Inclusion Complex Formation with Tetra-PEGylated Tetraphenylporphyrin and Face-to-Face Cyclodextrin Dimer through Unprecedented Molecular Threading

carbohydrates, drug development

Do cyclodextrin dimers hold the future of therapeutic CDs? Could be…

Herein, a host–guest inclusion complex formation between tetra-PEGylated tetraphenylporphyrin with a per-O-methylated cyclodextrin dimer through the molecular threading process that is physically unexpected to occur is described. Although the molecular size of the PEGylated porphyrin is much greater than that of the CD dimer, the sandwich-type porphyrin/CD dimer 1 : 1 inclusion complex was spontaneously formed in water. The ferrous porphyrin complex binds O2 reversibly in an aqueous solution, which functions as an artificial oxygen carrier in vivo. Pharmacokinetic study using rats revealed that the inclusion complex showed a long circulation in blood in contrast to the complex without PEG. The O2 adduct of the ferrous complex shows similar O2 binding affinity with natural hemoglobin and a long circulation time in blood, leading to the simple supramolecular complex that can be used as an artificial O2 carrier in vivo.
Doshisha University – Hiroaki Kitagishi and Qiyue Mao

See the full article here: Inclusion Complex Formation with Tetra-PEGylated Tetraphenylporphyrin and Face-to-Face Cyclodextrin Dimer through Unprecedented Molecular Threading

Sialic acid-targeted cyclodextrin-based nanoparticles deliver CSF-1R siRNA and reprogram tumour-associated macrophages for immunotherapy of prostate cancer

drug delivery, drug development

Another important paper on cyclodextrin-assisted gene therapy from the GENEGUT consortium leader University College Cork (Caitriona O’Driscoll) now proposing a sialic acid-targeted cyclodextrin-based nanoparticle to specifically deliver CSF-1R siRNA to M2 macrophages. This targeted cyclodextrin-based siRNA drug delivery system provides a potential strategy for prostate cancer immunotherapy.
Monique Mendonça, Jianfeng Guo et al

See the article here

Use of Artificial Intelligence in Drug Development: WACKER, CordenPharma, LMU, and HU Berlin Train Machine Learning Algorithm for the Formulation of RNA Actives

carbohydrates, drug development, drug discovery

As an active member of an international team developing ways to deliver oligonucleotides (GENEGUT) we cheer for novel approaches in this field.
Now, WACKER, Corden Pharma – A Full-Service CDMO, Ludwig-Maximilian University, and Humboldt University use AI in drug development: they train machine learning algorithms for the formulation of RNA actives.
The aim is to develop a new generation of lipid nanoparticles (LNPs), which are a key component of RNA-based pharmaceuticals. Based on these formulations, a machine learning algorithm is to be trained that automatically identifies the best constituents for new RNA formulations – as yet a particularly time-consuming and costly development stage. The three-year project will start on April 1, 2023, and is receiving funding of some €1.4 million from the German Federal Ministry for Economic Affairs and Energy.

See the full press release here

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

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

Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia

carbohydrates, drug development, ,

Positive Phase 1/2 clinical data published on uproleselan (GMI-1271), a novel E-selectin antagonist that disrupts cell survival pathways, enhance chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo.
The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies.
Brian Jonas, Jane Jane Liesveld, Dale Bixby, Paula Marlton, John Magnani, Helen Thackray, Eric Feldman, Pamela Becker et al. – GlycoMimetics

See the full clinical trials report here.

Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia