betadex and Brain-Neoplasms

Biological barriers are the main defense systems of the homeostasis of the organism and protected organs. The blood-brain barrier (BBB), formed by the endothelial cells of brain capillaries, not only provides nutrients and protection to the central nervous system but also restricts the entry of drugs, emphasizing its importance in the treatment of neurological diseases. Cyclodextrins are increasingly used in human pharmacotherapy. Due to their favorable profile to form hydrophilic inclusion complexes with poorly soluble active pharmaceutical ingredients, they are present as excipients in many marketed drugs. Application of cyclodextrins is widespread in formulations for oral, parenteral, nasal, pulmonary, and skin delivery of drugs. Experimental and clinical data suggest that cyclodextrins can be used not only as excipients for centrally acting marketed drugs like antiepileptics, but also as active pharmaceutical ingredients to treat neurological diseases. Hydroxypropyl-β-cyclodextrin received orphan drug designation for the treatment of Niemann-Pick type C disease. In addition to this rare lysosomal storage disease with neurological symptoms, experimental research revealed the potential therapeutic use of cyclodextrins and cyclodextrin nanoparticles in neurodegenerative diseases, stroke, neuroinfections and brain tumors. In this context, the biological effects of cyclodextrins, their interaction with plasma membranes and extraction of different lipids are highly relevant at the level of the BBB.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Cyclodextrins; Excipients; Humans; Mice; Nanoparticles; Neurodegenerative Diseases; Niemann-Pick Disease, Type C; Stroke

The detection of methylation level in O

Topics: beta-Cyclodextrins; Biosensing Techniques; Brain Neoplasms; DNA; DNA Methylation; Glioblastoma; Graphite; Humans; Immunoassay; Magnetite Nanoparticles; Nanocomposites; O(6)-Methylguanine-DNA Methyltransferase

Therapeutic development of histone deacetylase inhibitors (HDACi) has been hampered by a number of barriers to drug delivery, including poor solubility and inadequate tissue penetration. Nanoparticle encapsulation could be one approach to improve the delivery of HDACi to target tissues; however, effective and generalizable loading of HDACi within nanoparticle systems remains a long-term challenge. We hypothesized that the common terminally ionizable moiety on many HDACi molecules could be capitalized upon for loading in polymeric nanoparticles. Here, we describe the simple, efficient formulation of a novel library of β-cyclodextrin-poly (β-amino ester) networks (CDN) to achieve this goal. We observed that network architecture was a critical determinant of CDN encapsulation of candidate molecules, with a more hydrophobic core enabling effective self-assembly and a PEGylated surface enabling high loading (up to ∼30% w/w), effective self-assembly of the nanoparticle, and slow release of drug into aqueous media (up to 24 days) for the model HDACi panobinostat. We next constructed a library of CDNs to encapsulate various small, hydrophobic, terminally ionizable molecules (panobinostat, quisinostat, dacinostat, givinostat, bortezomib, camptothecin, nile red, and cytarabine), which yielded important insights into the structural requirements for effective drug loading and CDN self-assembly. Optimized CDN nanoparticles were taken up by GL261 cells in culture and a released panobinostat was confirmed to be bioactive. Panobinostat-loaded CDNs were next administered by convection-enhanced delivery (CED) to mice bearing intracranial GL261 tumors. These studies confirm that CDN encapsulation enables a higher deliverable dose of drug to effectively slow tumor growth. Matrix-assisted laser desorption/ionization (MALDI) analysis on tissue sections confirms higher exposure of tumor to drug, which likely accounts for the therapeutic effects. Taken in sum, these studies present a novel nanocarrier platform for encapsulation of HDACi via both ionic and hydrophobic interactions, which is an important step toward better treatment of disease via HDACi therapy.

Topics: Amines; Animals; Antineoplastic Agents; beta-Cyclodextrins; Brain Neoplasms; Delayed-Action Preparations; Drug Delivery Systems; Histone Deacetylase Inhibitors; Hydrophobic and Hydrophilic Interactions; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Panobinostat; Polyesters; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Xenograft Model Antitumor Assays

Small interfering ribonucleic acid (siRNA) has the potential to revolutionize therapeutics since it can knockdown very efficiently the target protein. It is starting to be widely used to interfere with cell infection by HIV. However, naked siRNAs are unable to get into the cell, requiring the use of carriers to protect them from degradation and transporting them across the cell membrane. There is no information about which is the most efficient endocytosis route for high siRNA transfection efficiency. One of the most promising carriers to efficiently deliver siRNA are cyclodextrin derivatives. We have used nanocomplexes composed of siRNA and a β-cyclodextrin derivative, AMC6, with a very high transfection efficiency to selectively knockdown clathrin heavy chain, caveolin 1, and p21 Activated Kinase 1 to specifically block clathrin-mediated, caveolin-mediated and macropinocytosis endocytic pathways. The main objective was to identify whether there is a preferential endocytic pathway associated with high siRNA transfection efficiency. We have found that macropinocytosis is the preferential entry pathway for the nanoparticle and its associated siRNA cargo. However, blockade of macropinocytosis does not affect AMC6-mediated transfection efficiency, suggesting that macropinocytosis blockade can be functionally compensated by an increase in clathrin- and caveolin-mediated endocytosis.

Topics: Animals; beta-Cyclodextrins; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Nanoparticles; Pinocytosis; Rats; RNA, Small Interfering; Transfection

In this paper, we examined arsthinol-cyclodextrin complexes, which display an anticancer activity. The association constants were 17,502±522 M(-1) for hydroxypropyl-β-cyclodextrin and 12,038±10,168 M(-1) for randomized methylated β-cyclodextrin. (1)H NMR experiments in solution also confirmed the formation of these complexes and demonstrated an insertion of the arsthinol (STB) with its dithiarsolane extremity into the wide rim of the hydroxypropyl-β-cyclodextrin cavity. Complexed arsthinol was more effective than arsenic trioxide (As2O3) and melarsoprol on the U87 MG cell line. Importantly, in the in vivo study, we observed significant antitumor activity against heterotopic xenografts after i.p. administration and did not see any signs of toxicity. This remains to be verified using an orthotopic model.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; beta-Cyclodextrins; Brain Neoplasms; Cell Line, Tumor; Excipients; Female; Glioma; Humans; Injections, Intraperitoneal; Magnetic Resonance Spectroscopy; Melarsoprol; Mice; Mice, Nude; Oxides; Xenograft Model Antitumor Assays

Camptothecin (CPT), a plant alkaloid, is a potent anticancer drug in cell culture studies but it is clinically inactive due to rapid hydrolysis under physiological conditions. The drug exists in two forms depending on the pH value, an active lactone form at pH below 5 and an inactive carboxylate form at basic pH and this is a reversible reaction. In this study, nanoparticulate delivery systems were developed with either amphiphilic cyclodextrins, poly(lactide-co-glycolide) or poly-ɛ-caprolactone in order to maintain the active lactone form and prevent the drug from hydrolysis. All nanoparticles were prepared with nanoprecipitation technique. Mean particle sizes were 130-280nm and surface charges were negative. The encapsulation efficiency was significantly higher for amphiphilic cyclodextrin nanoparticles when compared to polymeric nanoparticles. Nanoparticle formulations based on cyclodextrins showed a controlled release profile extended up to 12 days. 6-O-Capro-β-cyclodextrin (1.44μg/60μL CPT) and concentrated 6-O-Capro-β-cyclodextrin (2.88μg/60μL CPT) nanoparticles significantly modified the growth or lethality of the 9L gliomas, since the median survival time was 26 days for the untreated group and between 27 and 33 days for amphiphilic cyclodextrin nanoparticle groups. These results indicate that, CPT-loaded amphiphilic cyclodextrin nanoparticles may provide a promising carrier system for the effective delivery of CPT in comparison to polymeric analogues.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents, Phytogenic; beta-Cyclodextrins; Brain Neoplasms; Camptothecin; Cell Line, Tumor; Drug Carriers; Drug Compounding; Female; Glioma; Lactic Acid; Nanoparticles; Neoplasm Transplantation; Particle Size; Polyesters; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Inbred F344; Surface-Active Agents

Cannabinoids induce the expression of the cyclooxygenase-2 (COX-2) isoenzyme in H4 human neuroglioma cells via a pathway independent of cannabinoid- or vanilloid receptor activation. The underlying mechanism was recently shown to involve increased synthesis of ceramide, which in turn leads to activation of p38 and p42/44 mitogen-activated protein kinases (MAPKs). The present study investigates a possible contribution of membrane lipid rafts to cannabinoid-induced COX-2 expression. To address this issue, we tested the influence of methyl-beta-cyclodextrin (MCD), a membrane cholesterol depletor, on COX-2 expression by the endocannabinoid analogue R(+)-methanandamide (R(+)-MA). Incubation of H4 cells with MCD was associated with a loss of lipid raft integrity and a substantial inhibition of R(+)-MA-induced COX-2 expression and subsequent formation of prostaglandin E2. Moreover, MCD was shown to suppress signal transduction steps upstream to COX-2 induction by R(+)-MA. Accordingly, the cholesterol depletor suppressed R(+)-MA-induced formation of ceramide as well as phosphorylation of p38 and p42/44 MAPKs. Together, our results suggest that R(+)-MA induces COX-2 expression in human neuroglioma cells via a pathway linked to lipid raft microdomains.

Topics: Arachidonic Acids; beta-Cyclodextrins; Blotting, Western; Brain Neoplasms; Cell Line; Cell Line, Tumor; Ceramides; Cholesterol; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Glioma; Humans; Isoenzymes; MAP Kinase Signaling System; Membrane Microdomains; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction