsequently reclaimed from isolated samples. The tumor-associated phages were amplified and the biopanning cycle was repeated five times to enrich for high affinity tumor-selective binding peptides. Finally, a tri-peptide motif, KLP, which showed homology with laminin 5 (a ligand for ,3,1 integrin), was identified as a binding peptide for peritoneal tumors of gastric cancer. Phage clones displaying the sequence KLP showed 64-fold higher binding to peritoneal tumors than control phage and were preferentially distributed in tumors rather than in normal organs after intraperitoneal injection into mice. In addition, the KLP phages were more likely to bind to cancer cells in malignant ascites derived from a patient with recurrent gastric cancer. Synthesized peptide containing the motif KLP (SWKLPPS) also showed a strong binding activity to peritoneal tumors without cancer growth effect. Liposomes conjugated with SWKLPPS peptide appeared significantly more often in tumors than control liposomes after intraperitoneal injection into mice. Furthermore, modification of liposomes with SWKLPPS peptide enhanced the antitumor activity of adriamycin on gastric cancer cells. The peptide motif KLP seems a potential targeting ligand for the treatment of peritoneal metastasis of gastric cancer. (Cancer Sci 2006; 97: 1075,1081) [source] Superparamagnetic Hyperbranched Polyglycerol-Grafted Fe3O4 Nanoparticles as a Novel Magnetic Resonance Imaging Contrast Agent: An In Vitro AssessmentADVANCED FUNCTIONAL MATERIALS, Issue 16 2009Liang Wang Abstract Hyperbranched polyglycerol-grafted, magnetic Fe3O4 nanoparticles (HPG-grafted MNPs) are successfully synthesized by surface-initiated ring-opening multibranching polymerization of glycidol. Reactive hydroxyl groups are immobilized on the surface of 6,9,nm Fe3O4 nanoparticles via effective ligand exchange of oleic acid with 6-hydroxy caproic acid. The surface hydroxyl groups are treated with aluminum isopropoxide to form the nanosized macroinitiators. The successful grafting of HPG onto the nanoparticles is confirmed by infrared and X-ray photoelectron spectroscopy. The HPG-grafted MNPs have a uniform hydrodynamic diameter of (24.0,±,3.0) nm, and are very stable in aqueous solution, as well as in cell culture medium, for months. These nanoparticles have great potential for application as a new magnetic resonance imaging contrast agent, as evidenced by their lack of cytotoxicity towards mammalian cells, low uptake by macrophages, excellent stability in aqueous medium and magnetic fields, and favorable magnetic properties. Furthermore, the possibility of functionalizing the hydroxyl end-groups of the HPG with cell-specific targeting ligands will expand the range of applications of these MNPs. [source] Dendrimer-Functionalized Shell-crosslinked Iron Oxide Nanoparticles for In-Vivo Magnetic Resonance Imaging of Tumors,ADVANCED MATERIALS, Issue 9 2008Xiangyang Shi A powerful magnetic nanoprobe with folic acid (FA)-targeting ligands is fabricated by dendrimer functionalization of Fe3O4 nanoparticles (NPs) precoated with crosslinkable and biocompatible polymer multilayer shells. This magnetic probe allows for magnetic resonance imaging of FA receptor-overexpressing tumor cells in vitro and of an early-stage tumor model in vivo (see picture). [source] A Polycation Scaffold Presenting Tunable "Click" Sites: Conjugation to Carbohydrate Ligands and Examination of Hepatocyte-Targeted pDNA DeliveryMACROMOLECULAR BIOSCIENCE, Issue 6 2010Chen-Chang Lee Abstract A versatile polycation scaffold that can easily be modified with targeting ligands has been designed, synthesized, and characterized. A series of galactose-containing polymers has been produced to demonstrate the ease of modification of this polynucleotide delivery vehicle motif via the click reaction and to study how various structural modifications affect recognition by ASGPr on hepatocytes. A small library of structures was created where DCS and alkyl spacer length between the targeting group and the polymer backbone was varied. The novel polymer scaffold described proves to be a valuable tool for understanding structure/activity relationships of complexes made with receptor-targeted polymers. [source] Recent developments in carbohydrate-decorated targeted drug/gene deliveryMEDICINAL RESEARCH REVIEWS, Issue 2 2010Hailong Zhang Abstract Targeted delivery of a drug or gene to its site of action has clear therapeutic advantages by maximizing its therapeutic efficiency and minimizing its systemic toxicity. Generally, targeted drug or gene delivery is performed by loading a macromolecular carrier with an appropriate drug or gene, and by targeting the drug/gene carrier to specific cell or tissue with the help of specific targeting ligand. The emergence of glycobiology, glycotechnology, and glycomics and their continual adaptation by pharmaceutical scientists have opened exciting avenue of medicinal applications of carbohydrates. Among them, the biocompatibility and specific receptor recognition ability confer the ability of carbohydrates as potential targeting ligands for targeted drug and gene delivery applications. This review summarizes recent progress of carbohydrate-decorated targeted drug/gene delivery applications. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 2, 270,289, 2010 [source] Multicolor in vivo targeted imaging to guide real-time surgery of HER2-positive micrometastases in a two-tumor coincident model of ovarian cancerCANCER SCIENCE, Issue 6 2009Michelle Longmire One of the primary goals of oncological molecular imaging is to accurately identify and characterize malignant tissues in vivo. Currently, molecular imaging relies on targeting a single molecule that while overexpressed in malignancy, is often also expressed at lower levels in normal tissue, resulting in reduced tumor to background ratios. One approach to increasing the specificity of molecular imaging in cancer is to use multiple probes each with distinct fluorescence to target several surface antigens simultaneously, in order to identify tissue expression profiles, rather than relying on the expression of a single target. This next step forward in molecular imaging will rely on characterization of tissue based on fluorescence and therefore will require the ability to simultaneously identify several optical probes each attached to different targeting ligands. We created a novel ,coincident' ovarian cancer mouse model by coinjecting each animal with two distinct cell lines, HER2+/red fluorescent protein (RFP), SKOV3 and HER2,/RFP+ SHIN3-RFP, in order to establish a model of disease in which animals simultaneously bore tumors with two distinct phenotypes (HER2+/RFP,, HER2,/RFP+), which could be utilized for multicolor imaging. The HER2 receptor of the SKOV3 cell line was targeted with a trastuzumab,rhodamine green conjugate to create green tumor implants, whereas the RFP plasmid of the SHIN3 cells created red tumor implants. We demonstrate that real-time in vivo multicolor imaging is feasible and that fluorescence characteristics can then serve to guide the surgical removal of disease. (Cancer Sci 2009; 100: 1099,1104) [source] Enhanced Growth Inhibition of Hepatic Multicellular Tumor Spheroids by Lactosylated Poly(ethylene glycol)-siRNA Conjugate Formulated in PEGylated PolyplexesCHEMMEDCHEM, Issue 9 2007Motoi Oishi Prof. Abstract PEGylated polyplexes (lac-PEGylated polyplexes) composed of poly(L -lysine) and lactosylated poly(ethylene glycol)-small interfering RNA conjugate, which inhibits the RecQL1 gene product, were revealed to show an appreciable growth inhibition of multicellular HuH-7 spheroids (human hepatocarcinoma cell lines) for up to 21 days (IC50=6,nM); this system used as an in,vitro three-dimensional (3D) model mimicking the in,vivo biology of tumors. The PEGylated polyplexes thus prepared had a size of approximately 110,nm with clustered lactose moieties on their periphery as targeting ligands for the asialoglycoprotein-receptor-expressing HuH-7 cells. In contrast, OligofectAMINE/siRNA (cationic lipoplex) was observed to have almost no growth-inhibitory effect against HuH-7 spheroids, even though the lipoplex showed a stronger growth-inhibitory effect than the lac-PEGylated polyplexes on conventional monolayer-cultured HuH-7 cells. The FITC-tagged conjugate in the lac-PEGylated polyplexes showed smooth penetration into the HuH-7 spheroids compared with that in the lipoplexes, as observed by confocal fluorescence-scanning microscopy. This indicates that the small size of approximately 100,nm and the reduced nonspecific interaction due to the nonionic and hydrophilic lactosylated PEG layer contributes to the smooth penetration of the PEGylated polyplexes into the spheroid interior, eventually facilitating their uptake into the cells composing the spheroids. Cellular apoptosis indicating programmed cell death was also observed in the HuH-7 spheroids treated with the PEGylated polyplexes, revealing that the observed growth inhibition was indeed induced by the RNAi of the RecQL1 siRNA. These data suggest that the smart PEGylated polyplexes can indeed penetrate into the multiple cell layers of 3D tumor masses in,vivo, exerting therapeutic effects through the RNAi. [source] | ||||||||||||||||