Cyclodextrin in Vaccines: Enhancing Efficacy and Stability

carbohydrates, ,

Great review from Gamze Varan at Hacettepe University on Cyclodextrin in Vaccines.
In the context of vaccines, cyclodextrins can effectively encapsulate antigens, ensuring their protection from degradation and improving their immunogenicity. Cyclodextrins offer stability advantages to vaccines by preventing the degradation of labile vaccine components during storage and transportation. Furthermore, cyclodextrins can serve as adjuvants, potentiating the immune response triggered by vaccines.

Future Pharmacology | Free Full-Text | Cyclodextrin in Vaccines: Enhancing Efficacy and Stability (mdpi.com)

Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs

carbohydrates, drug delivery,

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules are described, by reducing clearance and increasing systemic coverage. A PROTAC-in-cyclodextrin liposome system was developed where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.
This is a unique industrial collaboration between Genentech, Arvinas & Bristol Myers Squibb.
#cyclodextrin #liposome #drugdelivery

Pharmaceutics | Free Full-Text | Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs (mdpi.com)

High-Cholesterol Diet in Combination With Hydroxypropyl-β-Cyclodextrin Induces NASH-Like Disorders in the Liver of Rats

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We are hearing a lot about how the cholesterol complexation ability of certain cyclodextrins, especially hydroxypropyl-beta-CD can be used to treat various diseases, like Alzheimer’s, Niemann Pick type C, atherosclerosis, familial hypercholesterolemia and many more.
But can this be a double-edged sword? This fascinating research suggests that High-Cholesterol Diet in Combination With Hydroxypropylβ-Cyclodextrin Induces NASH-Like Disorders in the Liver of Rats

You can read the full article here!

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial

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Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.
Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed the critical role of systemically administered hydroxypropyl-β-cyclodextrin (HP-β-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-β-CD and biomarkers of NPC were assessed in pediatric and adult patients with NPC1.
Cyclo Therapeutics, Inc. –  Caroline Hastings, Sharon Hrynkow et al

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial – ScienceDirect

Cyclodextrin-based anti-microbial therapy

carbohydrates, drug development, ,

Cyclodextrin-based antimicrobial/antiviral therapy discovered at the University of Southern California
A rapidly deployable nanoscale biodegradable system using hydroxypropyl beta cyclodextrin-based combination product is presented as an agnostic barrier blocking pathogenic microbes that has localized on the mucocutaneous lining of the conjunctiva, mouth and nose, lung, or gastrointestinal tract. The cyclodextrin may bind the viral particles and/or disrupt viral entry mechanisms by removing cholesterol from viral particles to reduce infectivity. Cyclodextrins also may facilitate the removal of the viral cholesterol molecules, thus rendering them less viable.
Stan Louie; Gianluca Lazzi; Jean-Marie Bouteiller

You can read the patent on Espacenet!

Reversible Light-Induced Dimerization of Secondary Face Azobenzene-Functionalized β-Cyclodextrin Derivatives

drug delivery,

Fantastic cyclodextrin chemistry by Carmen Ortiz Mellet, Jose Manuel Garcia Fernandez, and Francisco Mendicuti et al.
β-cyclodextrin (βCyD) derivatives equipped with aromatic appendages at the secondary face exhibit tailorable self-assembling capabilities. Supramolecular species can thus form that, at their turn, can engage in further co-assembling with third components in a highly regulated manner; the design of nonviral gene delivery systems is an illustrative example.

See the full article here!

Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells

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Vaccination has drastically decreased mortality due to coronavirus disease 19 (covid19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alternative strategies, such as inhibition of virus entry by interference with angiotensin-I-converting enzyme 2 (ACE2) receptors could be warranted. Cyclodextrins (CDs) are cyclic oligosaccharides that are able to deplete cholesterol from membrane lipid rafts, causing ACE2 receptors to relocate to areas devoid of lipid rafts. To explore the possibility of reducing SARS-CoV-2 entry, hydroxypropyl-β-cyclodextrin (HPβCD) was tested in a HEK293T-ACE2hi cell line stably overexpressing human ACE2 and Spike-pseudotyped SARS-CoV-2 lentiviral particles. Exposure of HEK293T-ACEhi cells to concentrations of HPβCD starting from 2.5 mM to 10 mM showed a concentration-dependent reduction of approximately 50% of the membrane cholesterol content. In addition, incubation of HEK293T-ACEhi cells with HIV-S-CoV-2 pseudotyped particles in the presence of increasing concentrations of HPβCD (from 0.1 to 10 mM) displayed a concentration-dependent effect on SARS-CoV-2 entry efficiency. These data indicate that HPβCD is a candidate for use as a SARS-CoV-2 prophylactic agent.

Silvia Alboni, Valentina Secco, Bianca Papotti, Antonietta Vilella, Maria Pia Adorni, Francesca Zimetti, Laurent Schaeffer, tascedda fabio, Michele Zoli, Pascal Leblanc, Erica Villa

See the full article here: Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells

Hexapeptide decorated β-cyclodextrin delivery system for targeted therapy of bone infection

carbohydrates, drug delivery

Fascinating cyclodextrin conjugation chemistry from Southwest Jiaotong University in order to target the hydroxyapatite component of the bone. We are also highly involved in conjugating peptides and carbohydrates to create actives and drug delivery systems. Have you ever considered a peptide-CD conjugate for such an application?

See the full article here