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

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 GenentechArvinas & Bristol Myers Squibb.
#cyclodextrin #liposome #drugdelivery

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A Cyclodextrin-Based pH-Responsive MicroRNA Delivery Platform Targeting Polarization of M1 to M2 Macrophages for Sepsis Therapy

It is so great to see new ideas rising in cyclodextrin-supported gene therapy. Nucleic acid-based drugs have therapeutic potential, although their poor stability and low delivery efficiency have hindered their widespread use.
A pH-sensitive nano-drug delivery system comprising β-cyclodextrin-poly(2-(diisopropylamino)ethyl methacrylate)/distearoyl phosphoethanolamine-polyethylene glycol (β-CD-PDPA/DSPE-PEG) is synthesized and developed to target M1 macrophages and miR-223 is encapsulated into nanoparticles (NPs) for sepsis treatment. NPs/miR-223 demonstrated in vitro pH responsiveness with favorable biosafety, stability, and high delivery efficiency. In vivo studies demonstrate that NPs/miR-223 are preferentially accumulated and retained in the inflammation site, thereby reducing inflammation and improving the survival rate of mice with sepsis while exhibiting ideal biosafety. Mechanically, NPs/miR-223 regulates macrophage polarization by targeting Pknox1 and inhibiting the activation of the NF-κB signaling pathway, thereby achieving an anti-inflammatory effect. Collectively, it is demonstrated that the miRNA delivery vector described here provides a new approach for sepsis treatment and accelerates the advancement of nucleic acid drug therapy.

A Cyclodextrin‐Based pH‐Responsive MicroRNA Delivery Platform Targeting Polarization of M1 to M2 Macrophages for Sepsis Therapy – Ding – Advanced Healthcare Materials – Wiley Online Library

Aggregation Behavior of Cyclodextrin-Based [3]Rotaxanes

Today’s #cyclodextrin:
I have shared several papers and patents already on the fascinating and widespread applications of rotaxanes, from cosmetics through drug delivery to advanced materials.
In this paper Yosuke Akae and Patrick Theato report on an important practical aspect of their use, particularly on the aggregation of cyclodextrin (CD)-based [3]rotaxane, which forms a hexagonal packing type aggregation derived from hydrogen bond formation among CD units in a similar manner to polyrotaxane species. This aggregation could be controlled by solvent type on dispersion treatment, axle end structures, and modification of CD.

To the full article, please follow this link!

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

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!

Multifunctional Cyclodextrins Carriers for Pulmonary Drug Delivery: Prospects and Potential

today’s cyclodextrin:
is about multifunctional CD for Pulmonary Drug Delivery.
The paper focuses on inhaled CDs-based carriers, pulmonary applications of CDs with particular emphasis on aerosolization fate, powder dispersion behavior, pharmacokinetic outcomes, and long-term stability performance and the prospects and potential for translating inhaled CDs-based carrier systems. The bottom-line marks CD-based carriers for the growth of pulmonary medicines in the upcoming years.
Dr. Piyush Pradeep Mehta & Dr. Vividha Dhapte

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Kit for preparing a medicament, cannabinoid composition, and preparation method

today’s #cyclodextrin:
Vayamed Cannakits® hits the markets: novel formulation kits enabling a cannabis-enriched Nasal Spray, and Vaginal/Rectal Suppositories is now available. This innovation makes Vayamed the first cannabis company in Germany to expand the therapy spectrum with new dosage forms.
Depending on the final formulation, the kit contains an excipient mixture composed of vegetable oil, hydroxylated fat, and 2-hydroxypropyl-β-cyclodextrin or polyethylene glycol stearate.
Marco Ternelli – Sanity Group

See the full patent on Espacenet

Oculis announces positive top-line results from diamond Stage 1 Phase 3 trial in diabetic macular edema with OCS-01 eye drops

today’s #cyclodextrin:
Oculis, a global biopharmaceutical company purposefully driven to save sight and improve eye care, announced positive top line results from Stage 1 of its Phase 3 trial of OCS-01 (dexamethasone formulated in gamma-cyclodextrin #nanoparticles) eye drops in Diabetic Macular Edema (DME). DME is the leading cause of visual loss and legal blindness in patients with diabetes, affecting around 37 million people worldwide, with a significant number of patients left untreated due to a lack of convenient treatment options.
OCS-01, in this 3-month trial, has met both clinical efficacy endpoints (main BCVA change, proportion of patients with 3 lines gain) that are required for regulatory approval if met at 12 months treatment duration.

See the official annoucement here

The Role of Cyclodextrin in the Construction of Nanoplatforms: From Structure, Function and Application Perspectives

The Role of Cyclodextrin in the Construction of Nanoplatforms: From Structure, Function and Application Perspectives
Drug delivery systems consisting of cyclodextrins (CyDs) have kept constant attention for good compatibility, negligible toxicity, and improved pharmacokinetics of drugs. The unique hollow structure has endowed a lot of functions, such as the inclusion of guest molecules, functional modification of active hydroxyl groups, and noncovalent interactions. Besides, the polyhydroxy structure has further extended the functions of CyDs by inter/intramolecular interactions and chemical modification. Furthermore, the versatile functions of the complex contribute to physicochemical characteristics alteration of the drugs, therapeutic talent, stimulus-responsive switch, self-assemble capability, and fiber formation. This review attempts to list the recent progress of CyDs and discuss their roles in the drug delivery system. Future perspectives of the construction of CyD-based drug delivery systems are also discussed at the end of this review, which may be the possible direction for the construction of more rational and cost-effective delivery vehicles.

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Drug complexes: Perspective from Academic Research and Pharmaceutical Market

today’s cyclodextrin:
Drug complexes: Perspective from Academic Research and Pharmaceutical Market
Despite numerous research efforts, drug delivery through the oral route remains a major challenge to formulation scientists. The oral delivery of drugs poses a significant challenge because more than 40% of new chemical entities are practically insoluble in water. Low aqueous solubility is the main problem encountered during the formulation development of new actives and for generic development. A complexation approach has been widely investigated to address this issue, which subsequently improves the bioavailability of these drugs. This review discusses the various types of complexes such as metal complex (drug-metal ion), organic molecules (drug-caffeine or drug-hydrophilic polymer), inclusion complex (drug-cyclodextrin), and pharmacosomes (drug-phospholipids) that improves the aqueous solubility, dissolution, and permeability of the drug along with the numerous case studies reported in the literature. Besides improving solubility, drug-complexation provides versatile functions like improving stability, reducing the toxicity of drugs, increasing or decreasing the dissolution rate, and enhancing bioavailability and biodistribution. Apart, various methods to predict the stoichiometric ratio of reactants and the stability of the developed complex are discussed.
Siva Ram MunnangiAhmed YoussefNagarjuna NaralaPreethi LakkalaSagar NaralaSateesh Kumar Vemula, Ph.D. & Michael Repka  

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ɑ-cyclodextrin (A), β-cyclodextrin (B), γ-cyclodextrin (C), Hydroxypropyl-β-cyclodextrin (D), Cucurbit(7)uril (E), Cucurbit(8)uril (F), sulfonatocalix(4)arene (G) & sulfonatocalix(8)arene (H).