Microneedle/CD-MOF-mediated transdural controlled release of methylprednisolone sodium succinate after spinal cord injury.

A new method of transdural delivering drugs to the spinal cord has been developed, involving the use of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). This epidural microneedle array, dubbed MNs@CD-MOF@MPSS, can be utilized to deliver methylprednisolone sodium succinate (MPSS) to the site of spinal cord injury (SCI) in a controlled manner. MNs allows to generate micropores in the dura for direct drug delivery to the spinal cord, overcoming tissue barriers and targeting damaged regions. Additionally, the CD-MOF provides a secondary extended release after separating from the MNs. In in vitro study, inward MNs increased cellular absorption of MPSS and then reduced LPS-induced M1 polarization of microglia. And animal studies have shown that this method of drug delivery results in improved BMS scores and a reduction in M1 phenotype microphage and glial scar formation. Furthermore, the downregulation of the NLRP3-positive inflammasome and related pro-inflammatory cytokines was observed. In conclusion, this new drug platform has potential for clinical application in spinal cord diseases and is a valuable composite for minimally transdural controlled drug delivery. STATEMENT OF SIGNIFICANCE: This research presents a new epidural microneedle patch made up of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). The epidural microneedle patch boasts high drug loading capacity, the ability to penetrate the dura, and controlled release. When loaded with methylprednisolone sodium succinate (MPSS), it effectively reduces inflammation and improves neurological function after spinal cord injury. Therefore, it is a novel and promising drug platform for the treatment of spinal cord diseases in a clinical setting.

ß-Cyclodextrins as affordable antivirals to treat coronavirus infection.

The SARS-CoV-2 pandemic made evident that there are only a few drugs against coronavirus. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety profile. Starting from a list of 116 drug candidates, we used molecular modelling tools to rank the 44 most promising inhibitors. Next, we tested their efficacy as antivirals against α and ß coronaviruses, such as the HCoV-229E and SARS-CoV-2 variants. Four drugs, OSW-1, U18666A, hydroxypropyl-ß-cyclodextrin (HßCD) and phytol, showed in vitro antiviral activity against HCoV-229E and SARS-CoV-2. The mechanism of action of these compounds was studied by transmission electron microscopy and by fusion assays measuring SARS-CoV-2 pseudoviral entry into target cells. Entry was inhibited by HßCD and U18666A, yet only HßCD inhibited SARS-CoV-2 replication in the pulmonary Calu-3 cells. Compared to the other cyclodextrins, ß-cyclodextrins were the most potent inhibitors, which interfered with viral fusion via cholesterol depletion. ß-cyclodextrins also prevented infection in a human nasal epithelium model ex vivo and had a prophylactic effect in the nasal epithelium of hamsters in vivo. All accumulated data point to ß-cyclodextrins as promising broad-spectrum antivirals against different SARS-CoV-2 variants and distant alphacoronaviruses. Given the wide use of ß-cyclodextrins for drug encapsulation and their high safety profile in humans, our results support their clinical testing as prophylactic antivirals.

Mannose-methyl-ß-cyclodextrin suppresses tumor growth by targeting both colon cancer cells and tumor-associated macrophages.

Methylated ß-cyclodextrin (MßCD) can extract cholesterol from lipid rafts and induce apoptosis in cancer cells by inhibiting activation of the PI3K-Akt-Bad pathway. In this study, we modified MßCD with mannose (Man-MßCD) and assessed its in vitro and in vivo potential for targeting colon cancer cells expressing the mannose receptor (MR) and tumor-associated macrophages (TAM). Man-MßCD showed a significantly greater level of cellular association with colon-26 cells and M2 macrophages, and much more prominent anticancer activity than that of MßCD against MR-positive colon-26 cells. These results revealed that autophagy was the main mechanism of cell death associated with Man-MßCD. Furthermore, compared with MßCD, Man-MßCD significantly reduced tumor development following intravenous delivery to tumor-bearing mice, with no apparent side effects. Thus, Man-MßCD has the potential to be a novel anticancer drug.

Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and ß-cyclodextrin nanoparticles.

Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of ß-cyclodextrin (ß-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of ß-CD to reduce cholesterol in fibroblasts from NPC1 patients. ß-CD was used in its free and nanoparticulate form. We also evaluated the ß-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing ß-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining ß-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free ß-CD. The results obtained are promising regarding the combined use of ß-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease.

Implementation of a Hospital-based Brexanolone Program.

Postpartum depression (PPD) is a serious complication of childbearing affecting ∼1 in 7 mothers. Left unrecognized and untreated, it is associated with negative outcomes for mothers and their infants. Building upon research suggesting that, for some women, hormonal fluctuations after childbirth contribute to the onset of depression, clinical trials have found promise in a novel treatment approach, brexanolone infusion. In 2019, the Food and Drug Administration (FDA) approved brexanolone as the first medication with an indication specifically for PPD. Delivering brexanolone treatment to patients in need requires overcoming some logistical and clinical challenges that are unique to this approach. This brief report describes the process by which a university-affiliated obstetric-gynecologic hospital in the northeast United States successfully implemented a program to administer this novel treatment to women with PPD.

Cyclodextrin-mediated conjugation of macrophage and liposomes for treatment of atherosclerosis.

Current pharmacological treatments of atherosclerosis often target either cholesterol control or inflammation management, to inhibit atherosclerotic progression, but cannot lead to direct plaque lysis and atherosclerotic regression, partly due to the poor accumulation of medicine in the atherosclerotic plaques. Due to enhanced macrophage recruitment during atheromatous plaque progression, a macrophage-liposome conjugate was facilely constructed for targeted anti-atherosclerosis therapy via synergistic plaque lysis and inflammation alleviation. Endogenous macrophage is utilized as drug-transporting cell, upon membrane-modification with a ß-cyclodextrin (ß-CD) derivative to form ß-CD decorated macrophage (CD-MP). Adamantane (ADA) modified quercetin (QT)-loaded liposome (QT-NP), can be conjugated to CD-MP via host-guest interactions between ß-CD and ADA to form macrophage-liposome conjugate (MP-QT-NP). Thus, macrophage carries liposome "hand-in-hand" to significantly increase the accumulation of anchored QT-NP in the aorta plaque in response to the plaque inflammation. In addition to anti-inflammation effects of QT, MP-QT-NP efficiently regresses atherosclerotic plaques from both murine aorta and human carotid arteries via CD-MP mediated cholesterol efflux, due to the binding of cholesterol by excess membrane ß-CD. Transcriptome analysis of atherosclerotic murine aorta and human carotid tissues reveal that MP-QT-NP may activate NRF2 pathway to inhibit plaque inflammation, and simultaneously upregulate liver X receptor to promote cholesterol efflux.

A Hybrid Supramolecular Polymeric Nanomedicine for Cascade-Amplified Synergetic Cancer Therapy.

Supramolecular nanomedicines have shown great merits in cancer therapy, but their clinical translation is hampered by monotonous therapeutic modality and unsatisfactory antitumor performance. Herein, a hybrid supramolecular polymeric nanomedicine (SNPs) is developed based on ß-cyclodextrin/camptothecin (CPT) host-guest molecular recognition and iron-carboxylate coordination. Iron ions stabilizing SNPs catalyze the conversion of intracellular hydrogen peroxide into highly toxic hydroxyl radical through a Fenton reaction, which further cleaves the thioketal linker of the supramolecular monomer to release potent CPT, thus amplifying the therapeutic efficacy by combining chemodynamic therapy and chemotherapy. The combination therapy stimulates antitumor immunity and promotes intratumoral infiltration of cytotoxic T lymphocytes by triggering immunogenic cell death. In synergy with PD-L1 checkpoint blockade, SNPs enables enhanced immune therapy and a long-term tumor remission.

PtBi-ß-CD-Ce6 Nanozyme for Combined Trimodal Imaging-Guided Photodynamic Therapy and NIR-II Responsive Photothermal Therapy.

Combined photothermal/photodynamic therapy is a promising strategy to achieve an enhanced anticancer effect. However, hypoxia is one of the representative characteristics of the microenvironment of solid tumors, which not only attenuates the therapeutic effects but also promotes tumor invasion and metastasis. Herein, a PtBi-ß-CD-Ce6 nanoplatform for the generation of sustained O2 was constructed for more effective tumor therapy. In detail, the catalase (CAT)-like nanozyme, PtBi, which could decompose H2O2 to produce O2, was modified with ß-cyclodextrin (ß-CD). O2 would be converted into 1O2 by PtBi-ß-CD-Ce6 for enhanced photodynamic therapy (PDT) under 650 nm laser irradiation. In addition, by reason of excellent absorption in the near-infrared-II (NIR-II) region, PtBi-ß-CD-Ce6 was used for photoacoustic imaging (PA) and photothermal imaging (PT)-guided photothermal therapy (PTT) in the NIR-II biowindow. Furthermore, PtBi-ß-CD-Ce6 could be elected to serve as a contrast agent for X-ray computed tomography (CT) imaging due to the apparent X-ray attenuation capability of the Pt and Bi elements themselves. Therefore, by integrating the advantages of overcoming the hypoxia function and photothermal effect into a single nanoplatform, PtBi-ß-CD-Ce6 showed an immense possibility in multimodal imaging-guided combined PDT/PTT.

ß-Cyclodextrin-containing polymer treatment of cutaneous lupus and influenza improves outcomes.

Nucleic acid (NA)-containing damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) are implicated in numerous pathological conditions from infectious diseases to autoimmune disorders. Nucleic acid-binding polymers, including polyamidoamine (PAMAM) dendrimers, have demonstrated anti-inflammatory properties when administered to neutralize DAMPs/PAMPs. The PAMAM G3 variant has been shown to have beneficial effects in a cutaneous lupus erythematosus (CLE) murine model and improve survival of mice challenged with influenza. Unfortunately, the narrow therapeutic window of cationic PAMAM dendrimers makes their clinical development challenging. An alternative nucleic acid-binding polymer that has been evaluated in humans is a linear ß-cyclodextrin-containing polymer (CDP). CDP's characteristics prompted us to evaluate its anti-inflammatory potential in CLE autoimmune and influenza infectious disease mouse models. We report that CDP effectively inhibits NA-containing DAMP-mediated activation of Toll-like receptors (TLRs) in cell culture, improves healing in lupus mice, and does not immunocompromise treated animals upon influenza infection but improves survival even when administered 3 days after infection. Finally, as anticipated, we observe limited toxicity in animals treated with CDP compared with PAMAM G3. Thus, CDP is a new anti-inflammatory agent that may be readily translated to the clinic to combat diseases associated with pathological NA-containing DAMPs/PAMPs.

Treatment of canine cutaneous leishmaniasis by Leishmania (Viannia) braziliensis in dogs with furazolidone and ß-cyclodextrin: case report.

Euthanasia of animals is not accepted as a control for cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis and drugs used in humans for the treatment of leishmaniasis are not allowed for animals in Brazil. Miltefosine was authorized for dogs infected by Leishmania infantum with variable results for L. braziliensis. Thus, nine dogs infected with Leishmania (V.) braziliensis were treated by a combination of furazolidone and ß-cyclodextrin. The nine dogs were mongrels, weighing between 4-17 kg and 3-10 years old. These dogs had ulcerous lesions in different regions such as scrotal tissue, auricular pavilion and nostrils. Serological, molecular and protozoal culture techniques were used for laboratory diagnosis. The treatment used furazolidone + ß-cyclodextrin complex (1: 2) at a concentration of 60 mg/mL given orally at a dose of 15 mg/kg every 12 hours. The re-epithelialization of lesions occurred between 35 and 41 days of treatment. During fourteen months the animals were monitored and there was no reactivation of lesions or growth of the protozoan in a culture medium of the biopsies. This study demonstrated that treatment with FZD and CD is effective in reducing the cutaneous lesions caused by L. braziliensis in dogs.

Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy.

In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and ß-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity.

Erlotinib complexation with randomly methylated ß-cyclodextrin improves drug solubility, intestinal permeability, and therapeutic efficacy in non-small cell lung cancer.

The purpose of this study was to investigate the impact of anticancer drug erlotinib-randomly methylated-ß-cyclodextrin complex (ERL-RAMEB CD) on drug solubility and dissolution rate. Phase solubility study showed erlotinib displayed maximum solubility in RAMEB CD solution and the stability constant (Kc) was calculated to be 370 ± 16 M-1. The optimal formulation was obtained with ERL-RAMEB CD in a 1:1 molar ratio using the co-lyophilization technique. Differential scanning calorimetry (DSC) and Scanning electron microscopy (SEM) verified the inclusion of complex formation. In vitro dissolution study confirmed ERL-RAMEB CD as a favorable approach to increase drug dissolution with a 1.5-fold increase than free ERL at 1 h. An improved dissolution with ∼88.4% drug release at 1 h was observed, in comparison with Erlotinib with ∼58.7% release in 45 min. The in vitro cytotoxicity results indicated that the ERL-RAMEB CD inclusion complex reduced cell viability than free erlotinib. Caco-2 cell uptake that is indicative of drug intestinal permeability resulted in a 5-fold higher uptake of ERL-RAMEB CD inclusion complex than the ERL solution. Hence, ERL-RAMEB CD complexation displays a strong potential to increase dissolution and permeability of erlotinib leading eventually to enhanced oral bioavailability.

Use of an antiviral mouthwash as a barrier measure in the SARS-CoV-2 transmission in adults with asymptomatic to mild COVID-19: a multicentre, randomized, double-blind controlled trial.

OBJECTIVES: To determine if commercially available mouthwash with ß-cyclodextrin and citrox (bioflavonoids) (CDCM) could decrease the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) salivary viral load. METHODS: In this randomized controlled trial, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR-positive patients aged 18-85 years with asymptomatic to mild coronavirus disease 2019 (COVID-19) symptoms for <8 days were recruited. A total of 176 eligible patients were randomly assigned (1:1) to CDCM or placebo. Three rinses daily were performed for 7 days. Saliva sampling was performed on day 1 at 09.00 (T1), 13.00 (T2) and 18.00 (T3). On the following 6 days, one sample was taken at 15.00. Quantitative RT-PCR was used to detect SARS-CoV-2. RESULTS: The intention-to-treat analysis demonstrated that, over the course of 1 day, CDCM was significantly more effective than placebo 4 hours after the first dose (p 0.036), with a median percentage (log10 copies/mL) decrease T1-T2 of -12.58% (IQR -29.55% to -0.16%). The second dose maintained the low median value for the CDCM (3.08 log10 copies/mL; IQR 0-4.19), compared with placebo (3.31 log10 copies/mL; IQR 1.18-4.75). At day 7, there was still a greater median percentage (log10 copies/mL) decrease in salivary viral load over time in the CDCM group (-58.62%; IQR -100% to -34.36%) compared with the placebo group (-50.62%; IQR -100% to -27.66%). These results were confirmed by the per-protocol analysis. CONCLUSIONS: This trial supports the relevance of using CDCM on day 1 (4 hours after the initial dose) to reduce the SARS-CoV-2 viral load in saliva. For long-term effect (7 days), CDMC appears to provide a modest benefit compared with placebo in reducing viral load in saliva.

Supramolecular Polymerization-Induced Nanoassemblies for Self-Augmented Cascade Chemotherapy and Chemodynamic Therapy of Tumor.

The clinical application of chemodynamic therapy is impeded by the insufficient intracellular H2 O2 level in tumor tissues. Herein, we developed a supramolecular nanoparticle via a simple one-step supramolecular polymerization-induced self-assembly process using platinum (IV) complex-modified ß-cyclodextrin-ferrocene conjugates as supramolecular monomers. The supramolecular nanoparticles could dissociate rapidly upon exposure to endogenous H2 O2 in the tumor and release hydroxyl radicals as well as platinum (IV) prodrugs in situ, which is reduced into cisplatin to significantly promote the generation of H2 O2 in the tumor tissue. Thus, the supramolecular nanomedicine overcomes the limitation of conventional chemodynamic therapy via the self-augmented cascade radical generation and drug release. In addition, dissociated supramolecular nanoparticles could be readily excreted from the body via renal clearance to effectively avoid systemic toxicity and ensure long term biocompatibility of the nanomedicine. This work may provide new insights on the design and development of novel supramolecular nanoassemblies for cascade chemo/chemodynamic therapy.

Novel pH-Triggered Doxorubicin-Releasing Nanoparticles Self-Assembled by Functionalized ß-Cyclodextrin and Amphiphilic Phthalocyanine for Anticancer Therapy.

Cyclodextrins (CDs), as pharmaceutical excipients with excellent biocompatibility, non-immunogenicity, and low toxicity in vivo, are widely used to carry drugs by forming inclusion complexes for improving the solubility and stability of drugs. However, the limited space of CDs' lipophilic central cavity affects the loading of many drugs, especially with larger molecules. In this study, ß-CDs were modified by acetonization to improve the affinity for the chemotherapy drug doxorubicin (DOX), and doxorubicin-adsorbing acetalated ß-CDs (Ac-CD:DOX) self-assembled to nanoparticles, followed by coating with the amphiphilic zinc phthalocyanine photosensitizer ZnPc-(PEG)5 for antitumor therapy. The final product ZnPc-(PEG)5:Ac-CD:DOX was demonstrated to have excellent stability and pH-sensitive drug release characteristics. The cell viability and apoptosis assay showed synergistic cytotoxic effects of chemotherapy and phototherapy. The mechanism of cytotoxicity was analyzed in terms of intracellular reactive oxygen species, mitochondrial membrane potential, and subcellular localization. More importantly, in vivo experiments indicated that ZnPc-(PEG)5:Ac-CD:DOX possessed significant tumor targeting, prominent antitumor activity, and less side effects. Our strategy expands the application of CDs as drug carriers and provides new insights into the development of CD chemistry.

New drugs 2020, part 3.

This article reviews eight drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.

Postpartum Depression: Identification and Treatment in the Clinic Setting.

Perinatal care, including the management of mental health issues, often falls under the auspices of primary care providers. Postpartum depression (PPD) is a common problem that affects up to 15% of women. Most women at risk can be identified before delivery based on psychiatric history, symptoms during pregnancy, and recent psychosocial stressors. Fortunately, there have been a variety of treatment studies using antidepressants, nonpharmacologic interactions, and most recently, allopregnanolone (Brexanolone) infusion that have shown benefits. The most commonly used screening scale, Edinburgh Postnatal Depression Scale, a 10-item self-rated scale, has been translated into a variety of languages.