Hydroxypropyl-beta-cyclodextrin: From Drug Delivery Enhancer to Biomedical Agent

Hydroxypropyl-beta-cyclodextrin (HP-β-CD) is a chemically modified derivative of natural β-cyclodextrin (β-CD), produced by the hydroxypropylation of β-CD's hydroxyl groups at the 2-, 3-, and/or 6-positions. The structural modification makes Hydroxypropyl-beta-cyclodextrin more soluble in water than its parent compound with a solubility rate above 100 mg/mL. The molecule maintains its seven-membered α-1,4-linked D-glucopyranose ring which characterizes β-CD and sustains its conical hydrophobic cavity, but achieves enhanced hydrophilicity through hydroxypropyl substituents. The result is a highly amphiphilic molecule with a hydrophobic inner cavity and a hydrophilic outer surface, making it an ideal inclusion host for hydrophobic guest molecules. The inclusion complexation ability of Hydroxypropyl-beta-cyclodextrin is central to its functionality. The hydrophobic cavity accommodates various poorly soluble or unstable substances, while the hydrophilic outer surface enhances their solubility in water and their bioavailability. The molecule's ability to possess both hydrophobic and hydrophilic properties drives its extensive application across pharmaceuticals, biomedical research, cosmetics, food stabilization, and environmental remediation. By modulating the binding strength and drug release kinetics, formulators can extend the duration of drug action, reduce dosing frequency, and improve patient compliance. Its low toxicity, favorable safety profile, and regulatory acceptance-including FDA approval for intravenous use - further endorse its utility in advanced drug delivery systems.

Hydroxypropyl-beta-cyclodextrin Barrier Prevents Respiratory Viral Infections

The ability to enhance mucocutaneous defense is an alternative strategy to agnostically prevent pathogenic attachment, which is required for viral infection. Cyclodextrins (CDs) are sugar polymers structurally similar to native mucin glycoproteins and are compatible with nasal epithelial cells. Known to interact and sequester viral membrane cholesterol, cyclodextrins have demonstrated antiviral properties against enveloped viruses by disrupting lipid rafts and cell cholesterol depletion. This study describes the screening and characterization of the antiviral effects of various types of cyclodextrins to prevent and reduce the severity of mucocutaneous viral infection. In addition, the physiochemical characteristics must meet the features required for intranasal delivery without compromising any physiological function of the target cells. This study contributes to the knowledge of cyclodextrins as antivirals by providing a comparison of different modified beta and gamma-cyclodextrins, as well as by proving the efficacy of Hydroxypropyl-beta-cyclodextrin-based intranasal formulations in a murine SARS-CoV-2 model. The dynamic evolution of SARS-CoV-2 and other respiratory viruses has led to the emergence of more transmittable variants that are resistant to current antivirals, immunotherapies, and vaccination strategies. Here, we present evidence for the use of Hydroxypropyl-beta-cyclodextrin-based treatments as an effective intervention agnostic to all SARS-CoV-2 variants.[1]

Hydroxypropyl-beta-cyclodextrin and HPGCD were selected as candidates for antiviral testing. Methyl beta cyclodextrins (MBCDs), such as CRYSMEB, have potential detrimental hemolytic activity; because of these safety concerns, this formulation was eliminated from further considerations. These in silico, in vitro, and in vivo studies provide evidence for the application of beta-cyclodextrin-based formulations to prevent viral infections. Here, we show that not all cyclodextrins exert the same effects across SARS-CoV-2 variants. Molecular docking studies identified that HPGCD has reduced binding affinity to spike protein variants compared to HPBCD. In addition to preventing SARS-CoV-2 infection, we have identified the potential of Hydroxypropyl-beta-cyclodextrin as an agnostic barrier capable of inhibiting lentivirus, MHV, and H1N1 infections. Treatment with 5% HPBCD + 0.5% CMC (w/v) was able to reduce infection of the SARS-CoV-2 Delta variant by 94%, as quantified by qRTPCR in murine lung tissue. In summary, this report suggests the novel usage of HPBCD-based formulations for the prevention of viruses, such as SARS-CoV-2, through an intranasal approach. Additional in vivo studies affirm the safety and efficacy of HPBCD as an antiviral barrier when administered intranasally in the K18-hACE2 murine model. We propose that intranasal formulations based on HPBCD could provide additional benefits in preventing respiratory viral infections.

2-Hydroxypropyl-β-cyclodextrins and the Blood-Brain Barrier

The blood-brain barrier (BBB) is a complex biological system that selectively permits movement of substances from the blood to the CNS. Most pharmacologic agents are restricted from crossing the BBB in substantial amounts; thus the BBB represents a key challenge in developing drugs that can access the brain and CNS to treat neurological pathophysiology such as that found in NPC1. One particular type of cyclodextrin, Hydroxypropyl-beta-cyclodextrin (HPβCD), has gained attention as a potential therapeutic intervention for NPC1. In the United States and European Union, two different HPβCD products, VTS-270 and Trappsol Cyclo have received orphan drug designations for the treatment of NPC1. VTS-270 is a specific and well-characterized mixture of Hydroxypropyl-beta-cyclodextrin, with a tightly controlled molar substitution specification and a defined molecular “fingerprint” of the different chemical species present in the mixture based on Kleptose HPB (Roquette Pharma, France). Additionally, recruitment has recently been announced for investigation of Trappsol Cyclo in a phase 1 and a phase 1/2 study. Due to their relatively large size and the physicochemical properties, Hydroxypropyl-beta-cyclodextrin products are not expected to passively cross the BBB in substantial amounts and thus, questions surrounding the ability of HPβCD to cross the BBB are central to the understanding of potential efficacy in the NPC setting.[2]

There is an unmet medical need for disease-modifying therapies that address NPC1 neurological manifestations. Consequently, the BBB represents an important consideration for novel NPC1 drugs. Based upon physicochemical properties, findings in animal models, early clinical studies, and patient case reports, the evidence to date suggests that Hydroxypropyl-beta-cyclodextrin does not cross the BBB in therapeutically relevant amounts in the NPC1 setting. Administration directly to the CNS is expected to provide the greatest NPC1 neurological efficacy; this concept was supported by a phase 1/2a clinical study. Conversely, intravenous administration is not expected to have a clinically meaningful benefit on the CNS manifestations of NPC1 and has not yet been prospectively studied in NPC1 patients. Clinical trials of different Hydroxypropyl-beta-cyclodextrin agents are currently underway and the route of administration is an important point of consideration for the anticipated results of these trials with regard to safety, tolerability, and efficacy in the NPC1 population.

Hydroxypropyl-beta-cyclodextrin Attenuates the Chronic Inflammatory Response to Experimental Stroke

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. Hydroxypropyl-beta-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPβCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or Hydroxypropyl-beta-cyclodextrin 3 times per week, with treatment beginning 1 week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomic, and behavioral analyses.[3]

Chronic stroke infarct and peri-infarct regions of HPβCD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, Hydroxypropyl-beta-cyclodextrin reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPβCD also preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, Hydroxypropyl-beta-cyclodextrin improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity.

References

[1]Lu A, Ebright B, Naik A, Tan HL, Cohen NA, Bouteiller JC, Lazzi G, Louie SG, Humayun MS, Asante I. Hydroxypropyl-Beta Cyclodextrin Barrier Prevents Respiratory Viral Infections: A Preclinical Study. Int J Mol Sci. 2024 Feb 8;25(4):2061. doi: 10.3390/ijms25042061. PMID: 38396738; PMCID: PMC10888609.

[2]Calias P. 2-Hydroxypropyl-β-cyclodextrins and the Blood-Brain Barrier: Considerations for Niemann-Pick Disease Type C1. Curr Pharm Des. 2017;23(40):6231-6238. doi: 10.2174/1381612823666171019164220. PMID: 29065825; PMCID: PMC5824462.

[3]Becktel DA, Zbesko JC, Frye JB, Chung AG, Hayes M, Calderon K, Grover JW, Li A, Garcia FG, Tavera-Garcia MA, Schnellmann RG, Wu HJ, Nguyen TV, Doyle KP. Repeated Administration of 2-Hydroxypropyl-β-Cyclodextrin (HPβCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke. J Neurosci. 2022 Jan 12;42(2):325-348. doi: 10.1523/JNEUROSCI.0933-21.2021. Epub 2021 Nov 24. PMID: 34819339; PMCID: PMC8802936.