betadex and Pancreatic-Neoplasms

Pancreatic cancer is the fourth-leading cause of death from cancer in Japan, after lung, colorectal, and stomach cancers and has the lowest survival among these tumors, because of not only no symptoms, no screening tool and no biomarkers but also high rates of recurrence and metastasis. In addition, pancreatic cancer has excessive stroma which serves as a severe biological barrier for anticancer drug delivery and successful treatment. Therefore, there are many challenges for drug delivery systems for the treatment of pancreatic cancer. Recently, we developed self-assembly PEGylation retaining activity (SPRA) technology, which comprises a reversible pegylated protein complex without loss of bioactivity. SPRA technology is based on a host-guest interaction between PEGylated β-cyclodextrin and adamantane-appended protein. In this review, first pancreatic cancer is introduced, second, principle drug delivery systems for the treatment of pancreatic cancer are described, and third the concept of SPRA technology as well as examples of SPRA proteins, especially focusing on the potential of SPRA-bromelain for treatment of pancreatic cancer, are introduced.

Topics: Adamantane; Antineoplastic Agents; beta-Cyclodextrins; Body Fluids; Bromelains; Drug Delivery Systems; Humans; Macromolecular Substances; Pancreatic Neoplasms; Polyethylene Glycols; Pressure

Fibrotic stroma, a critical character of pancreatic tumor microenvironment, provides a critical barrier against the penetration and efficacy of various antitumor drugs. Therefore, new strategies are urgently needed to alleviate the fibrotic mass and increase the drug perfusion within pancreatic cancer tissue. In our current work, we developed a β-cyclodextrin (β-CD) modified matrix metalloproteinase-2 (MMP-2) responsive liposome, integrating antifibrosis and chemotherapeutic drugs for regulation of pancreatic stellate cells (PSCs), a key source of the fibrosis, and targeted delivery of cytotoxic drugs for pancreatic cancer therapy. These liposomes disassembed into two functional parts upon MMP-2 cleavage at the tumor site. One part was constituted by the β-CDs and the antifibrosis drug pirfenidone, which was kept in the stroma and inhibited the expression of collagen I and TGF-β in PSCs, down-regulating the fibrosis and decreasing the stromal barrier. The other segment, the RGD peptide-modified-liposome loading the chemotherapeutic drug gemcitabine, targeted and killed pancreatic tumor cells. This integrated nanomedicine, showing an increased drug perfusion without any overt side effects, may provide a potential strategy for improvement of the pancreatic cancer therapy.

Topics: beta-Cyclodextrins; Drug Delivery Systems; Drug Liberation; Fibrosis; Humans; Liposomes; Matrix Metalloproteinase 2; Nanomedicine; Pancreatic Neoplasms; Pancreatic Stellate Cells; Stromal Cells; Tumor Microenvironment

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

This study characterized the therapeutic efficacy of a systemically administered formulation of 3-bromopyruvate (3-BrPA), microencapsulated in a complex with β-cyclodextrin (β-CD), using an orthotopic xenograft mouse model of pancreatic ductal adenocarcinoma (PDAC).. The presence of the β-CD-3-BrPA complex was confirmed using nuclear magnetic resonance spectroscopy. Monolayer as well as three-dimensional organotypic cell culture was used to determine the half-maximal inhibitory concentrations (IC50) of β-CD-3-BrPA, free 3-BrPA, β-CD (control), and gemcitabine in MiaPaCa-2 and Suit-2 cell lines, both in normoxia and hypoxia. Phase-contrast microscopy, bioluminescence imaging (BLI), as well as zymography and Matrigel assays were used to characterize the effects of the drug in vitro. An orthotopic lucMiaPaCa-2 xenograft tumor model was used to investigate the in vivo efficacy.. β-CD-3-BrPA and free 3-BrPA demonstrated an almost identical IC50 profile in both PDAC cell lines with higher sensitivity in hypoxia. Using the Matrigel invasion assay as well as zymography, 3-BrPA showed anti-invasive effects in sublethal drug concentrations. In vivo, animals treated with β-CD-3-BrPA demonstrated minimal or no tumor progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the β-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for β-CD-3-BrPA.. The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of β-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered.

Topics: Animals; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Cell Movement; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Compounding; Humans; Male; Mice; Pancreatic Neoplasms; Pyruvates; Spheroids, Cellular; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Several formulations have been proposed to improve the systemic delivery of novel cancer therapeutic compounds, including cyclodextrin derivatives. We aimed to synthesize and characterize of CDF-β-cyclodextrin inclusion complex (1:2) (CDFCD).. The compound was characterized by Fourier transform infrared, differential scanning calorimetry, powder X-ray diffraction studies, H1 & C13 NMR studies and scanning electron microscopic analysis. Its activity was tested against multiple cancer cell lines, and in vivo bioavailability was checked.. CDF-β-cyclodextrin was found to lower IC(50) value by half when tested against multiple cancer cell lines. It preferentially accumulated in the pancreas, where levels of CDF-β-cyclodextrin in mice were 10 times higher than in serum, following intravenous administration of an aqueous CDF-β-cyclodextrin preparation.. Novel curcumin analog CDF preferentially accumulates in the pancreas, leading to its potent anticancer activity against pancreatic cancer cells. Synthesis of such CDF-β-cyclodextrin self-assembly is an effective strategy to enhance its bioavailability and tissue distribution, warranting further evaluation for CDF delivery in clinical settings for treatment of human malignancies.

Topics: Animals; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Drug Carriers; Female; Halogenation; Humans; Mice; Models, Molecular; Pancreas; Pancreatic Neoplasms; Solubility

In the current study we investigated the role of caveolin-1 (cav-1) in pancreatic adenocarcinoma (PC) cell migration and invasion; initial steps in metastasis. Cav-1 is the major structural protein in caveolae; small Omega-shaped invaginations within the plasma membrane. Caveolae are involved in signal transduction, wherein cav-1 acts as a scaffolding protein to organize multiple molecular complexes regulating a variety of cellular events. Recent evidence suggests a role for cav-1 in promoting cancer cell migration, invasion and metastasis; however, the molecular mechanisms have not been described. The small monomeric GTPases are among several molecules which associate with cav-1. Classically, the Rho GTPases control actin cytoskeletal reorganization during cell migration and invasion. RhoC GTPase is overexpressed in aggressive cancers that metastasize and is the predominant GTPase in PC. Like several GTPases, RhoC contains a putative cav-1 binding motif.. Analysis of 10 PC cell lines revealed high levels of cav-1 expression in lines derived from primary tumors and low expression in those derived from metastases. Comparison of the BxPC-3 (derived from a primary tumor) and HPAF-II (derived from a metastasis) demonstrates a reciprocal relationship between cav-1 expression and p42/p44 Erk activation with PC cell migration, invasion, RhoC GTPase and p38 MAPK activation. Furthermore, inhibition of RhoC or p38 activity in HPAF-II cells leads to partial restoration of cav-1 expression.. Cav-1 expression inhibits RhoC GTPase activation and subsequent activation of the p38 MAPK pathway in primary PC cells thus restricting migration and invasion. In contrast, loss of cav-1 expression leads to RhoC-mediated migration and invasion in metastatic PC cells.

Topics: beta-Cyclodextrins; Caveolin 1; Cell Line, Tumor; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Neoplasm Invasiveness; Pancreatic Neoplasms; Protein Binding; Protein Transport; rho GTP-Binding Proteins; rhoC GTP-Binding Protein

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

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Benzo(a)pyrene; beta-Cyclodextrins; Bile Acids and Salts; Carcinogens, Environmental; Cyclodextrins; Drug Synergism; Humans; Lipids; Pancreatic Neoplasms; Solubility