Adenosine Encapsulation and Characterization through Layer-by-Layer Assembly of Hydroxypropyl-ß-Cyclodextrin and Whey Protein Isolate as Wall Materials.

Adenosine, as a water-soluble active substance, has various pharmacological effects. This study proposes a layer-by-layer assembly method of composite wall materials, using hydroxypropyl-ß-cyclodextrin as the inner wall and whey protein isolate as the outer wall, to encapsulate adenosine within the core material, aiming to enhance adenosine microcapsules' stability through intermolecular interactions. By combining isothermal titration calorimetry with molecular modeling analysis, it was determined that the core material and the inner wall and the inner wall and the outer wall interact through intermolecular forces. Adenosine and hydroxypropyl-ß-cyclodextrin form an optimal 1:1 complex through hydrophobic interactions, while hydroxypropyl-ß-cyclodextrin and whey protein isolate interact through hydrogen bonds. The embedding rate of AD/Hp-ß-CD/WPI microcapsules was 36.80%, and the 24 h retention rate under the release behavior test was 76.09%. The method of preparing adenosine microcapsules using composite wall materials is environmentally friendly and shows broad application prospects in storage and delivery systems with sustained release properties.

Regulating Tumor-Associated Macrophage Polarization by Cyclodextrin-Modified PLGA Nanoparticles Loaded with R848 for Treating Colon Cancer.

Purpose: This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-ß-CD). Methods: R848-loaded PLGA nanoparticles modified with 2-HP-ß-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo. Results: The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-ß-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival. Conclusion: The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.

The protective effects of naringenin, a citrus flavonoid, non-complexed or complexed with hydroxypropyl-ß-cyclodextrin against multiorgan damage caused by neonatal endotoxemia.

BACKGROUND: Endotoxemia is a severe and dangerous clinical syndrome that results in elevated morbidity, especially in intensive care units. Neonates are particularly susceptible to endotoxemia due to their immature immune systems. There are few effective treatments for neonatal endotoxemia. One group of compounds with potential in the treatment of neonatal inflammatory diseases such as endotoxemia is the flavonoids, mainly due to their antioxidant and anti-inflammatory properties. Among these, naringenin (NGN) is a citrus flavonoid which has already been reported to have anti-inflammatory, antioxidant, anti-nociceptive and anti-cancer effects. Unfortunately, its clinical application is limited by its low solubility and bioavailability. However, cyclodextrins (CDs) have been widely used to improve the solubility of nonpolar drugs and enhance the bioavailability of these natural products. OBJECTIVE: We, therefore, aimed to investigate the effects of NGN non-complexed and complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on neonatal endotoxemia injuries in a rodent model and describe the probable molecular mechanisms involved in NGN activities. METHOD: We used exposure to a bacterial lipopolysaccharide (LPS) to induce neonatal endotoxemia in the mice. RESULTS: It was found that NGN (100 mg/kg i.p.) exposure during the neonatal period reduced leukocyte migration and decreased pro-inflammatory cytokine (TNF-α, IL-1ß and IL-6) levels in the lungs, heart, kidneys or cerebral cortex. In addition, NGN upregulated IL-10 production in the lungs and kidneys of neonate mice. The administration of NGN also enhanced antioxidant enzyme catalase and SOD activity, reduced lipid peroxidation and protein carbonylation and increased the reduced sulfhydryl groups in an organ-dependent manner, attenuating the oxidative damage caused by LPS exposure. NGN decreased ERK1/2, p38MAPK and COX-2 activation in the lungs of neonate mice. Moreover, NGN complexed with HPßCD was able to increase the animal survival rate. CONCLUSION: NGN attenuated inflammatory and oxidative damage in the lungs, heart and kidneys caused by neonatal endotoxemia through the MAPK signaling pathways regulation. Our results show that NGN has beneficial effects against neonatal endotoxemia and could be useful in the treatment of neonatal inflammatory injuries.

Preparation and characterization of starch/PBAT film containing hydroxypropyl-ß-cyclodextrin/ethyl lauroyl arginate/cinnamon essential oil microcapsules and its application in the preservation of strawberry.

Cinnamon essential oil (CEO) was emulsified by hydroxypropyl-ß-cyclodextrin/ ethyl lauroyl arginate (HPCD/LAE) complex to make nanoemulsions, which were then incorporated into maltodextrin (MD) to prepare HPCD/LAE/CEO/MD microcapsules by spray drying. The starch/polybutylene adipate terephthalate (starch/PBAT, SP) based extrusion-blowing films containing above microcapsules were developed and used as packaging materials for strawberry preservation. The morphology, encapsulation efficiency, thermal and antibacterial properties of microcapsules with different formulations were investigated. The effects of microcapsules on the physicochemical and antimicrobial properties of SP films were evaluated. When the formula was 4 % HPCD/LAE-3% CEO-10% MD (HL-3C-MD), the microcapsule had the smallest particle size (3.3 µm), the highest encapsulation efficiency (84.51 %) of CEO and the best antibacterial effect. The mechanical and antimicrobial properties of the SP film were enhanced while the water vapor transmittance and oxygen permeability decreased with the incorporation of HL-3C-MD microcapsules. The films effectively reduced the weight loss rate (49.03 %), decay rate (40.59 %) and the total number of colonies (2.474 log CFU/g) and molds (2.936 log CFU/g), thus extending the shelf life of strawberries. This study revealed that the developed SP films containing HPCD/LAE/CEO microcapsules had potential applications in degradable bioactive food packaging materials.

Folate-Appended Hydroxypropyl-ß-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-ß-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-ß-CyD (FA-HP-ß-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-ß-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-ß-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-ß-CyD against AML cells was stronger than that of HP-ß-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-ß-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-ß-CyD suppressed the proliferation of AML cells in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double-deficient mice with AML. These results suggest that FA-HP-ß-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy.

Hydroxypropyl-ß-cyclodextrin inhibits the development of triple negative breast cancer by enhancing antitumor immunity.

Triple negative breast cancer (TNBC) is regarded as one of the most aggressive forms of breast cancer. Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) has been used as a therapeutic agent for Niemann-Pick disease Type C (NPC). However, the exact actions and mechanisms of HP-ß-CD on TNBC are not fully understood. To examine the influence of HP-ß-CD on the proliferation and migration of TNBC cell lines, particularly 4T1 and MDA-MB-231 cells, a range of assays, including MTT, scratch, cell cycle, and clonal formation assays, were performed. Furthermore, the effectiveness of HP-ß-CD in the treatment of TNBC was assessed in vivo using a 4T1 tumor-bearing BALB/c mouse model. We demonstrated the anti-proliferation and anti-migration effect of HP-ß-CD on TNBC both in vitro and in vivo. High cholesterol diet can attenuate HP-ß-CD-inhibited TNBC growth. Mechanistically, HP-ß-CD reduced tumor cholesterol levels by increasing ABCA1 and ABCG1-mediated cholesterol reverse transport. HP-ß-CD promoted the infiltration of T cells into the tumor microenvironment (TME) and improved exhaustion of CD8+ T cells via reducing immunological checkpoint molecules expression. Additionally, HP-ß-CD inhibited the recruitment of tumor associated macrophages to the TME via reducing CCL2-p38MAPK-NF-κB axis. HP-ß-CD also inhibited the epithelial mesenchymal transition (EMT) of TNBC cells mediated by the TGF-ß signaling pathway. In summary, our study suggests that HP-ß-CD effectively inhibited the proliferation and metastasis of TNBC, highlighting HP-ß-CD may hold promise as a potential antitumor drug.

Effect of Cyclodextrin Complex Formation on Solubility Changes of Each Drug Due to Intermolecular Interactions between Acidic NSAIDs and Basic H2 Blockers.

One of the solubilization of poorly water-soluble drugs is the use of cyclodextrin (CD)-based inclusion complexes. On the other hand, few studies have investigated how CD functions on the solubility of drugs in the presence of multiple drugs that interact with each other. In this study, we used indomethacin (IND) and diclofenac (DIC) as acidic drugs, famotidine (FAM) and cimetidine (CIM) as basic drugs, and imidazole (IMZ), histidine (HIS), and arginine (ARG) as compounds structurally similar to basic drugs. We attempted to clarify the effect of ß-CD on the solubility change of each drug in the presence of multiple drugs. IND and DIC formed a eutectic mixture in the presence of CIM, IMZ, and ARG, which greatly increased the intrinsic solubility of the drugs as well as their affinity for ß-CD. Furthermore, the addition of high concentrations of ß-CD to the DIC-FAM combination, which causes a decrease in solubility due to the interaction, improved the solubility of FAM, which was decreased in the presence of DIC. These results indicate that ß-CD synergistically improves the solubility of drugs in drug-drug combinations, where the solubility is improved, whereas it effectively improves the dissolution rate of drugs in situations where the solubility is reduced by drug-drug interactions, such as FAM-DIC. This indicates that ß-CD can be used to improve the physicochemical properties of drugs, even when they are administered in combination with drugs that interact with each other.

Herbicide and Cytogenotoxic Activity of Inclusion Complexes of Psidium gaudichaudianum Leaf Essential Oil and ß-Caryophyllene on 2-Hydroxypropyl-ß-cyclodextrin.

The present investigation aimed to develop inclusion complexes (ICs) from Psidium gaudichaudianum (GAU) essential oil (EO) and its major compound ß-caryophyllene (ß-CAR), and to evaluate their herbicidal (against Lolium multiflorum and Bidens pilosa) and cytogenotoxic (on Lactuca sativa) activities. The ICs were obtained using 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and they were prepared to avoid or reduce the volatility and degradation of GAU EO and ß-CAR. The ICs obtained showed a complexation efficiency of 91.5 and 83.9% for GAU EO and ß-CAR, respectively. The IC of GAU EO at a concentration of 3000 µg mL-1 displayed a significant effect against weed species B. pilosa and L. multiflorum. However, the ß-CAR IC at a concentration of 3000 µg mL-1 was effective only on L. multiflorum. In addition, the cytogenotoxic activity evaluation revealed that there was a reduction in the mitotic index and an increase in chromosomal abnormalities. The produced ICs were able to protect the EO and ß-CAR from volatility and degradation, with a high thermal stability, and they also enabled the solubilization of the EO and ß-CAR in water without the addition of an organic solvent. Therefore, it is possible to indicate the obtained products as potential candidates for commercial exploration since the ICs allow the complexed EO to exhibit a more stable chemical constitution than pure EO under storage conditions.

High-cholesterol diet in combination with hydroxypropyl-beta-cyclodextrin induces NASH-like disorders in the liver of rats.

Non-alcoholic fatty liver disease (NAFLD) is a general term for fatty liver disease not caused by viruses or alcohol. Fibrotic hepatitis, cirrhosis, and hepatocellular carcinoma can develop. The recent increase in NAFLD incidence worldwide has stimulated drug development efforts. However, there is still no approved treatment. This may be due in part to the fact that non-alcoholic steatohepatitis (NASH) pathogenesis is very complex, and its mechanisms are not well understood. Studies with animals are very important for understanding the pathogenesis. Due to the close association between the establishment of human NASH pathology and metabolic syndrome, several animal models have been reported, especially in the context of overnutrition. In this study, we investigated the induction of NASH-like pathology by enhancing cholesterol absorption through treatment with hydroxypropyl-beta-cyclodextrin (CDX). Female Sprague-Dawley rats were fed a normal diet with normal water (control group); a high-fat (60 kcal%), cholesterol (1.25 %), and cholic acid (0.5 %) diet with normal water (HFCC group); or HFCC diet with 2 % CDX water (HFCC+CDX group) for 16 weeks. Compared to the control group, the HFCC and HFCC+CDX groups showed increased blood levels of total cholesterol, aspartate aminotransferase, and alanine aminotransferase. At autopsy, parameters related to hepatic lipid synthesis, oxidative stress, inflammation, and fibrosis were elevated, suggesting the development of NAFLD/NASH. Elevated levels of endoplasmic reticulum stress-related genes were evident in the HFCC+CDX group. In the novel rat model, excessive cholesterol intake and accelerated absorption contributed to NAFLD/NASH pathogenesis.

Targeted intracellular delivery of antitubercular bioactive(s) to Mtb infected macrophages via transferrin functionalized nanoliposomes.

The packaging of antimicrobials/chemotherapeutics into nanoliposomes can enhance their activity while minimizing toxicity. However, their use is still limited owing to inefficient/inadequate loading strategies. Several bioactive(s) which are non ionizable, and poorly aqueous soluble cannot be easily encapsulated into aqueous core of liposomes by using conventional means. Such bioactive(s) however could be encapsulated in the liposomes by forming their water soluble molecular inclusion complex with cyclodextrins. In this study, we developed Rifampicin (RIF) - 2-hydroxylpropyl-ß-cyclodextrin (HP-ß-CD) molecular inclusion complex. The HP-ß-CD-RIF complex interaction was assessed by using computational analysis (molecular modeling). The HP-ß-CD-RIF complex and Isoniazid were co-loaded in the small unilamellar vesicles (SUVs). Further, the developed system was functionalized with transferrin, a targeting moiety. Transferrin functionalized SUVs (Tf-SUVs) could preferentially deliver their payload intracellularly in the endosomal compartment of macrophages. In in vitro study on infected Raw 264.7 macrophage cells revealed that the encapsulated bioactive(s) could eradicate the pathogen more efficiently than free bioactive(s). In vivo studies further revealed that the Tf-SUVs could accumulate and maintain intracellular bioactive(s) concentrations in macrophages. The study suggests Tf-SUVs as a promising module for targeted delivery of a drug combination with improved/optimal therapeutic index and effective clinical outcomes.

In Silico Study of Novel Cyclodextrin Inclusion Complexes of Polycaprolactone and Its Correlation with Skin Regeneration.

Three novel biomaterials obtained via inclusion complexes of ß-cyclodextrin, 6-deoxi-6-amino-ß-cyclodextrin and epithelial growth factor grafted to 6-deoxi-6-amino-ß-cyclodextrin with polycaprolactone. Furthermore, some physicochemical, toxicological and absorption properties were predicted using bioinformatics tools. The electronic, geometrical and spectroscopical calculated properties agree with the properties obtained via experimental methods, explaining the behaviors observed in each case. The interaction energy was obtained, and its values were -60.6, -20.9 and -17.1 kcal/mol for ß-cyclodextrin/polycaprolactone followed by the 6-amino-ß-cyclodextrin-polycaprolactone complex and finally the complex of epithelial growth factor anchored to 6-deoxy-6-amino-ß-cyclodextrin/polycaprolactone. Additionally, the dipolar moments were calculated, achieving values of 3.2688, 5.9249 and 5.0998 Debye, respectively, and in addition the experimental wettability behavior of the studied materials has also been explained. It is important to note that the toxicological predictions suggested no mutagenic, tumorigenic or reproductive effects; moreover, an anti-inflammatory effect has been shown. Finally, the improvement in the cicatricial effect of the novel materials has been conveniently explained by comparing the poly-caprolactone data obtained in the experimental assessments.

Preparation and characterization of inclusion complex of Myristica fragrans Houtt. (nutmeg) essential oil with 2-hydroxypropyl-ß-cyclodextrin.

Nutmeg essential oil (NEO) is a natural condimentwith versatile biological activities. However, the application of NEO in food has several limitations due to its poor stability and low aqueous solubility. To overcome the shortcomings, this paper focused on the preparation of the inclusion complex (IC) of NEO with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) by the coprecipitation method. The optimal condition was inclusion temperature 36 ℃, time 247 min, stirring speed 520 r/min, and wall-core ratio 12:1, resulting in a recovery of 80.63%. The formation of IC was verified by various methods such as scanning electron microscopy, Fourier transform infrared spectroscopy and nuclear magnetic resonance. The improvement of thermal stability, antioxidant, and nitrite scavenging activities of NEO after encapsulation was proven. Moreover, the controlled release of NEO from IC can be implemented by regulating the temperature and relative humidity. Overall, NEO/HP-ß-CD IC has great application potential in food industries.

Improving Solubility and Permeability of Hesperidin through Electrospun Orange-Peel-Extract-Loaded Nanofibers.

Orange peel, which is a rich source of polyphenolic compounds, including hesperidin, is produced as waste in production. Therefore, optimization of the extraction of hesperidin was performed to obtain its highest content. The influence of process parameters such as the kind of extraction mixture, its temperature and the number of repetitions of the cycles on hesperidin content, the total content of phenolic compounds and antioxidant (DPPH scavenging assay) as well as anti-inflammation activities (inhibition of hyaluronidase activity) was checked. Methanol and temperature were key parameters determining the efficiency of extraction in terms of the possibility of extracting compounds with the highest biological activity. The optimal parameters of the orange peel extraction process were 70% of methanol in the extraction mixture, a temperature of 70 °C and 4 cycles per 20 min. The second part of the work focuses on developing electrospinning technology to synthesize nanofibers of polyvinylpyrrolidone (PVP) and hydroxypropyl-ß-cyclodextrin (HPßCD) loaded with hesperidin-rich orange peel extract. This is a response to the circumvention of restrictions in the use of hesperidin due to its poor bioavailability resulting from low solubility and permeability. Dissolution studies showed improved hesperidin solubility (over eight-fold), while the PAMPA-GIT assay confirmed significantly better transmucosal penetration (over nine-fold). A DPPH scavenging assay of antioxidant activity as well as inhibition of hyaluronidase to express anti-inflammation activity was established for hesperidin in prepared electrospun nanofibers, especially those based on HPßCD and PVP. Thus, hesperidin-rich orange peel nanofibers may have potential buccal applications to induce improved systemic effects with pro-health biological activity.

Simultaneously Inhibiting P-gp Efflux and Drug Recrystallization Enhanced the Oral Bioavailability of Nintedanib.

INTRODUCTION: Nintedanib (NDNB) is a novel triple-angiokinase inhibitor for the treatment of lung cancer. However, the oral bioavailability of NDNB is only 4.7% owing to the poor solubility and the efflux of P-glycoprotein (P-gp). AIM: The aim was to explore the potential applications of a hydrogel of NDNB/hydroxypropyl-ß- cyclodextrin (HP-ß-CD) complex combined with a strong P-gp inhibitor Itraconazole (ITZ) for augmenting the oral delivery of NDNB. METHODS: The NDNB/HP-ß-CD complex was prepared and characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and molecular simulation and was subjected to in vitro and in situ studies. Then the NDNB/HP-ß-CD complex was dispersed in carbopol 934 hydrogel and the gel was evaluated for pharmacokinetic and pharmacodynamics studies. RESULTS: The HP-ß-CD and NDNB formed complex by van der Waals and hydrogen bonding interaction forces by XRD, FT-IR, and molecular simulation studies. When the molar ratio of NDNB/HP-ß-CD was 1:20, the complex exhibited high drug inclusion efficiency and excellent stability. The in situ perfusion results revealed that the permeability of the combination of complex and ITZ enhanced about 3.0-fold compared with the NDNB solution. The oral bioavailability of the sequential administration of ITZ and NDNB/HP-ß-CD complex gels was increased 3.5-fold by preventing recrystallization, extending the residence time in the gastrointestinal tract, and inhibiting P-gp in comparison with NDNB soft capsules. The co-therapy with NDNB/HP-ß-CD complex gels and ITZ exerted a strong anti-tumor effect. CONCLUSION: In conclusion, NDNB/HP-ß-CD complex gels combined with P-gp inhibitor were a potential strategy for enhancing the oral bioavailability and anti-tumor effect of NDNB.

Anticancer Activity of Novel Difluorinated Curcumin Analog and Its Inclusion Complex with 2-Hydroxypropyl-ß-Cyclodextrin against Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify novel drugs with improved delivery to improve treatment outcomes. Curcumin is one such compound that can inhibit multiple signaling pathways and CSCs. However, curcumin's clinical applicability for treating PDAC is limited because of its poor solubility in water and metabolic instability. Hence, we developed a difluorinated curcumin (CDF) analog that accumulates selectively in the pancreas and inhibits PDAC growth in vitro and in vivo. In the present work, we developed its 2-hydroxy-propyl-ß-cyclodextrin (HCD) inclusion complex to increase its water solubility and hydrolytic stability. The CDFHCD inclusion complex was characterized by spectroscopic, thermal, and microscopic techniques. The inclusion complex exhibited increased aqueous solubility, hydrolytic stability, and antiproliferative activity compared to parent CDF. Moreover, CDF and CDFHCD inhibited colony and spheroid formation, and induced cell cycle and apoptosis in PDAC cell lines. Hence, CDFHCD self-assembly is an efficient approach to increase water solubility and anticancer therapeutic efficacy, which now warrants advancement towards a clinical proof of concept in PDAC patients.

Insights into recent preclinical studies on labelled cyclodextrin-based imaging probes: Towards a novel oncological era.

As malignancies remain one of the major health concerns worldwide, increasing focus has been centered around the application of cyclodextrins (CDs) in cancer imaging and therapy due to their outstanding inclusion forming capability. Albeit the physicochemical properties of CDs were intensively elucidated, the spread of their clinical application is limited by the relative paucity of knowledge about their pharmacokinetic profile, especially biodistribution. Studies applying fluorescently- CDs, or CD-based MRI contrast agents revealed much about pharmacokinetics and diagnostic applications; however, derivatives labelled with positron emitters seem superior molecular probes in the investigation of the route of CDs in biological niche. In vivo imaging based on preclinical tumor-bearing model systems are well-suited to evaluate the whole-body distribution of the two most frequently assessed CDs: randomly methylated ß-cyclodextrin (RAMEB), and hydroxypropyl-ß-cyclodextrin (HPBCD). Exploiting the firm signaling interaction between cancer-related cyclooxygenase-2, prostaglandin E2 (PGE2) and RAS oncoprotein, radioconjugated, PGE2-affine CDs project the establishment of novel imaging probes and therapeutic agents. Currently, we provide an overview of the preclinical studies on CD pharmacokinetics highlighting the significance of the integration of translational discoveries into human patient care.

A comparative study on inclusion complex formation between formononetin and ß-cyclodextrin derivatives through multiscale classical and umbrella sampling simulations.

Formononetin, a naturally occurring isoflavone exhibits a wide range of therapeutic applications including antioxidant, anti-tumor, antiviral, anti-diabetic and neuroprotective activities. However, the low hydro-solubility of formononetin has limited its prospective use in cosmetic, neutraceutical and pharmaceutical industries. Cyclodextrins (CDs), especially ß-CD and its derivatives have emerged as promising agents to improve the water solubility of poorly hydrosoluble compounds by the formation of inclusion complexes. We employed multiscale (1000 ns) explicit solvent and umbrella sampling molecular dynamics (MD) simulations to study the interactions and thermodynamic parameters of inclusion complex formation between formononetin and five most commonly used ß-CD derivatives. Classical MD simulations revealed two possible binding conformations of formononetin inside the central cavity of hydroxypropyl-ß-CD (HP-ß-CD), randomly methylated-ß-CD (ME-ß-CD), and sulfobutylether-ß-CD (SBE-ß-CD). The binding conformation with the benzopyrone ring of formononetin inside the central cavity of ß-CD derivatives was more frequent than the phenyl group occupying the hydrophobic cavity. These interactions were supported by a variety of non-bonded contacts including hydrogen bonds, pi-lone pair, pi-sigma, and pi-alkyl interactions. Formononetin showed favorable end-state MD-driven thermodynamic binding free energies with all the selected ß-CD derivatives, except succinyl-ß-CD (S-ß-CD). Furthermore, umbrella sampling simulations were used to investigate the interactions and thermodynamic parameters of the host-guest inclusion complexes. The SBE-ß-CD/formononetin inclusion complex showed the lowest binding energy signifying the highest affinity among all the selected host-guest inclusion complexes. Our study could be used as a standard for analyzing and comparing the ability of different ß-CD derivatives to enhance the hydro-solubility of poorly soluble molecules.

Investigation of 2-Hydroxypropyl-ß-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann-Pick Type C Using Quantitative Proteomics.

Niemann-Pick, type C (NPC) is a fatal, neurovisceral lysosomal storage disorder with progressive neurodegeneration and no FDA-approved therapy. Significant efforts have been focused on the development of therapeutic options, and 2-hydroxypropyl-ß-cyclodextrin (HP-b-CD) has emerged as a promising candidate. In cell culture, HP-b-CD ameliorates cholesterol storage in endo/lysosomes, a hallmark of the disorder. Furthermore, in animal studies, treatment with HP-b-CD delays neurodegeneration and extends lifespan. While HP-b-CD has been promising in vitro and in vivo, a clear understanding of the mechanism(s) of action is lacking. Utilizing a neuron-like cell culture model of SH-SY5Y differentiated cells and U18666A to induce the NPC phenotype, we report here a large-scale mass-spectrometry-based proteomic study to evaluate proteome changes upon treatment with these small molecules. In this study, we show that differentiated SH-SY5Y cells display morphological changes representative of neuronal-like cells along with increased levels of proliferation markers. Inhibition of the NPC cholesterol transporter 1 protein by U18666A resulted in increased levels of known NPC markers including SCARB2/LIMP2 and LAMP2. Finally, 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. This finding further supports the need for a proteostasis strategy for NPC drug development. Moreover, proteins that were dysregulated in the U18666A model of NPC and normalized to control levels 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.

Encapsulation of Rosmarinus officinalis essential oil and of its main components in cyclodextrin: application to the control of the date moth Ectomyelois ceratoniae (Pyralidae).

BACKGROUND: Synthetic insecticides are the most useful tools for preventing losses caused by insect pest's infestation during storage. However, the use of pesticides should be limited because of the development of insect resistance and their adverse effects on human health and environment. In the last decades, natural insecticidal products, principally essential oils (EOs) and their active components, exhibited potential alternatives for pest control. Nevertheless, due to their volatile nature, encapsulation could be considered as the most appropriate solution. Therefore, this work aims to investigate the fumigant ability of inclusion complexes of Rosmarinus officinalis EO and its major constituents (1,8-cineole, α-pinene and camphor) with 2-hydroxypropyl-beta-cyclodextrin (HP-ß-CD) against Ectomyelois ceratoniae (Pyralidae) larvae. RESULTS: The encapsulation within HP-ß-CD reduced greatly the release rate of the encapsulated molecules. Therefore, free compounds were more toxic than those encapsulated. Moreover, results revealed that encapsulated volatiles exhibited interesting insecticidal toxicity towards E. ceratoniae larvae. In fact, after 30 days mortality rates were 53.85, 94.23, 3.85 and 42.31% for α-pinene, 1,8-cineole, camphor and EO, respectively, encapsulated within HP-ß-CD. In addition, results showed also that 1,8-cineole free and encapsulated was more effective toward E. ceratoniae larvae than the other tested volatiles. Additionally, the HP-ß-CD/volatiles complexes exhibited best persistence compared to the volatiles components. The half-life of the encapsulated α-pinene, 1,8-cineole, camphor and EO (7.83, 8.75, 6.87 and 11.20 days) was significantly longer than that of the free ones (3.46, 5.02, 3.38 and 5.58 days). CONCLUSION: These results sustain the utility of R. officinalis EO and its main components encapsulated in CDs as treatment to stored-date commodities. © 2023 Society of Chemical Industry.

Ocular Administration of Palonosetron in the Prevention of Cisplatin-Induced Nausea and Vomiting.

Cancer treatments are frequently associated with nausea and vomiting despite greatly improved preventive medication. Administration of antinausea agents as eye drops might provide easy and rapid access to the systemic circulation for prevention of nausea and vomiting and for the treatment of breakthrough nausea, but the ocular administration route has rarely been evaluated. Palonosetron is a second-generation 5-hydroxytryptamine 3 receptor antagonist approved for prevention and treatment of chemotherapy-induced nausea and vomiting. We compared ocular administration of palonosetron to non-active vehicle eye drops and to intravenous palonosetron in the prevention of cisplatin-induced nausea and vomiting in beagle dogs. Palonosetron ocular drops at the dose of 30 µg/kg reduced cumulative nausea over time as measured with the area under the visual analog scale curve by 98% compared with the vehicle and reduced nausea-associated dog behavior by 95%. Vomiting was completely prevented with repeated palonosetron ocular dosing. Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) palonosetron formulation was well tolerated locally at the palonosetron concentration of 3 mg/ml. Absorption of palonosetron from eye drops was fast. Ten minutes after ocular administration, palonosetron plasma concentrations were similar compared with intravenous administration, and remained similar for six hours. We conclude that palonosetron is rapidly absorbed into the systemic circulation from eye drops. Ocularly administered palonosetron was well tolerated in the HP-ß-CD formulation and was highly effective in the prevention of cisplatin-induced nausea and vomiting. Evaluation of the safety and efficacy of ocular administration of palonosetron is warranted in the prevention and treatment of chemotherapy-induced nausea and vomiting in clinical trials. SIGNIFICANCE STATEMENT: Palonosetron, an effective and well-tolerated antiemetic drug was rapidly absorbed into the systemic blood circulation when administered as eye drops. The achieved palonosetron blood concentrations prevented cisplatin-induced nausea and vomiting in beagle dogs. Palonosetron eye drops might provide an easy and quick method for administering palonosetron when parenteral administration is desired and intravenous administration is not feasible.