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Cyclodextrins (CDs) belong to a class of cyclic oligosaccharides characterized by their toroidal shape consisting of glucose units linked via α-1,4-glycosidic bonds. This distinctive toroidal shape exhibits a dual nature, comprising a hydrophobic interior and a hydrophilic exterior, making CDs highly versatile in various pharmaceutical products. They serve multiple roles: they act as solubilizers, stabilizers, controlled release promoters, enhancers of drug bioavailability, and effective means of masking undesirable tastes and odors. Taking advantage of these inherent benefits, CDs have been integrated into numerous nanoscale drug delivery systems. The resulting nanomaterials exploit the exceptional properties of CDs, including their ability to solubilize hydrophobic drugs for substantial drug loading, engage in supramolecular complexation for engineered nanomaterials, increase bioavailability for improved therapeutic efficacy, stabilize labile drugs, and exhibit biocompatibility and versatility. This paper compiles recent studies on CD functional nanoscale drug delivery platforms. First, we described the physicochemical and toxicological aspects of CDs, CD/drug inclusion complexation, and their impact on improving drug bioavailability. We then summarized applications for CD-functional nano delivery systems based on polymeric, hybrid, lipid-based nanoparticles, and CD-based nanofibers. Particular interest was in the targeted applications and the function of the CD molecules used. In most applications, CD molecules were used for drug solubilization and loading, while in some studies, CD molecules were employed for supramolecular complexation to construct nanoscale drug delivery systems. Finally, the review concludes with a thoughtful consideration of the current challenges and outlook., (© 2024 Wiley Periodicals LLC.)

Cyclodextrins (CDs) are ubiquitous excipients, constituted of cyclic glucopyranose units, and possess a unique dual nature, that of a hydrophobic interior and a hydrophilic exterior. This enables their interaction with lipid-affinitive compounds and hydrophilic compounds, thereby augmenting their application in pharmaceutical formulations as agents for improving solubility, as well as fundamental elements of advanced drug delivery systems. Additionally, CDs, upon suitable modification, can strategically participate in the interaction with cellular components and physical barriers, such as the blood-brain barrier, where their intricate and multifunctional engagement leads to various biological impacts. This review consolidates the crucial features of CDs and their derivatives, and summarizes the applications of them as drug delivery systems in neurodegenerative disorders, emphasizing their notable potentials.

Cyclodextrins (CDs) are unique cyclic compounds that can form inclusion complexes via host-guest complexation with a wide range of molecules, thereby altering their physicochemical properties. These molecules offer the formation of inclusion complexes without the formation of covalent bonds, making them suitable for a variety of applications in pharmaceutical and biomedical fields. Due to their supramolecular host-guest properties, CDs are being utilized in the fabrication of biomaterials, metal-organic frameworks, and nano-drug carriers. Additionally, CDs in combination with biomolecules are biocompatible and can deliver nano to macromolecules at the site of drug actions. However, the availability of free hydroxyl groups and a simple crosslinking process for supramolecular fabrication show immense opportunities for researchers in the field of tissue engineering and biomedical applications. In this review article, we have covered the historical development, various types of chemical frameworks, unique chemical and physical properties, and important applications of CDs in drug delivery and biomedical sciences., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Hydrogel-forming microneedle array patches (HFMAPs) are microneedles that create microconduits upon insertion and swelling in the skin, potentially allowing prolonged drug delivery without generating sharps waste. Delivering hydrophobic drugs using HFMAPs poses challenges, which can be addressed using solubility enhancers such as cyclodextrins (CDs). This study aimed to deliver risperidone (RIS) transdermally using HFMAPs. To enhance the aqueous solubility of RIS hydroxypropyl-beta-cyclodextrin (HP-β-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) were utilised and their performance was tested using phase solubility studies. The aqueous solubility of RIS was enhanced by 4.75-fold and 2-fold using HP-β-CD and HP-γ-CD, respectively. RIS-HP-β-CD complex (CX) and physical mixture (PM) directly compressed tablets were prepared and combined with HFMAPs. Among the tested formulations, RIS-HP-β-CD PM reservoirs with 11 x 11 PVA/PVP HFMAPs exhibited the best performance in ex vivo studies and were further evaluated in in vivo experiments using female Sprague Dawley rats. The extended wear time of the MAPs resulted in the sustained release of RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in plasma samples, lasting from 3 to 5 days with a 1-day application and up to 10 days with a 5-day application. For a 1-day application, HFMAPs showed greater systemic exposure to RIS compared to intramuscular control (AUC 0-t : 13330.05 ± 2759.95 ng/mL/hour versus 2706 ± 1472 ng/mL/hour). Moreover, RIS exposure was extended to 5 days (AUC 0-t : 12292.37 ± 1801.94 ng/mL/hour). In conclusion, HFMAPs could serve as an alternative for delivering RIS in a sustained manner, potentially improving the treatment of schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nanoparticles (NPs) have gained significant attention in recent years due to their potential applications in pharmaceutical formulations, drug delivery systems, and various biomedical fields. The versatility of colloidal NPs, including their ability to be tailored with various components and synthesis methods, enables drug delivery systems to achieve controlled release patterns, improved solubility, and increased bioavailability. The review discusses various types of NPs, such as nanocrystals, lipid-based NPs, and inorganic NPs (i.e., gold, silver, magnetic NPs), each offering unique advantages for drug delivery. Despite the promising potential of NPs, challenges such as physical instability and the need for surface stabilization remain. Strategies to overcome these challenges include the use of surfactants, polymers, and cyclodextrins (CDs). This review highlights the role of CDs in stabilizing colloidal NPs and enhancing drug solubility. The combination of CDs with NPs presents a synergistic approach that enhances drug delivery and broadens the range of biomedical applications. Additionally, the potential of CDs to enhance the stability and therapeutic efficacy of colloidal NPs, making them promising candidates for advanced drug delivery systems, is comprehensively reviewed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Efficient delivery of therapeutic agents to the lesion site or specific cells is an important way to achieve "toxicity reduction and efficacy enhancement". Macrocycles have always provided many novel ideas for drug or gene loading and delivery processes. Specifically, macrocycles represented by crown ethers, cyclodextrins, cucurbit[n]urils, calix[n]arenes, and pillar[n]arenes have unique properties, which are different cavity structures, good biocompatibility, and good stability. Benefited from these diverse properties, a variety of supramolecular drug delivery systems can be designed and constructed to effectively improve the physical and chemical properties of guest molecules as needed. This review provides an outlook on the current application status and main limitations of macrocycles in supramolecular drug delivery systems.

Eugenol (Eug) holds potential as a treatment for bacterial rhinosinusitis by nasal powder drug delivery. To stabilization and solidification of volatile Eug, herein, nasal inhalable γ-cyclodextrin metal-organic framework (γ-CD-MOF) was investigated as a carrier by gas-solid adsorption method. The results showed that the particle size of Eug loaded by γ-CD-MOF (Eug@γ-CD-MOF) distributed in the range of 10-150 μm well. In comparison to γ-CD and β-CD-MOF, γ-CD-MOF has higher thermal stability to Eug. And the intermolecular interactions between Eug and the carriers were verified by characterizations and molecular docking. Based on the bionic human nasal cavity model, Eug@γ-CD-MOF had a high deposition distribution (90.07 ± 1.58%). Compared with free Eug, the retention time Eug@γ-CD-MOF in the nasal cavity was prolonged from 5 min to 60 min. In addition, the cell viability showed that Eug@γ-CD-MOF (Eug content range 3.125-200 µg/mL) was non-cytotoxic. And the encapsulation of γ-CD-MOF could not reduce the bacteriostatic effect of Eug. Therefore, the biocompatible γ-CD-MOF could be a potential and valuable carrier for nasal drug delivery to realize solidification and nasal therapeutic effects of volatile oils., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The incidence of breast cancer has been increasing over the last four decades, although the mortality rate has decreased. Endocrine therapy and chemotherapy are the most used options for cancer treatment but several obstacles are still attributed to these therapies. Smart materials, such as nanocarriers for targeting, delivery and release of active ingredients, sensitive to intrinsic-stimuli (pH-responsive, redox-responsive, enzyme- responsive, and thermo-responsive) and extrinsic-stimuli (ultrasound-responsive, magnetic-responsive, light-responsive) have been studied as a novel strategy in breast cancer therapy. Cyclodextrins (CDs) are used in the design of these stimuli-responsive drug carrier and delivery systems, either through inclusion complexes with hydrophobic molecules or covalent bonds with large structures to generate new materials. The present work aims to gather and integrate recent data from in vitro and in vivo preclinical studies of CD-based stimuli- responsive systems to contribute to the research in treating breast cancer. All drug carriers showed high in vitro release rates in the presence of a stimulus. The stimuli-responsive nanoplatforms presented biocompatibility and satisfactory results of IC 50 , inhibition of cell viability and antitumor activity against several breast cancer cell lines. Additionally, these systems led to a significant reduction in drug dosages, which encouraged possible clinical studies for better alternatives to traditional antitumor therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The engineering of a new type of trifunctional biopolymer-based nanosponges polymerized by cross-linking beta-cyclodextrin ethylene diamine (βCD-EDA) with bifunctional hairy nanocellulose (BHNC) is reported herein. We refer to the highly cross-linked polymerized BHNC-βCD-EDA network as BBE. βCD-EDA and BHNC were cross-linked at various ratios with the help of DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium) as a green activator in deionized water as a solvent, which resulted in different morphological shapes of BBE. Some of these structures were chiral due to cross-linked liquid crystalline structures. A comprehensive characterization study was done to show their unique morphological, structural, and dimensional properties of BBEs. Moreover, to further investigate and to confirm the surface modification of the precursors and final BBE structures, Fourier transform infrared and nuclear magnetic resonance spectroscopy, thermogravimetric analysis, Brunauer-Emmett-Teller analysis, and X-ray diffraction were applied. The hairy nanocellulose particles were considered as the backbone, and the immobilized cyclodextrin cavities can capture doxorubicin, which was used as a model drug molecule via host-guest inclusion complexation. Finally, the obtained BBE networks showed different and sustained drug release profiles and pH responsiveness. BBE biopolymers were tested as biocompatible nanocarriers for controlled release. We realize that these structures are too big for anti-cancer drug delivery by injection or oral intake, but these structures have a high potential to be applied in wound dressing and implants. They could also be used for capturing antibiotics, dyes, and organic compounds from wastewater.

Recent progresses in the integration of CDs and montmorillonite, as well as applications of CD-containing montmorillonite hybrid host systems are summarized in this review. Several efficient synthesis strategies, such as ion exchange, metal coordination, supramolecular strategies, polymerizations and organic synthesis methods, have been discussed during the preparation of CDs/montmorillonite hybrid composites. In particular, diverse instrumental techniques were highly recommended for characterizing the as-obtained hybrid systems, including their chemical composition and structures, crystallinity, surface/self-assembled morphologies, as well as other particular physiochemical properties, providing a direct guide for promoting the desired structures and exploring various applications. It should be noted that the introduction of functional groups, as well as the integration of CDs and montmorillonite granted the thus obtained CD-containing montmorillonite hybrid host systems a lot of unique features, providing great opportunities for expanding the practical applications to a series of biological and environmental areas, such as biosensors, sorption and decontamination of bio/environmental hazardous materials, biostudies about aqueous dispersity, stability and biocompatibility, drug loading and target delivery, controlled and sustained drug release, as well as antibacterial.

Background: There is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. Therefore, the combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may also reduce colorectal cancer risk. Histone deacetylase (HDAC) plays an essential role in the progression of colon cancer. Butyric acid (BA) is a kind of HDAC inhibitor and thus shows tumor suppression to colon cancer. However, the volatile and corrosive nature of BA presents challenges in practical application. In addition, its clinical application is limited due to its non-targeting ability and low bioavailability. We aimed to synthesize a novel dual-prodrug of 5-ASA and BA, referred as BBA, to synergistically inhibit colon cancer. Further, based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-β-cyclodextrin (CM-β-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-β-CD., Results: It was found that BBA/FA-PEG-CM-β-CD showed significant inhibition in cell proliferation against colon cancer cells SW620. It showed a pro-longed in vivo circulation and mainly accumulated in tumor tissue. More importantly, BBA/FA-PEG-CM-β-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts., Conclusions: Therefore, BBA/FA-PEG-CM-β-CD may have clinical potential in colon cancer therapy., (© 2021. The Author(s).)

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 β-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.

Doxorubicin (DOX) is an effective chemotherapeutic agent used for the treatment of various types of cancer. However, its poor solubility, undesirable side effects, and short half-life have remained a challenge. We used a formulation based on graphene oxide as an anticancer drug delivery system for DOX in MCF-7 breast cancer cells, to address these issues. In vitro release studies confirmed that the synthesized formulation has an improved release profile in acidic conditions (similar to the tumor microenvironment). Further in vitro studies, including MTT, uptake, and apoptosis assays were performed. The toxic effects of the nanocarrier on the kidney, heart and liver of healthy rats were also evaluated. We observed that the DOX-loaded carrier improved the cytotoxic effect of DOX on the breast cell line compared to free DOX. In summary, our results introduce the DOX-loaded carrier as a potential platform for in vitro targeting of cancer cells and suggest further studies are necessary to investigate its in vivo anti-cancer potential., (© 2021 Ainaz Mihanfar et al., published by De Gruyter.)

Graphene displays various properties like optical, electrical, mechanical, etc. resulting in a large range of applications in biosensing, bio-imaging, medical and electronic devices. The graphene-based nanomaterials show disadvantages like hydrophobic surface, degradation of biomolecules (proteins and amino acids) and toxicity to the human and microbes by permeating into the cells and thus, limiting the use in the biomedical field. Conjugation of carbohydrates like chitin, cyclodextrins and cellulose with graphene results in thermal stability, oxygen repulsive ability, fire-retardant and gelling properties with better biodegradability, biocompatibility and safety leading to the formation of environment-friendly biopolymers. This article delivers an overview of the molecular interaction of different carbohydrates-derived from natural sources like marine, plants and microbes with graphene nanosheets to extend the applications in tissue engineering, surgical materials, biosensing and novel drug delivery for prolonged action in the treatment of breast and hepatic cancers., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Macro biomolecules are of vital importance in regulating the biofunctions in organisms, in which proteins (including peptides when mentioned below) and nucleic acids (NAs) are the most important. Therefore, these proteins and NAs can be applied as "drugs" to regulate the biofunctions from abnormal to normal. Either for proteins and NAs, the most challenging thing is to avoid the biodegradation or physicochemical degradation before they reach the targeted location, and then functions as complete functional structures. Hence, appropriate delivery systems are very important which can protect them from these degradations. Cyclodextrins (CDs) based delivery systems achieved mega successes due to their outstanding pharmaceutical properties and there have been several reviews on CDs based small molecule drug delivery systems recently. But for biomolecules, which are getting more and more important for modern therapies, however, there are very few reviews to systematically summarize and analyze the CDs-based macro biomolecules delivery systems, especially for proteins. In this review, there were some of the notable examples were summarized for the macro biomolecules (proteins and NAs) delivery based on CDs. For proteins, this review included insulin, lysozyme, bovine serum albumin (BSA), green fluorescent protein (GFP) and IgG's, etc. deliveries in slow release, stimulating responsive release or targeting release manners. For NAs, this review summarized cationic CD-polymers and CD-cluster monomers as NAs carriers, notably, including the multicomponents targeting CD-based carriers and the virus-like RNA assembly method siRNA carriers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

NMR spectroscopy is an effective technique, applicable for studying bioactive materials or drug delivery systems in order to obtain comprehensive details related to structural and dynamic characteristics at atomic resolution. The applications of NMR spectroscopy have been increased considerably as a result of the combination of advancement in technological NMR instrumentation and scientific knowledge. This chapter is dedicated to highlight the applications of NMR spectroscopy in drug:cyclodextrin complexes using both liquid- and solid-state NMR spectroscopy.

Stimulated by researches in materials chemistry and medicine fields, drug delivery has entered a new stage of development. Drug delivery systems have been extensively studied according to the differences in the drug therapeutic environment such as pH, light, temperature, magnet, redox, enzymes, etc. Cyclodextrin is a smart tool that has been proven to be used in the preparation of drug delivery, and has become a new area of concern in recent years. In this review, we discuss recent research advances in smart stimuli-responsive cyclodextrin-based drug delivery. First, different stimuli-responsive drug delivery systems based on cyclodextrin are introduced and classified. Then, the characteristics of different types of stimuli-responsive drug delivery systems are described, and their applications are emphasized. Finally, current challenges and future development opportunities of smart stimuli-responsive drug delivery systems based on cyclodextrin are discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A combination of cocktail chemotherapy (CCT), photothermal therapy (PTT) and inhibition of angiogenesis was investigated as an effective approach to combat major challenges of multidrug resistance and non-targeted drug delivery encountered in conventional cancer therapy. An injectable nanocarrier was developed through functionalization of carbon nanotubes (CNTs) with rationally modified carbohydrate (β-Cyclodextrin-CD) derived pH and thermo responsive polymer. Embedding CNT to CD polymer offers a nanocarrier which effectively demonstrated CCT, high NIR triggered photothermal efficiency, anti-angiogenic potential for selective tumor homing as well as enhanced multi-drug resistance (MDR) reversal with minimal toxic effects on normal cells. The simultaneously loading with curcumin and doxorubicin hydrochloride exhibited synergistic effect for triggering antitumor effect in vitro and demonstrated down regulation of growth factors associated with angiogenesis ex-ovo. In-vivo studies ascertained that the nanocarrier synthesized with the rational for MDR reversal can lead to enhanced cancer cell death via multiple approaches., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cancer has been a threat to human health, so its treatment is a huge challenge to the present medical field. One of commonly used methods is the controlled release of anticancer drug to reduce the dose for patients, increase the stability of drug treatment and minimize side effects. Cyclodextrin is a kind of cyclic oligosaccharide produced by amylase hydrolysis. Because cyclodextrin contains a cavity structure and active hydroxyl groups, it has a positive effect on the study of the controlled release of anticancer drugs. This article reviews the controlled release of current anticancer drugs based on cyclodextrins as a "flexible switch", and discusses the classification of different types of release systems, highlighting their role in cancer treatment. Moreover, the opportunities and challenges of cyclodextrin as a magic switch in the controlled release of anticancer drugs are discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although many techniques have been devoted to promote therapeutic purposes of drug carrier systems, however, there are still many challenges in this area. Here, we designed co-loaded delivery systems, composed of curcumin loaded cyclodextrin-graphene oxide core (Cur@CD-GO) and gallic acid loaded chitosan shell nanofibers (Cur-Ga NF), which can promote the therapeutic efficiency of drugs. The synthesized nanofibres were fabricated by electrospinning technique with the coaxial system. Results showed that co-loaded delivery systems (Cur-Ga NF) provide better performance over single drug-loaded NFs (Cur@CD-GO). It was demonstrated that the nanofibers were successfully prepared, and the drugs in the core and sell of nanofibers were released in a controlled and sustained manner. The produced Cur-Ga NF, providing improved anti-cancer activity, antimicrobial activity, antioxidant activity and anti-inflammatory outcome as compared to single drug-loaded NFs. Our investigations showed that such co-delivery fiber systems could be employed as a promising nanocarrier for therapeutic applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cyclodextrins (CD) are a group of cyclic oligosaccharides with a cavity/specific structure that enables to form inclusion complexes (IC) with a variety of molecules through non-covalent host-guest interactions. By an elegant combination of CD with biocompatible, synthetic and natural polymers, different types of universal drug delivery systems with dynamic/reversible properties have been generated. This review presents the design of nano- and micro-carriers, hydrogels, and fibres based on the polymer/CD supramolecular systems highlighting their possible biomedical applications. Application of the most prominent hydrophobic aliphatic polyesters that exhibit biodegradability, represented by polylactide and polycaprolactone, is described first. Subsequently, particular attention is focused on materials obtained from hydrophilic polyethylene oxide. Moreover, examples are also presented for grafting of CD on polysaccharides. In summary, we show the application of host-guest interactions in multi-component functional biomaterials for controlled drug delivery.

Gram-negative bacteria possess numerous defenses against antibiotics, due to the intrinsic permeability barrier of their outer membrane (OM), explaining the recalcitrance of some common and life-threatening infections. We report the formulation of a new drug, PPA148, which shows promising activity against all Gram-negative bacteria included in the ESKAPEE pathogens. PPA148 was solubilized by inclusion complexation with cyclodextrin followed by encapsulation in liposomes. The complex and liposomal formulation presented increased activity against E. coli compared to the pure drug when assessed with the Kirby Bauer assay. The novel formulation containing 1 μg PPA148 reached similar efficacy levels equivalent to those of 30 μg of pure rifampicin. A range of biophysical techniques was used to explore the mechanism of drug uptake. Langmuir trough (LT) and neutron reflectivity (NR) techniques were employed to monitor the interactions between the drug and the formulation with model membranes. We found evidence for liposome fusion with the model Gram-negative outer membrane and for cyclodextrins acting as inner membrane (IM) permeation enhancers without presenting intrinsic antimicrobial activity. An antibiotic-in-cyclodextrin-in-liposomes (ACL) formulation was developed, which targets both the bacterial OM and IM, and offers promise as a means to breach the Gram-negative cell envelope.

Cyclodextrins (CDs) are cyclic oligosaccharides that form water-soluble inclusion complexes of lipophilic molecules. They are commonly used as pharmaceutical excipients. Recently it has been observed that CDs and CD complexes self-assemble in aqueous solutions to form transient clusters, nanoparticles and small microparticles. The critical aggregation concentration (cac) of the natural αCD, βCD and γCD in pure aqueous solutions is about 25, 8 and 9 mg/ml, respectively. The cac of 2-hydroxypropyl-β-cyclodextrin (HPβCD), that consists of a mixture of isomers, in pure aqueous solutions is significantly higher or about 118 mg/ml. Formation of guest/ CD complexes can increase or decrease the cac value. Due to the transient nature of the CD clusters and nanoparticles they can be difficult to detect and their presence is frequently ignored. However, formation of such particulate matter in aqueous CD solutions can lead to erroneous analytical results and product rejections during drug manufacturing. On the other hand, they have also given rise to formation of novel drug delivery systems with exceptional properties.

Although butylidenephthalide (BP) is an efficient anticancer drug, its poor bioavailability renders it ineffective for treating drug-resistant brain tumors. However, this problem is overcome through the use of noninvasive delivery systems, including intranasal administration. Herein, the bioavailability, drug stability, and encapsulation efficiency (EE, up to 95%) of BP were improved by using cyclodextrin-encapsulated BP in liposomal formulations (CDD1). The physical properties and EE of the CDD1 system were investigated via dynamic light scattering, transmission electron microscopy, UV-Vis spectroscopy, and nuclear magnetic resonance spectroscopy. The cytotoxicity was examined via MTT assay, and the cellular uptake was observed using fluorescence microscopy. The CDD1 system persisted for over 8 h in tumor cells, which was a considerable improvement in the retention of the BP-containing cyclodextrin or the BP-containing liposomes, thereby indicating a higher BP content in CDD1. Nanoscale CDD1 formulations were administered intranasally to nude mice that had been intracranially implanted with temozolomide-resistant glioblastoma multiforme cells, resulting in increased median survival time. Liquid chromatography-mass spectrometry revealed that drug biodistribution via intranasal delivery increased the accumulation of BP 10-fold compared to oral delivery methods. Therefore, BP/cyclodextrin/liposomal formulations have potential clinical applications for treating drug-resistant brain tumors.

The poor aqueous solubility of active pharmaceutical ingredients (APIs) places a limit on their therapeutic potential. Cyclodextrins (CDs) have been shown to improve the solubility of APIs, but the magnitude of the improvement depends on the structure of both the CDs and APIs. We have developed quantitative structure-property relationship (QSPR) models that predict the stability of the complexes formed by a popular poorly soluble antibiotic, cefuroxime axetil (CA) and different CDs. We applied this model to five CA-CD systems not included in the modeling set. Two out of three systems predicted to have poor stability and poor CA solubility, and both CA-CD systems predicted to have high stability and high CA solubility were confirmed experimentally. One of the CDs that significantly improved CA solubility, methyl-βCD, is described here for the first time, and we propose this CD as a novel promising excipient. Computational approaches and models developed and validated in this study could help accelerate the development of multifunctional CDs-based formulations.

The potential mammalian hepatotoxicity of a new class of GSH-responsive cyclodextrin-based nanosponges loaded with the anticancer drug doxorubicin (Dox-GSH-NS) was investigated. Previous studies showed that these nanosponges can release medicaments preferentially in cells having high GSH content, a common feature of chemoresistant cells, and showed enhanced anti-tumoral activity compared to free Dox in vitro and in vivo in cells with high GSH content. Following these promising results, we investigated here the Dox-GSH-NS hepatotoxicity in human HepG2 cells (in vitro) and in the organotypic cultures of rat precision-cut liver slices (PCLS, ex vivo), while their accumulation in rat liver was assessed in vivo. Moreover, the transport in Dox uptake, as well as its efflux, was studied in vitro. Overall, benefiting of the integration of different investigational models, a good safety profile of Dox-GSH-NSs was evidenced, and their hepatotoxicity resulted to be comparable with respect to free Dox both in vitro and ex vivo. Furthermore, in vivo studies showed that the hepatic accumulation of the Dox loaded in the NS is comparable with respect to the free drug. In addition, Dox-GSH-NSs are taken up by active mechanisms, and can escape the efflux drug pump, thus, contributing to overcoming drug resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications.

Complexation with cyclodextrins (CDs) has been widely and successfully used in pharmaceutical field, mainly for enhancing solubility, stability and bioavailability of a variety of drugs. However, some important drawbacks, including rapid removal from the bloodstream after in vivo administration, or possible replacement, in biological media, of the entrapped drug moieties by other molecules with higher affinity for the CD cavity, can limit the CDs effectiveness as drug carriers. This review is focused on combined strategies simultaneously exploiting CD complexation, and loading of the complexed drug into various colloidal carriers (liposomes, niosomes, polymeric nanoparticles, lipid nanoparticles, nanoemulsions, micelles) which have been investigated as a possible means for circumventing the problems associated with both such carriers, when used separately, and join their relative benefits in a unique delivery system. Several examples of applications have been reported, to illustrate the possible advantages achievable by such a dual strategy, depending on the CD-nanocarrier combination, and mainly resulting in enhanced performance of the delivery system and improved biopharmaceutical properties and therapeutic efficacy of drugs. The major problems and/or drawbacks found in the development of such systems, as well as the (rare) case of failures in achieving the expected improvements have also been highlighted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Herein, we describe the synthesis of poly(1,8-octamethylene citrate) materials modified in the bulk with 2-hydroxypropyl-β-cyclodextrin (cPOCCD), biodegradable elastomers with intrinsic sorption properties for drug delivery. The chemical structure, physicochemical properties, in vitro drug loading and release profiles of cPOCCD were investigated. Thus, cPOCCD polyesters absorb the studied drugs more effective and release them for a longer period of time than poly(1,8-octamethylene citrate) materials not containing cyclodextrins.

Cancer is increasingly becoming a serious threat to human life and health. Therefore, the development of safe and effective therapeutic agents against the disease is of crucial significance. Cyclodextrins (CDs) are cyclic oligosaccharides obtained by the enzymatic hydrolysis of starch, and constitute a class of cyclic oligosaccharides with external hydrophilic and internal hydrophobic properties and have been used widely in cancer therapy. Cyclodextrin has been extensively applied in nanomedicine therapy, gene therapy, cell therapy, immunotherapy, and chemotherapy. In this review, we summarize chemotherapy drugs for cancer treatment, classify various CD-based drug delivery systems, and describe their chemotherapy release and cancer treatment performance. In addition, current challenges and new opportunities for CD-based chemotherapeutic agents delivery systems are discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate whether a ternary system composed of hydroxypropyl-β-cyclodextrin (HP-βCD) further encapsulated into egg phosphatidylcholine liposomes (LUV) could prolong the action and reduce the toxicity of ropivacaine (RVC)., Methods: Dynamic light scattering and NMR were used to characterize the inclusion complex (RVC : HP-βCD), liposomal (RVC : LUV) and ternary (LUV : RVC : HP-βCD) systems containing 0.25% RVC. Their encapsulation efficiency, release kinetics, in-vitro cytotoxicity and in-vivo anaesthetic effect (paw-withdraw tests in mice) were also evaluated., Key Findings: 1 : 1 RVC : HP-βCD inclusion complex was encapsulated in liposomes (220.2 ± 20.3 nm size, polydispersity <0.25, zeta potentials = -31.7 ± 1.4 mV). NMR (diffusion-ordered spectroscopy (DOSY)) revealed stronger anaesthetic binding to LUV : RVC : HP-βCD (K a  = 342 m -1 ) than to RVC : HP-βCD (K a  = 128 m -1 ) or liposomal formulation (K a  = 22 m -1 ). The formulations promoted in-vitro sustained drug release and partially reverted the cytotoxicity of RVC against 3T3 fibroblasts in the profile: LUV : RVC : HP-βCD ≥ RVC : HP-βCD > RVC : LUV. Accordingly, in-vivo sensory block of free RVC (180 min) was prolonged ca. 1.7 times with the ternary system and RVC : HP-βCD (300 min) and 1.3 times with RVC : LUV (240 min)., Conclusions: These results confirm the suitability of this double-carrier system in clinical practice, to decrease the toxicity and prolong the anaesthesia time evoked by RVC., (© 2019 Royal Pharmaceutical Society.)

A kind of specific cyclodextrin polyrotaxanes (PRs) drug delivery system was developed for an effective drug delivery and enhancing antitumor effect. In this work, we prepared the PR by using α-CD derivatives and dicarboxyl-PEG ( M n = 4200) self-assembling and end-capping with β-CD derivatives. Then, we chose d-a-Tocopheryl polyethylene glycol 1000 succinate (TPGS) with an antitumor effect to modify the PR. The modified PRs have a certain anticancer effect and can assist the anticancer drug to treat cancer. The 10-hydroxycamptothecin (HCPT) was combined to the specific PRs by covalent bonds to prepare drug-loaded specificity PRs (PR-TPGS-HCPT). The enhanced antitumor activities of PR-TPGS-HCPT were studied by in vitro and in vivo experiments, and the experiment results proved that the TPGS could effectively assist the drug to treat cancer and prolong the lifetime of the tumor-bearing mice. Therefore, this research provides a promising drug-loaded material for the cancer treatment and the specific water-soluble PRs will have potential applications in the biomedical field.

The very low aqueous solubility of celecoxib (CCB) hampers its ocular bioavailability. Thus, the aim of this study was to develop topical eye drop formulations containing cyclodextrin (CD) and a biocompatible polymer in an aqueous microsuspension. Aqueous CCB eye drop formulations containing biocompatible carbohydrate nano- and microparticles were prepared and their physicochemical and mucoadhesive properties evaluated. In vitro and ex-vivo permeation studies were performed as well as retinal cell viability tests. The appearance of the eye drop formulations and their pH, osmolality and viscosity were within acceptable range. The formulations containing hyaluronic acid (HA), a natural polysaccharide found in the eye, displayed excellent mucoadhesive properties. An increasing CCB content of the eye drops, obtained by heating method (sonication at the temperature of 70 °C for 1 h) to form ternary CCB/CD/polymer complex, resulted in higher drug permeation through a semipermeable membrane, simulated artificial vitreous humor and scleral tissues, especially from the formulation containing randomly methylated βCD and HA (0.5% w/v). The CCB eye drops demonstrated no cytotoxicity in a human retina cell line., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In this study, the polymer-free electrospinning was performed in order to produce cyclodextrin/ibuprofen inclusion complex nanofibers, which could have potential as the fast dissolving oral drug delivery system. Ibuprofen is a poorly water-soluble nonsteroidal anti-inflammatory drug; however, the water solubility of ibuprofen can be significantly enhanced by inclusion complexation with cyclodextrins. Here, hydroxypropyl-beta-cyclodextrin (HPβCyD) was chosen both as a nanofiber matrix and host molecule for inclusion complexation in order to enhance water solubility and fast dissolution of ibuprofen. Ibuprofen was inclusion-complexed with HPβCyD in highly concentrated aqueous solutions of HPβCyD (200%, w/v) having two different molar ratios: 1:1 and 2:1 (HPβCyD/ibuprofen). The HPβCyD/ibuprofen-IC (1:1) aqueous solution was turbid having some undissolved/uncomplexed ibuprofen, whereas HPβCyD/ibuprofen-IC (2:1) aqueous solution was homogeneous and clear, indicating that ibuprofen was totally complexed with HPβCyD and becomes water soluble. Then, both HPβCyD/ibuprofen-IC solutions (1:1 and 2:1) were electrospun into bead-free and uniform nanofibers having ∼200 nm fiber diameter. The electrospun HPβCyD/ibuprofen-IC nanofibers were obtained as nanofibrous webs having self-standing and flexible character, which is appropriate for fast dissolving oral drug delivery systems. Ibuprofen was completely preserved during the electrospinning process, and the resulting electrospun HPβCyD/ibuprofen-IC nanofibers were produced without any loss of ibuprofen by preserving the initial molar ratio of 1:1 and 2:1 (HPβCyD/ibuprofen). X-ray diffraction and differential scanning calorimetry measurements indicated the presence of some crystalline ibuprofen in HPβCyD/ibuprofen-IC (1:1) nanofibers, whereas ibuprofen was totally in the amorphous state in HPβCyD/ibuprofen-IC (2:1) nanofibers. Nonetheless, both HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibrous webs have shown very fast dissolving character when contacted with water or when wetted with artificial saliva. In brief, our results revealed that electrospun HPβCyD/ibuprofen-IC nanofibrous webs have potential as fast dissolving oral drug delivery systems.

Ocular drug delivery has been a well-known route for the drug administration for the treatment of ocular diseases. However, numerous anatomical and physiological barriers prevailing in the eye itself create considerable challenges for achieving the necessitated therapeutic efficacy along with ocular bioavailability. However, recent advances in nanoengineered strategies hold definite promises in terms of devising improved ophthalmic medicines for the effective drug delivery to target the sites with enhanced ocular bioavailability. Curcumin, a hydrophobic polyphenol yellow colored compound, and its metabolic reduced product, tetrahydrocurcumin (THC), have been known for their beneficial pharmacological functions, such as anti-inflammatory or anti-oxidant activities at various tissue sites. However, the low aqueous solubility of these compounds results in their poor bioavailability, thereby limiting their widespread application. Therefore, in the present study, we investigated the changes in drug solubility by forming inclusion complexes with different derivatives of hydroxypropyl (HP)-cyclodextrins (CD). To this end, the spray drying technique was used for nanoengineering curcumin or THC-loaded formulations to improve the stability of formulations during the storage. The formulations were characterized in terms of physicochemical properties and cellular permeability. The results demonstrated that the encapsulation of curcumin (or THC) into the HP-CDs significantly increased the drug solubility and enhanced the corneal and retinal epithelial permeability. Curcumin or THC complexes in HP-CDs with improved bioavailability also induced anti-oxidant activity (SOD1, CAT1, and HMOX1) in higher levels in the ocular epithelial cells and showed oxidative protection effects in rabbit cornea tissues that will boost up their application in ocular medicine.

The rapid synthesis of nanoscale cyclodextrin metal-organic frameworks (CD-MOFs) was successfully achieved using a simple, environmentally friendly process, which involved seed-mediated crystallization combined with sonication. Short-chain starch nanoparticles isolated from debranched starch were used as seeds to promote the assembly of CD molecules on their surfaces. This process led to the formation of small uniform crystals by increasing orderliness and reducing aggregation. The influence of sonication time on the morphology and dimensions of CD-MOF crystals was investigated. CD-MOFs with a range of mean particle diameters (234-894 nm) could be produced by adjusting the sonication time. Compared to conventional methods, sonication offered a simple and effective means to obtain a high yield and thermal stability of the CD-MOF crystals. Glycyrrhizic acid (GA), a natural triterpene glycoside, is recognized for its potentially beneficial biological activities, such as antibacterial and anti-inflammatory properties. However, it's extremely low water-solubility and loading efficiency currently restrict its application. Fourier transformation infrared (FTIR) analysis provided information about the interactions between GA and CD-MOFs. Analysis of their encapsulation properties showed the potential of the CD-MOF crystals as effective nanocarriers for hydrophobic bioactive agents, such as drugs, vitamins, or nutraceuticals., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Polymers that are refillable and sustain local release will have a great impact in both preventing and treating local cancer recurrence as well as addressing non-resectable diseases. Polymerized cyclodextrin (pCD) disks, which reload drugs into molecular "pockets" in vivo through affinity interactions, have been previously shown to localize doxorubicin (Dox) to treat glioblastoma multiforme. However, one concern is whether drug refilling is influenced by competition from local biomolecules. In addition the impact of the polymer form on drug refilling is unknown. Herein, different pCD formulations were synthesized from γ-cyclodextrin (γ-CD) and were compared in vitro using competitive drug filling/refilling assays. Data reveal that affinity-based drug refilling occurs as a function of both the polymer form and the sustained release polymeric liquid (SRPL) dilution factor, pointing to the surface/volume ratio, as well as the CD pocket density, and the effects of the distance between pocket. In vitro refilling experiments with cholesterol demonstrated no interference with Dox filling of the CD polymer, while the presence of albumin only slightly reduced Dox filling of pCD-γ-MP (microparticle) and pCD-γ-SRPL forms, but not pCD-γ-disks. Moreover, whole serum competition did not inhibit filling or refilling of pCD-γ-MP with Dox at multiple concentrations and filling times, which indicates that this polymer (re)filling is primarily driven by affinity-based interactions that can overcome the physiological conditions which may limit other drug delivery approaches. This was supplemented by isolating variables through docking simulations and affinity measurements. These results attest to the efficiency of in vivo or in situ polymer filling/refilling in the presence of competitive biological molecules achieved partially through high affinity drug to polymer interactions.

Nowadays, active targeting of nanotherapeutics is a challenging issue. Here, we propose a rational design of a ternary nanoassembly (SAP) composed of nonionic amphiphilic β-cyclodextrins (amphiphilic CD) incorporating pheophorbide (Pheo) as a phototherapeutic and an adamantanyl-folic acid conjugate (Ada-FA) to target tumor cells overexpressing α-folate receptor (FR-α(+)). Dynamic light scattering and ζ-potential pointed out the presence of nanoassemblies bearing a negative surface charge (ζ = -51 mV). Morphology of SAP was investigated by atomic force microscopy and microphotoluminescence, indicating the presence of highly emissive near-spherical assemblies of about 280 nm in size. Complementary spectroscopic techniques such as ROESY-NMR, UV/vis and steady-state fluorescence revealed that the folic acid protrudes out of amphiphilic CD rims, prone for recognition with FR-α. Pheo was strongly loaded in the nanoassembly mostly in monomeric form, thus generating singlet oxygen ( 1 O 2 ) and consequentely showing phototherapeutic action. SAP remained stable until 2 weeks in aqueous solutions. Stability studies in biologically relevant media pointed out the ability of SAP to interact with serum proteins by means of the oligoethylenglycole fringe, without destabilization. Release experiments demonstrated the sustained release of Pheo from SAP in environments mimiking physiological conditions (∼20% within 1 week), plausibly suggesting low Pheo leaking and high integrity of the assembly within 24 h, time spent on average to reach the target sites. Cellular uptake of SAP was confirmed by confocal microscopy, pointing out that SAP was internalized into the tumoral cells expressing FR-α more efficiently than SP. SAP showed improved phototoxicity in human breast MCF-7 cancer cells FR-α(+) (IC 50 = 270 nM) with respect to human prostate carcinoma PC3 cells (IC 50 = 700 nM) that express a low level of that receptor (FR-α(-)). Finally, an improved phototoxicity in FR-α(+) MCF-7 cells (IC 50 = 270 nM) was assessed after treatment with SAP vs SP (IC 50 = 600 nM) which was designed without Ada-FA as a targeting unit.

Surgical sutures are vulnerable to bacterial infections and biofilm formation. At the suture site, pain and undesirable, excess inflammation are additionally detrimental to wound healing. The development of a polymerized cyclodextrin (pCD) coated surgical suture introduces the capability to locally deliver both anti-inflammatory and anti-microbial drugs throughout the phases of acute and chronic healing. Local delivery allows for the improvement of wound healing while reducing related systemic side effects and drug resistance. Through testing, it has been shown that the fabrication of our pCD coating minimally affects the suture's mechanical properties. In vitro studies show measurable and consistent drug delivery for nearly 5 weeks. The therapeutic level of this delivery is sufficient to show inhibition of bacterial growth for 4 weeks, and free-radical scavenging (an in vitro anti-inflammatory activity approximation) for 2 weeks. With this pCD coating technique, we maintain clinical performance standards while also introducing a long-term dual delivery system relevant to the wound healing timeframe. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019., (© 2019 Wiley Periodicals, Inc.)

Most of the drug molecules are partially insoluble in aqueous solution and then may accumulate in fat tissues hampering efficient therapy. Innovative drug delivery strategies have emerged in industry or academia over the last decades, however preserving the activity of the encapsulated drug, having high drug loading capacity and controlling drug release kinetics, are still challenging. In this context, we explored the preparation of new nanocarriers, namely nanocapsules, via a templating method, and using polysaccharides exhibiting biological functions. Cationic poly(cyclodextrin) (P(CD + )) and alginate (alg - ) were initially self-assembled layer-by-layer on colloidal gold nanoparticles. Removal of gold nanoparticles was then induced thorough cyanide-assisted hydrolysis, enabling the recovery of nanocapsules. A hydrophobic drug known to allow the mutation of genes inside cells, namely 4-hydroxy-tamoxifen, was loaded within the nanocapsules' shell via inclusion with the cyclodextrin cavities. The so-designed nanomaterials were incubated with immortalized podocytes to investigate i) their incorporation inside cells and ii) their efficiency for in vitro 4-hydroxy-tamoxifen-induced CreERT2 recombination. This work undoubtedly highlights a proof-of-concept for drug delivery using polysaccharides-based capsules with host properties., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A magnetic-pH dual responsive drug delivery system was prepared for antibacterial therapy to reduce the side effects on nonpathological cells or tissues. Iron oxide (Fe 3 O 4 ) core was surface-functionalized with silane coupling agents to link β‑cyclodextrin (β-CD) (CDMNP), and a polypseudorotaxanes shell where polyethyleneglycol chains threaded much CD molecules was further prepared on the magnetic Fe 3 O 4 core (CDMNP-PEG-CD) to enhance loading capacity of roxithromycin (ROX). CDMNP-PEG-CD with a hydrodynamic diameter of ~168 nm was cytocompatible, superparamagnetic, magnetic-responsive and stable for 180 min of storage. No significant interaction with serum albumin was shown for the nanocomposites. The in vitro release from ROX-loaded CDMNP-PEG-CD nanocomposites was about 76% of total drug within 30 min at pH 1.0, 1.6-fold of that at pH 7.4 and 2-fold of that at pH 8.0, presenting pH-responsive drug release behaviors. The nanocomposites showed positive antibacterial activity against both E. coli and S. aureus based on an agar diffusion method. The antibacterial activity of the nanocomposites was more sensitive against E. coli than S. aureus, and the inhibition halo against E. coli was 85% more than that of Fe 3 O 4 . CDMNP-PEG-CD nanocomposites allowed for the localization and fast concentration of hydrophobic drugs, providing a broad potential range of therapeutic applications., (Copyright © 2019. Published by Elsevier B.V.)

Gene therapy, with an important role in biomedicine, often requires vectors for gene condensation in order to avoid degradation, improve membrane permeation, and achieve targeted delivery. Macrocyclic molecules are a family of artificial receptors that can selectively bind a variety of guest species. Amphiphilic macrocycles, particularly those bearing cationic charges and their various assemblies represent a new class of promising non-viral vectors with intrinsic advantages in gene condensation and delivery. The most prominent examples include amphiphilic cyclodextrins, calixarenes and pillararenes. Herein, we systemically reviewed reported assemblies of amphiphilic macrocycles for gene delivery and therapy. The advantages and disadvantages of each type of macrocyclic amphiphiles for gene delivery, as well as the perspectives on the future development of this area are discussed., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Introduction: In recent years, new drug delivery systems have attempted to overcome the undesirable pharmacokinetic problems of various drugs. Among them, cyclodextrin nanosponges (CDNSs) attract great attention from researchers for solving major bioavailability problems such as inadequate solubility, poor dissolution rate, and the limited stability of some agents, as well as increasing their effectiveness and decreasing unwanted side effects. This novel system can also be prepared as different dosage forms., Areas Covered: This review will give an insight into the effects of CDNSs on the pharmacokinetic parameters and permeability of active agents. Different classes of drugs delivered by this system are mentioned and we designate which CD is used most widely in their production process. We also inform why this carrier can be introduced as a versatile carrying system in pharmaceutical fields. Registered patents about this novel system in various fields are also mentioned., Expert Opinion: The readers will be informed on CDNSs as a novel carrier especially for the delivery of drugs. Versatile characteristics and applications of them can also be known by this review. Finally, CDNSs may be introduced as a remarkable vehicle in the pharmaceutical market in coming years.

Cyclodextrins (CDs) are oligosaccharides that self-assemble in aqueous solutions to form transient clusters, nanoparticles and small microparticles. The critical aggregation concentration (cac) of the natural αCD, βCD and γCD in pure aqueous solutions was estimated to be 25, 8 and 9 mg/ml, respectively. The cac of 2-hydroxypropyl-β-cyclodextrin (HPβCD), that consists of mixture of isomers, was estimated to be significantly higher or 118 mg/ml. Addition of chaotropic agents (i.e. that disrupts non-covalent bonds such as hydrogen bonds) to the aqueous media increases the cac. Formation of drug/CD complexes can increase or decrease the cac. Due to the transient nature of the CD clusters and nanoparticles they can be difficult to detect and their presence is frequently ignored. However, they have profound effect on the physiochemical properties of CDs and their pharmaceutical applications. For example, the values of stability constants of drug/CD complexes can be both concentration dependent and method dependent. Like in the case of micelles water-soluble polymers can enhance the solubilizing effect of CDs. Also, formation of drug/CD complex nanoparticles appears to increase the ability of CDs to enhance drug delivery through some mucosal membranes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Fibrosis and dysphagic stricture of the esophagus is a major unaddressed problem often accompanying endoscopic removal of esophageal cancers and precancerous lesions. While weekly injections of antiproliferative agents show potential for improved healing, repeated injections are unlikely clinically and may alternatively be replaced by creating an esophageal drug delivery system. Affinity-based polymers have previously shown success for continuous delivery of small molecules for weeks to months. Herein, we explored the potential of an affinity-based microparticle to provide long-term release of an antiproliferative drug, sirolimus. In molecular docking simulations and surface plasmon resonance experiments, sirolimus was found to have suitable affinity for beta-cyclodextrin, while dextran, as a low affinity control, was validated. Polymerized beta-cyclodextrin microparticles exhibited 30 consecutive days of delivery of sirolimus during in vitro release studies. In total, the polymerized beta-cyclodextrin microparticles released 36.9 mg of sirolimus per milligram of polymer after one month of incubation in vitro. Taking daily drug release aliquots and applying them to PT-K75 porcine mucosal fibroblasts, we observed that cyclodextrin microparticle delivery preserved bioactivity of sirolimus inhibiting proliferation by 27-67% and migration of fibroblasts by 28-100% of buffer treated controls in vitro. Testing for esophageal injection site losses, no significant loss was incurred under simulated saliva flow for 10 min, and 16.7% of fluorescently labeled polymerized cyclodextrin microparticle signal was retained at 28 days after submucosal injection in esophageal tissue ex vivo versus only 4% of the initial amount remaining for free dye molecules injected alone. By combining affinity-based drug delivery for continuous long-term release with a microparticle platform that is injectable yet remains localized in tissue interstitium, this combination platform demonstrates promise for preventing esophageal fibrosis and stricture.

Cyclodextrins, one of safe excipients, are able to form host-guest complexes with fitted molecules given the unique nature imparted by their structure in result of a number of pharmaceutical applications. On the other hand, targeted or responsive materials are appealing therapeutic platforms for the development of next-generation precision medications. Meanwhile, cyclodextrin-based polymers or assemblies can condense DNA and RNA in result to be used as genetic therapeutic agents. Armed with a better understanding of various pharmaceutical mechanisms, especially for cancer treatment, researchers have made lots of works about cyclodextrin-based drug delivery systems in materials chemistry and pharmaceutical science. This Review highlights recent advances in cyclodextrin-based delivery systems for cancer treatment capable of targeting or responding to the physiological environment. Key design principles, challenges and future directions, including clinical translation, of cyclodextrin-based delivery systems are also discussed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hydrogel biomaterials are pervasive in biomedical use. Applications of these soft materials range from contact lenses to drug depots to scaffolds for transplanted cells. A subset of hydrogels is prepared from physical cross-linking mediated by host-guest interactions. Host macrocycles, the most recognizable supramolecular motif, facilitate complex formation with an array of guests by inclusion in their portal. Commonly, an appended macrocycle forms a complex with appended guests on another polymer chain. The formation of poly(pseudo)rotaxanes is also demonstrated, wherein macrocycles are threaded by a polymer chain to give rise to physical cross-linking by secondary non-covalent interactions or polymer jamming. Host-guest supramolecular hydrogels lend themselves to a variety of applications resulting from their dynamic properties that arise from non-covalent supramolecular interactions, as well as engineered responsiveness to external stimuli. These are thus an exciting new class of materials., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The objective of the article is to provide a comprehensive review on the application of cyclodextrin complexation in the delivery of drugs, bioactive molecules or macromolecules, with more emphasis on targeted drug delivery. Classically the cyclodextrins have been considered only as a means of improving the solubility of drugs; however, many attempts have been made to use cyclodextrins as drug delivery carriers. The cyclodextrin surface can be modified with various ligands for active targeting of drugs. It can also be passively targeted through various triggering mechanisms like thermal, magnetic, pH dependent, light dependent, ultrasound, etc. A comprehensive literature review has been done in the area of drug delivery using cyclodextrins. Applications of inclusion complexes in the drug delivery through various routes with examples are discussed. This review focuses on receptor mediated active targeting as well as stimuli responsive passive targeting of drugs/genes by using cyclodextrins. The article provides a detailed insight of the use of cyclodextrins and their derivatives on the targeted delivery of the drugs/genes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Patients diagnosed with osteosarcoma are currently treated with intravenous injections of anticancer agents after tumor resection. However, due to remaining neoplastic cells at the site of tumor removal, cancer recurrence often occurs. Successful bone regeneration combined with the control of residual cancer cells presents a challenge for tissue engineering. Cyclodextrins loaded with chemotherapeutic drugs reversibly release the drugs over time. Hydroxyapatite bone biomaterials coated with doxorubicin-loaded cyclodextrin should release the drug with time after implantation directly at the original tumor site and may be a way to eliminate residual neoplastic cells. In the present study, we have carried out in vitro studies to evaluate such a drug-delivery system and have shown that doxorubicin released from cyclodextrin-coated hydroxyapatite retained biological activity and exhibited longer and higher cytotoxic effects on both cancer (osteosarcoma cells) and healthy cells (primary osteoblasts and endothelial cells) compared to biomaterials without cyclodextrin loaded with doxorubicin. Furthermore, doxorubicin released from biomaterials with cyclodextrin moderately induced the expression of tumor suppressor protein p53 whereas p21 expression was similar to control cells. In addition, hypoxic conditions, which occur after implantation until blood-flow to the area is regenerated, protected endothelial cells and primary osteoblasts from doxorubicin-induced cytotoxicity. This chemo-protective effect was far less prominent for the osteosarcoma cells. These findings indicate that a hydroxyapatite-cyclodextrin-doxorubicin chemotherapeutic strategy may enhance the drug-targeting effect on tumor cells while protecting the more sensitive healthy cells for a period of time after implantation. A successful integration of such a drug delivery system might allow healthy cells to initially survive during the doxorubicin exposure period, while eliminating residual neoplastic cells., (Copyright © 2018 Elsevier B.V. All rights reserved.)

With the development of materials science and pharmaceutics, the application of mesoporous silica nanoparticles with a gated switch in the field of drug delivery has attracted much attention in the past decades. Cyclodextrins (CD) as promising gated materials have become a new area of interest in recent years due to their properties of self-assembly and function of host-guest interaction. CD is one kind of extensively studied host molecules and the host-guest interactions with different guest molecules can respond to different signals, and thus can be applied as intelligent gated switches for smart drug carriers. Switchable gatekeepers based on CD hosts with different guest molecules (such as benzimidazole, azobenzene, and ferrocene) respond to different stimuli modes (such as pH, light, and redox) that change the host-guest interactions and trigger drug release. The different structural features, mechanisms of action, and potent applications of these switchable gatekeepers are discussed. In addition, some personal perspectives and challenge on this field are presented.