betadex and Adenocarcinoma

The development of biocompatible vector for hydrophobic drug delivery remains a longstanding issue in cancer therapy. We design and synthesis a drug delivery system based on HPG modified β-CD (β-CD-HPG) by conjugating HPG branches onto β-CD core and its structure was confirmed by NMR, FTIR, GPC and solubility. In vitro biocompatibility tests showed that HPG modification significantly improved red blood cells morphology alteration and hemolysis cause by β-CD and β-CD-HPG displayed cell safety apparently in a wide range of 0.01-1mg/mL. An anti-cancer drug, docetaxel, was effectively encapsulated into β-CD-HPG which was confirmed by DSC analysis. This copolymer could form nanoparticles with small size (<200nm) and exhibited better DTX loading capacity and controlled release kinetics without initial burst release behavior compared with β-CD. Furthermore, antitumor assay in vitro show that β-CD-HPG/DTX effectively inhibited proliferation of human breast adenocarcinoma cells. Therefore, β-CD-HPG/DTX exhibit great potential for cancer chemotherapy.

Topics: Adenocarcinoma; beta-Cyclodextrins; Breast Neoplasms; Cell Line; Delayed-Action Preparations; Docetaxel; Drug Screening Assays, Antitumor; Erythrocytes; Female; Glycerol; Hemolysis; Humans; Polymers; Taxoids

The systemic palliative chemotherapy of locally extended gastrointestinal and hepatobiliary tumors is associated with a considerable burden for the patient. The aim of this project was to develop a new drug release system to improve the local stent therapy in these patients as a proof of concept study. For this purpose, polymer filaments were modified with drug-loaded polymer microgels that allow selective release of the active substance by photochemical triggering using laser radiation. Integrated into a stent system, the better local tumor control could thus contribute to a significant increase in the quality of life of patients.. A standard mammalian cell line and two carcinoma cell lines were established. By Fluorescence activated cell sorting (FACS), the cytotoxicity of the different materials was determined in vitro before and after drug loading with the chemotherapeutic agent 5-Fluorouracil (5-FU). For this purpose, the locally applied 5-FU concentration was previously determined by Bromdesoxyuridin assay. 5-FU dimer was synthesized by photo-induced dimerization of 5-FU in the presence of benzophenone in methanol. The chemical structure of 5-FU dimer was confirmed with Hydrogen-1 nuclear magnetic resonance and Fluorine-19 nuclear magnetic resonance. 5-FU dimer is nonsoluble in water and can be easily incorporated in polymer microgels modified with hydrophobic binding domains (cyclodextrin). After laser irradiation, 5-FU dimer decomposes and 5-FU can be released from microgels. Finally, the measurements were repeated after this laser-induced drug release.. In FACS analysis, neither the microgels nor the microgel cumarin complexes showed a significant difference in comparison with the negative control with H2O and therefore no toxic effect on the cell lines. After loading with the 5-FU dimer, there was no significant cell death (contrary to the pure 5-FU monomer, which dose had been previously tested as highly toxic). After laser-induced dissociation back to monomer and the associated drug release, FACS analysis showed cytotoxicity.. It was possible to develop 5-FU dimerloaded microgels, which show no cytotoxic effect on cell lines before laser irradiation. After dissociation back to 5-FU monomer by selective photochemical triggering using laser irradiation, the active substance was released. Thus, a new drug release system has been created and tested in vitro. For further development, integration into a stent system and for in vivo follow-up evaluation more studies need to be conducted.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; beta-Cyclodextrins; Bromodeoxyuridine; Cell Line, Tumor; Dimerization; Drug Delivery Systems; Fibroblasts; Flow Cytometry; Fluorouracil; Hydrophobic and Hydrophilic Interactions; Lasers; Palliative Care; Pancreatic Neoplasms; Solubility; Stents

In this study, we evaluated the polyamidoamine starburst dendrimer (dendrimer, generation 2: G2) conjugate with 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-cyclodextrin (GUG-β-CDE (G2)) as a gene transfer carrier. The in vitro gene transfer activity of GUG-β-CDE (G2, degree of substitution (DS) of cyclodextrin (CyD) 1.8) was remarkably higher than that of dendrimer (G2) conjugate with α-CyD (α-CDE (G2, DS 1.2)) and that with β-CyD(β-CDE (G2, DS 1.3)) in A549 and RAW264.7 cells. The particle size, ζ-potential, DNase I-catalyzed degradation, and cellular association of plasmid DNA (pDNA) complex with GUG-β-CDE (G2, DS 1.8) were almost the same as those of the other CDEs. Fluorescent-labeled GUG-β-CDE (G2, DS 1.8) localized in the nucleus 6 h after transfection of its pDNA complex in A549 cells, suggesting that nuclear localization of pDNA complex with GUG-β-CDE (G2, DS 1.8), at least in part, contributes to its high gene transfer activity. GUG-β-CDE (G2, DS 1.8) provided higher gene transfer activity than α-CDE (G2, DS 1.2) and β-CDE (G2, DS 1.3) in kidney with negligible changes in blood chemistry values 12 h after intravenous injection of pDNA complexes with GUG-β-CDE (G2, DS 1.8) in mice. In conclusion, the present findings suggest that GUG-β-CDE (G2, DS 1.8) has the potential for a novel polymeric pDNA carrier in vitro and in vivo.

Topics: Adenocarcinoma; Animals; beta-Cyclodextrins; Biological Transport; Cell Line, Transformed; Cell Line, Tumor; Cell Nucleus; Chemical Phenomena; Dendrimers; Female; Gene Transfer Techniques; Humans; Kidney; Macrophages; Mice; Mice, Inbred BALB C; Nanoparticles; Particle Size; Surface Properties; Tissue Distribution

We previously reported that glucuronylglucosyl-β-cyclodextrin (GUG-β-CyD) conjugate with polyamidoamine starburst dendrimer (GUG-β-CDE conjugate) with the average degree of substitution (DS) of cyclodextrin (CyD) of 1.8 (GUG-β-CDE conjugate (DS 1.8)), showed remarkably higher gene transfer activity than α-CyD/dendrimer conjugate (α-CDE conjugate (DS 1.2)) and β-CyD/dendrimer conjugate (β-CDE conjugate (DS 1.3)) in vitro and in vivo. In this study, to clarify the enhancing mechanism for high gene transfer activity of GUG-β-CDE conjugate (DS 1.8), we investigated the physicochemical properties, cellular uptake, endosomal escape and nuclear translocation of the plasmid DNA (pDNA) complexes as well as pDNA release from the complexes. The particle size, ζ-potential and cellular uptake of GUG-β-CDE conjugate (DS 1.8)/pDNA complex were mostly comparable to those of α-CDE conjugate (DS 1.2) and β-CDE conjugate (DS 1.3). Meanwhile, GUG-β-CDE conjugate (DS 1.8)/pDNA complex was likely to have high endosomal escaping ability and nuclear localization ability in A549 and RAW264.7 cells. In addition, the pDNA condensation and decondensation abilities of GUG-β-CDE conjugate (DS 1.8) were lower and higher than that of α-CDE conjugate (DS 1.2) or β-CDE conjugate (DS 1.3), respectively. These results suggest that high gene transfer activity of GUG-β-CDE conjugate (DS 1.8) could be, at least in part, attributed to high endosomal escaping ability, nuclear localization ability and suitable pDNA release from its complex.

Topics: Active Transport, Cell Nucleus; Adenocarcinoma; Adenocarcinoma of Lung; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Buffers; Cell Line, Tumor; Cell Nucleus; Dendrimers; DNA; Endocytosis; Endosomes; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Mice; Nucleic Acid Conformation; Particle Size; Transfection

CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) is a novel synthetic retinoic acid derivative that has been shown to selectively induce apoptosis in human lung cancer cells. This compound, however, is limited in its application due to its low solubility in aqueous solutions. One technique for increasing the solubility and bioavailability of a cytotoxic agent is the formation of inclusion complexes with cyclodextrins. Herein, we report the formation and characterization of a 2:1 complex between β-cyclodextrin (β-CD) and CD437. It is shown that CD437 is a tight binder of β-CD with an overall association constant of 2.6±0.6×10(7)M(-2). In addition, we demonstrate (a) that β-CD-derived complexation enhances the aqueous solubility of CD437, and (b) that a significant increase in the toxicity of CD437 against a human lung adenocarcinoma cell line can be achieved by co-treatment with β-CD.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Cell Proliferation; Humans; Lung Neoplasms; Models, Molecular; Retinoids; Solubility

To investigate a possible increase of basolateral expression of carcinoembryonic antigen (CEA) by interfering with the apical transport machinery, we studied the effect of cholesterol depletion on CEA sorting and secretion.. Cholesterol depletion was performed in polarized Caco-2 cells using lovastatin and methyl-beta-cyclodextrin.. We show that CEA is predominantly expressed and secreted at the apical surface. Reduction of the cholesterol level of the cell by 40%-50% with lovastatin and methyl-beta-cyclodextrin led to a significant change of the apical-to-basolateral transport ratio towards the basolateral membrane.. As basolateral expression of CEA has been suggested to have anti-inflamatory properties, Cholesterol depletion of enterocytes might be a potential approach to influence the course of inflammatory bowel disease.

Topics: Adenocarcinoma; Anticholesteremic Agents; beta-Cyclodextrins; Biological Transport; Caco-2 Cells; Carcinoembryonic Antigen; Cell Line, Tumor; Cell Membrane; Cholesterol; Colonic Neoplasms; Humans; Inflammatory Bowel Diseases; Lovastatin

A stable 1:1 host-guest complex is formed between a silicon(IV) phthalocyanine conjugated axially with two permethylated beta-cyclodextrin units and a tetrasulfonated porphyrin. The complex exhibits a light-harvesting property and works as an efficient photosensitizing system, killing HT29 human colon adenocarcinoma cells with an IC50 value of 0.09 microM. [structure: see text].

Topics: Adenocarcinoma; beta-Cyclodextrins; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Screening Assays, Antitumor; Humans; Indoles; Isoindoles; Light; Molecular Structure; Organosilicon Compounds; Photochemotherapy; Porphyrins; Water

The metastasizing subline of the rat pancreatic adenocarcinoma BSp73 expresses a set of membrane molecules, the combination of which has not been detected on non-metastasizing tumor lines. Hence, it became of interest whether these molecules function independently or may associate and exert specialized functions as membrane complexes. Separation of CD44v4-v7 containing membrane complexes in mild detergent revealed an association with the alpha3 integrin, annexin I, EpCAM, and the tetraspanins D6.1A and CD9. EpCAM and the tetraspanins associate selectively with CD44 variant (CD44v), but not with the CD44 standard (CD44s) isoform. The complexes are found in glycolipid-enriched membrane (GEM) microdomains, which are dissolved by stringent detergents, but the complexes are not destroyed by methyl-beta-cyclodextrin (MbetaCD) treatment, which implies that complex formation does not depend on a lipid-rich microenvironment. However, a complex-associated impact on cell-matrix and cell-cell adhesion as well as on resistance towards apoptosis essentially depended on the location in GEMs. Thus, CD44v-specific functions may well be brought about by complex formation of CD44v with EpCAM, the tetraspanins, and the alpha3 integrin. Because CD44v4-v7-EpCAM complex-specific functions strictly depended on the GEM localization, linker or signal-transducing molecules associating with the complex are likely located in GEMs.

Topics: Adenocarcinoma; Animals; Annexin A1; Antibodies, Monoclonal; Antigens, CD; Antigens, Neoplasm; Apoptosis; beta-Cyclodextrins; Cell Adhesion; Cell Adhesion Molecules; Cell Division; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Cyclodextrins; Detergents; Epithelial Cell Adhesion Molecule; Genetic Variation; Hyaluronan Receptors; Integrins; Membrane Microdomains; Membrane Proteins; Mutagenesis, Site-Directed; Pancreatic Neoplasms; Precipitin Tests; Protein Isoforms; Rats

The anti-tumour activity of methyl-beta-cyclodextrin (MEBCD), a cyclic oligosaccharide known for its interaction with the plasma membrane, was investigated in vitro and in vivo and compared with that of doxorubicin (DOX) in the human tumour models MCF7 breast carcinoma and A2780 ovarian carcinoma. In vitro proliferation was assessed using the MTT assay. In vivo studies were carried out using xenografted Swiss nude mice injected weekly i.p. with MEBCD at 300 or 800 mg kg(-1) or DOX at 2 mg kg(-1), during 2 months. Under these conditions, MEBCD was active against MCF7 and A2780 cell lines and tumour xenografts. For each tumour model, the tumoral volume of the xenografted mice treated with MEBCD was at least twofold reduced compared with the control group. In the MCF7 model, MEBCD (800 mg kg(-1)) was more active than DOX (2 mg kg(-1)). After 56 days of treatment with MEBCD, no toxicologically meaningful differences were observed in macroscopic and microscopic parameters compared with controls. The accumulation of MEBCD in normal and tumour tissues was also assessed using a chromatographic method. Results indicated that after a single injection of MEBCD, tumour, liver and kidneys accumulated the highest concentrations of MEBCD. These results provided a basis for the potential therapeutic application of MEBCD in cancer therapy.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; beta-Cyclodextrins; Breast Neoplasms; Cell Division; Cyclodextrins; Female; Humans; Lethal Dose 50; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured