Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

carbohydrates, drug development,

There are multiple challenges in developing carbohydrate/cyclodextrin-based drugs that we also face at CarboHyde every day. One is to develop proper analytical techniques, which are especially difficult for biological samples and if the drug is not a single compound but a mixture of components (just like HP-b-CD used in Niemann-Pick C). While HP-b-CD has been promising in vitro and in vivo, a clear understanding of the mechanism(s) of action is lacking.
That being said, we particularly welcome the study disclosing method for a large-scale mass-spectrometry-based proteomic study to evaluate proteome changes upon treatment with these small molecules. Investigation of HP-b-CD treatment was performed where we observe that, although HP-b-CD reduces cholesterol storage, levels of NPC1 and NPC2 are not normalized to control levels. The following changes in the proteome suggest that HP-b-CD promotes exocytosis in this neuron-like model. Utilizing state-of-the-art mass spectrometry analysis, these data demonstrate newly reported changes with pharmacological perturbations related to NPC disease and provide insight into the mechanisms of HP-b-CD as a potential therapeutic.
Antony Cougnoux, (Karolinska Institutet), Melissa Pergande, Fidel Serna-Perez, and Stephanie Cologna (University of Illinois Chicago)

See the full article here: Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing

drug delivery,

today’s cyclodextrin:
Core–shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Antonino Puglisi and coworkers report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild-type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood–brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain.

University of Natural Resources and Life Sciences, Vienna (BOKU): Peter van Oostrum, Erik Reimhult
Università degli Studi di Catania: Noemi Bognanni, Graziella Vecchio
Ege University: Ece Bayir
University of Oxford: Dawn Shepherd, Frances Platt

See the full article here: Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing

Confocal micrographs of Npc1-deficient CHO after incubation with 0.1 mg/mL FITC-CySPION for 72 h showing co-localization, with Pearson’s coefficient of 0.37, between FITC-CySPION (green) and LysoTracker Deep Red within the lysosomal compartments (red) within the ROI preproduced on the right. The used excitation wavelengths and fluorescence maxima are indicated in the figures. The field of view is 290 × 290 µm2.

Thymoquinone: Hydroxypropyl-β-cyclodextrin Loaded Bacterial Cellulose for the Management of Wounds

carbohydrates

Yet another cool carbohydrate combination is now proposed for wound healing. Iza Radecka, Sam S., and their team at University of Wolverhampton incorporated thymoquinone within bacterial cellulose, utilizing cyclodextrin as a novel method of solubilizing hydrophobic compounds.

See the full article here: Thymoquinone: Hydroxypropyl-β-cyclodextrin Loaded Bacterial Cellulose for the Management of Wounds

Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics

Today's cyclodextrin,

today’s cyclodextrin:
is a nice piece of research from a collaboration between Università di Pisa and CarboHyde‘s CSO, Milo Malanga investigating the use of silylated-acetylated cyclodextrins as #chiral #sensors for the enantiodiscrimination of fluorinated anesthetics

Alessandra Recchimurzo, Federica Balzano, Gloria Uccello Barretta, Luca Gherardi and Federica Aiello

See the full article here: Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics

Alveron Pharma starts the first clinical trial of a new drug for the treatment of intracranial hemorrhage

drug development, ,

today’s #cyclodextrin:
this may be a historic moment. Since sugammadex, no new cyclodextrin has been dosed in humans as an active ingredient for a novel indication. Yesterday, Alveron Pharma finally announced that it starts the first clinical trial of a new drug for the treatment of intracranial hemorrhage.
OKL-1111, is an undisclosed new cyclodextrin drug for the treatment of Intracranial Haemorrhage (ICH) and other life-threatening bleeds associated with the use of anticoagulants or platelet inhibitors. The clinical trial is taking place in the UK and will investigate safety, pharmacokinetics, and pharmacodynamics in man.
ICH is a devastating condition with a 30-50% mortality rate and is also responsible for approximately 50% of disabilities associated with stroke as a whole. The use of anticoagulants or platelet inhibitors greatly increases the probability and severity of ICH, and with an aging population, this is a growing problem. One of the major reasons for poor outcomes in ICH is that patients are treated too late with reversal agents. Current mainstream therapies require the identity of the anticoagulant, consultation with an expert, dose calculations with some requiring patient weight, and reconstitution of multiple vials of powder into solution. This process can take over one hour.
Alveron’s drug OKL-1111 is positioned as a rapid, first-line therapy as it has a truly universal mode of action, not requiring anticoagulant identification. OKL-1111 is being developed as a ready-to-use solution for injection also eliminating a very time-consuming preparation step. The pre-clinical safety data indicates a very low risk of thrombotic overshoot, reducing the need for expert risk/benefit evaluation prior to use. OKL-1111 has the potential for rapid administration with greatly improved outcomes.
OKL-1111’s product profile is also potentially suitable for use in ambulances which may become feasible with the introduction of mobile diagnostic technologies. This would further reduce the time to treatment, radically improving outcomes.
The drug OKL-1111 originates from a joint research project between Okklo Life Sciences and Sanquin Blood Supply Foundation.

Congratulations to Ben Nichols, Harshad (Hash) Patel, Stephan Peters, Alex Zwiers and all involved, worked and persisted in making this happen. I admire your work and cross fingers for your success in this important therapeutic target.

See the official post here: Alveron Pharma starts the first clinical trial of new drug for treatment of intracranial hemorrhage

Science ranks high in Biden’s 2024 budget plan

Egyéb kategória

Biden’s plan allocates $25 billion, an increase of about $6.5 billion from 2023, for activities authorized by the Creating Helpful Incentives to Produce Semiconductors (CHIPS) and Science Act. That legislation aims to boost the global competitiveness of US research by allowing major increases in funding for the National Science Foundation (NSF), the Department of Energy’s (DOE) Office of Science, and the National Institute of Standards and Technology (NIST).

See the full article here: Science ranks high in Biden’s 2024 budget plan

Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability

drug delivery

today’s cyclodextrin:
is about developing antisense oligonucleotide tablet formulations using high-speed electrospinning. Hydroxypropyl-beta-cyclodextrin (HPβCD) was used as a stabilizer and an electrospinning matrix from one of the best pharma groups in Hungary (FirePharma Research Group BME – Budapest University of Technology and Economics) collaborating with Janssen Inc.

The fibrous HPβCD–antisense oligonucleotide formulations showed no sign of physical or chemical degradation over the 1-year stability study, which also shows the suitability of the HPβCD matrix for the formulation of biopharmaceuticals. The obtained results demonstrate possible solutions for the challenges of electrospinning, such as scale-up and downstream processing of the fibers.

Edit Hirsch, Márió Nacsa, Edina Szabó, Panna Vass, Julia Domjan, Attila Farkas,Zsuzsanna Eke, Tamás Vigh, Sune Klint Andersen, Geert Verreck, György Marosi and Zsombor Kristof Nagy et al

See the full article here: Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability


Pharmaceutical composition comprising a gamma-cyclodextrin-based polymer

drug discovery

today’s cyclodextrin:
it makes me particularly happy to post about the recent success of Heegon Kim and RENATUS, as I have known and admired Heegon’s work for a while and we share a vision of the importance of developing CD-based therapies. Renatus develops gamma-cyclodextrin-based polymer to prevent or treat cholesterol metabolism-related diseases to minimize cell membrane cholesterol extraction, thus exhibiting an excellent anti-inflammatory effect by causing no cytotoxicity and hemolytic activity, making intracellular cholesterol metabolism and release easy and effectively inhibiting the release of IL-1β, MCP-1, and TNF-α.

See the complete patent here: PHARMACEUTICAL COMPOSITION COMPRISING GAMMA-CYCLODEXTRIN POLYMER AND USE THEREOF