Nutraceutical Concepts and Dextrin‐Based Delivery Systems

Nutraceuticals are bioactive or chemical compounds acclaimed for their valuable biological activities and health-promoting effects. The global community is faced with many health concerns such as cancers, cardiovascular and neurodegenerative diseases, diabetes, arthritis, osteoporosis, etc. The effect of nutraceuticals is similar to pharmaceuticals, even though the term nutraceutical has no regulatory definition. The usage of nutraceuticals, to prevent and treat the aforementioned diseases, is limited by several features such as poor water solubility, low bioavailability, low stability, low permeability, low efficacy, etc. These downsides can be overcome by the application of the field of nanotechnology manipulating the properties and structures of materials at the nanometer scale. In this review, the linear and cyclic dextrin, formed during the enzymatic degradation of starch, are highlighted as highly promising nanomaterials- based drug delivery systems. The modified cyclic dextrin, cyclodextrin (CD)-based nanosponges (NSs), are well-known delivery systems of several nutraceuticals such as quercetin, curcumin, resveratrol, thyme essential oil, melatonin, and appear as a more advanced drug delivery system than modified linear dextrin. CD-based NSs prolong and control the nutraceuticals release, and display higher biocompatibility, stability, and solubility of poorly water-soluble nutraceuticals than the CD-inclusion complexes, or uncomplexed nutraceuticals. In addition, the well-explored CD-based NSs pathways, as drug delivery systems, are described. Although important progress is made in drug delivery, all the findings will serve as a source for the use of CD-based nanosystems for nutraceutical delivery. To sum up, our review introduces the extensive literature about the nutraceutical concepts, synthesis, characterization, and applications of the CD-based nano delivery systems that will further contribute to the nutraceutical delivery with more potent nanosystems based on linear dextrins

Cyclodextrin inclusion complexes with caffeoylquinic acids as bioactive compounds

Neochlorogenic acid, a less-studied caffeoylquinic acid, isomer of chlorogenic acid, has been seen to possess antioxidant, antifungal, anti-inflammatory and anticarcinogenic effects, which makes it an interesting bioactive compound for incorporation in drugs, nutraceuticals or functional foods. However, its poor solubility in water and susceptibility to oxidation make such a task difficult. To overcome that, its encapsulation in cyclodextrins (CDs) is proposed. The fluorescence of neochlorogenic acid in different pH conditions was analyzed, and caffeic acid was proved to be the fluorescent moiety in the molecule. An encapsulation model whereby the ligand poses two potential complexation sites (caffeic and D-(-)-quinic moieties), showed that α-CD and HP-β-CD formed the best inclusion complexes with neochlorogenic acid, followed by M-β-CD, β-CD and γ-CD. Molecular docking with the two best CDs gave better scores for α-CD, despite HP-β-CD providing stabilization through H-bonds. The encapsulation of chlorogenic acid led to a similar CD order and scores, although constants were higher for α-CD, β-CD and M-β-CD, lower for HP-β-CD, and negligible for γ-CD. The solubility and the susceptibility to oxidation of neochlorogenic acid improved after complexation with α-CD and HP-β-CD, while the antioxidant activity of both isomers was maintained. These results could lead to obtaining more stable inclusion complexes with caffeoylquinic acids for applications in the pharmaceutical industry

Dextrin-Based Nanohydrogels for Rokitamycin Prolonged Topical Delivery

Macrolides are widely used antibiotics with a broad spectrum of activity. The development of drug carriers to deliver this type of antibiotics has attracted much research. The present study aims at developing new swellable dextrin-based nanohydrogels for the topical delivery of rokitamycin, as model macrolide. Rokitamycin is a synthetic analogous of macrolides with advantageous characteristics as far as bacterial uptake and post-antibiotic effect are concerned. It is also indicated for the treatment of severe infections caused by Acanthamoeba and for topical infections. The nanohydrogels have been prepared from two types of cross-linked polymers obtained by using β-cyclodextrin or Linecaps(®) was provided by the Roquette Italia SPA (Cassano Spinola, Al, Italy) as building blocks. The cross-linked polymers have been then formulated into aqueous nanosuspensions refined and tuned to achieve the incorporation of the drug. Cross-linked β-cyclodextrin (β-CD) and Linecaps(®) (LC) polymers formed dextrin-based nanohydrogels with high swelling degree and mucoadhesion capability. Rokitamycin was loaded into the nanohydrogels displaying an average size around 200 nm with negative surface charge. In vitro kinetic profiles of free and loaded drug in nanohydrogels were compared at two pH levels. Interestingly, a sustained and controlled release was obtained at skin pH level due to the high degree of swelling and a pH responsiveness possibly. The results collected suggest that these nanohydrogels are promising for the delivery of rokitamycin and may pave the way for the topical delivery of other macrolide antibiotics

Intratumoural Delivery of mRNA Loaded on a Cationic Hyper-Branched Cyclodextrin-Based Polymer Induced an Anti-Tumour Immunological Response in Melanoma

Funding text 1 This work is the result of a contract for the University of Turin (Italy) for Training (For Y.K.M.) and for A.M. and a RTDA contract from the D.M 1062/2021 (Ministero dell’Università e della Ricerca) for the University of Turin. This research acknowledges support from the Project CH4.0 under the MIUR program “Dipartimenti di Eccellenza 2023–2027”. J.C. acknowledges that they have a contract with the European Research Council—ERC Starting Grant 848325 for financial support. Funding text 2 This research was partially funded by The Italian Ministry of Enterprises and Made in Italy (project acronym CN-RNA) under the PNRR among the initiatives aimed towards creating an integrated system of research and innovation infrastructures (PNRR M4C2 PROJECTS).mRNA technology has demonstrated potential for use as an effective cancer immunotherapy. However, inefficient in vivo mRNA delivery and the requirements for immune co-stimulation present major hurdles to achieving anti-tumour therapeutic efficacy. Therefore, we used a cationic hyper-branched cyclodextrin-based polymer to increase mRNA delivery in both in vitro and in vivo melanoma cancer. We found that the transfection efficacy of the mRNA-EGFP-loaded Ppoly system was significantly higher than that of lipofectamine and free mRNA in both 2D and 3D melanoma cancer cells; also, this delivery system did not show cytotoxicity. In addition, the biodistribution results revealed time-dependent and significantly higher mEGFP expression in complexes with Ppoly compared to free mRNA. We then checked the anti-tumour effect of intratumourally injected free mRNA-OVA, a foreign antigen, and loaded Ppoly; the results showed a considerable decrease in both tumour size and weight in the group treated with OVA-mRNA in loaded Ppoly compared to other formulations with an efficient adaptive immune response by dramatically increasing most leukocyte subtypes and OVA-specific CD8+ T cells in both the spleen and tumour tissues. Collectively, our findings suggest that the local delivery of cationic cyclodextrin-based polymer complexes containing foreign mRNA antigens might be a good and reliable concept for cancer immunotherapy.publishersversionpublishe

Time course study of oxyresveratrol inclusion complexes in aqueous solutions

The stilbenes are bioactive molecules with a big amount of health benefits and many possibilities in pharmaceutical industry. Several authors have reported a high number of properties for these compounds, including anticancer, antioxidant, anti-inflammatory, antidiabetic, neuroprotective or antimicrobial activities. However, their low aqueous solubility and their ease degradation could lead to low concentration of bioactive compound in the target tissue. For this reason, in the present study, the inclusion complexes of oxyresveratrol with α-, β-, and γ- cyclodextrins are characterized using DSC, TGA, SEM and molecular docking in order to increase the stability of the molecule. All these techniques showed that β-cyclodextrin (β-CD) forms the best complexes. The stability of oxyresveratrol and oxyresveratrol/ β-CD complexes in different aqueous solutions was evaluated by measuring oBrix, pH and UV-Vis spectra. The effect of encapsulation on the solubility and antioxidant activity of oxyresveratrol was also analysed. The results indicated that solutions were stable for at least five weeks, especially when stored in darkness, and that cyclodextrin supplementation leads to a higher concentration and antioxidant capacity of the solubilized bioactive compound than when it is not used. These results and the increase in antioxidant activity could be interesting for the pharmaceutical industry and for drugs enriched in oxyresveratrol

Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery

In recent years, the development of various cyclodextrin (CD)-based nanosponges (NSs) has gained great importance in the controlled and-or targeted release of drugs due to their versatility and simple preparation. In this chapter, an introduction of different administration routes is explained. Further, different ways to obtain CD-NSs and their classification are shown with a brief explanation of the characterization of the inclusion complexes. Finally, illustrative examples in diverse processes or diseases will be reviewed and explained to demonstrate the potential of CD-NSs. Therefore, this division will serve to compile information on CD-NSs in recent years and to illustrate to readers how to generate and apply different derivatives of interest

Molecular complexation of several bioactive compounds with cyclodextrins : In vitro and in vivo applications

Introducción El desarrollo de nuevos productos está en auge. La sociedad cada día demanda nuevas cualidades y la industria intenta satisfacer esta demanda con el estudio y adicción de nuevas sustancias bioactivas. No obstante, muchas de estas sustancias necesitan ser añadidas con una molécula matriz que mejore sus propiedades. En este punto, unas moléculas conocidas como ciclodextrinas (CDs) adquirieron hace unos años un protagonismo que a día de hoy aun mantienen. Debido a su interior hidrofóbico y exterior hidrofílico, presentan la propiedad de incluir una amplia variedad de moléculas orgánicas e inorgánicas, comúnmente denominadas moléculas huésped (complejo de inclusión), aumentando así la solubilidad aparente de distintas moléculas hidrofóbicas y parcialmente hidrofóbicas; de esta propiedad, se derivan muchas otras propiedades secundarias. Por ello, es intención de esta tesis doctoral mostrar su potencial in vitro e in vivo en diversas aplicaciones. Objetivos 1. Demostrar el potencial de las ciclodextrinas en distintos campos, para ello se dividará el trabajo en 3 grandes bloques: a. Bloque 1: caracterización de diversos complejos de inclusión de inclusión con ciclodextrinas comerciales. b. Bloque 2: Estudiar distintas aplicaciones de las ciclodextrinas en química analítica, industria alimentaria y farmacológica. c. Bloque 3: Estudiar la síntesis, caracterización y aplicación del polímero denominado nanoesponja de ciclodextrinas. Metodología Para el bloque 1, distintas técnicas de cómo HPLC, fluorescencia, RMN, DSC o modelado molecular fueron usadas para caracerizar los complejos. Para el bloque 2, metodologías de digestión in vitro, extracción de compuestos o el uso de modelos de alimentos fueron puestos a punto y utilizados. Para el bloque 3, se sintetizaron los polímeros y se caracterizaron los complejos de inclusión mediante técnicas del apartado 1. Se utilizó en nematodo Caenorhabditis elegans para estudiar el efecto sobre la extensión de la vida media de compuestos bioactivos encapsulados. Conclusiones En el bloque 1, hemos visto el potencial para encapsular distintos compuestos bioactivos con ciclodextrinas. En el bloque 2, vimos como efectivamente las ciclodextrinas pudieron separar isómeros (química analítica), estabilizar compuestos alimentarios (industria alimentaria) o usarse en enfermedades raras (farmacología). En el bloque 3, pudimos ver como el polímero ofrece una liberación suave del compuesto bioactivo por su características poliméricas así como su efecto en la vida media de C.elegans. En definitiva, esta tesis en su conjunto representa un importante avance en el conocimiento relacionado con ciclodextrinas en distintos campos: nuevos métodos de separación de moléculas, de estabilización de alimentos y fármacos… Además, establece nuevas metodologías para trabajar con ellas en distintos campos como química analítica, ciencia alimentaria y farmacéutica.Introduction The development of new products is booming. The society every day demands new product qualities and the industry tries to satisfy this demand with the study and addiction of new bioactive substances. However, many of these substances need to be added with a matrix molecule that improves their properties. At this point, some molecules known as cyclodextrins acquired a prominence a few years ago that they still maintain today. Due to their hydrophobic interior and hydrophilic exterior, they have the property of including a wide variety of organic and inorganic molecules, commonly called host molecules (inclusion complex), thus increasing the apparent solubility of different hydrophobic and partially hydrophobic molecules; from this property, many other secondary properties are derived. Therefore, it is the aim of this Ph.D thesis to show its potential in vitro and in vivo in various applications. Objectives 1. Demonstrate the potential of cyclodextrins in different fields, for this work will be divided into 3 large blocks: a. Block 1: characterization of several inclusion complexes with commercial cyclodextrins. b. Block 2: Study different applications of cyclodextrins in analytical chemistry, food industry and pharmacology. c. Block 3: Study the synthesis, characterization and application of the polymer Cyclodextrin-based Nanosponges. Methodology For block 1, different techniques such as HPLC, fluorescence, NMR, DSC or molecular modeling were used to characterize the complexes. For block 2, methodologies of in vitro digestion, extraction of compounds or the use of food models were developed and used. For block 3, the polymers were synthesized and the inclusion complexes were characterized by techniques of section 1. Caenorhabditis elegans model was used to study the effect on lifespan of encapsulated bioactive compounds. Conclusiones In block 1, we have shown the potential to encapsulate different bioactive compounds with cyclodextrins. In block 2, we saw how cyclodextrins could effectively separate isomers (analytical chemistry), stabilize food compounds (food industry) or to be used in rare diseases (pharmacology). In block 3, we could see how the polymer offers a gentle release of the bioactive compound for its polymeric characteristics as well as its effect on the half-life of C.elegans. In short, this thesis as a whole represents an important advance in the knowledge related to cyclodextrins in different fields: new methods of separation of molecules, stabilization of food and drugs ... In addition, it establishes new methodologies to work with them in different fields such as chemistry analytical, food science and pharmaceutical

Characterization of Resveratrol, Oxyresveratrol, Piceatannol and Roflumilast as Modulators of Phosphodiesterase Activity. Study of Yeast Lifespan

Our desire to live longer has led to an ever-increasing number of novel antiaging products. However, few molecules have any real effect and new ones need to be studied before they can be used commercially. In this contribution, activation of the caloric restriction (CR) pathway was studied using different three (resveratrol, oxyresveratrol and piceatannol)—a family with demonstrated bioactivity on phosphodiesterase activity. The high-affinity phosphodiesterase type 2 (PDE2) of Saccharomyces cerevisiae was expressed in Escherichia coli, purified and characterized. The activity and the inhibitory activity of each stilbene was studied, and the findings were compared in vitro and in silico with those obtained with roflumilast—a human PDE4 inhibitor widely used in chronic obstructive pulmonary diseases. Finally, an in vivo chronological lifespan assay using WT S. cerevisiae and ΔPDE2 S. cerevisiae strains was carried out. It was demonstrated that stilbenes can modulate yPDE2 activity, increasing the lifespan of the yeast by 18% over a control (in combination with other pathways). In addition, roflumilast increased the lifespan in the WT strain. The findings as a whole would increase the range of lifespan products available and suggest novel uses for approved drugs

Developing Novel Hydroxypropyl-β-Cyclodextrin-Based Nanosponges as Carriers for Anticancer Hydrophobic Agents: Overcoming Limitations of Host–Guest Complexes in a Comparative Evaluation

This study aimed to design and fabricate novel hydroxypropyl-β-cyclodextrin-based hypercrosslinked polymers, called nanosponges, as carriers for anticancer hydrophobic agents and compare them with host–guest complexes of hydroxypropyl-β-cyclodextrin, a remarkable solubilizer, to investigate their application in improving the pharmaceutical properties of the flavonoid naringenin, a model hydrophobic nutraceutical with versatile anticancer effects. For this purpose, three new nanosponges, crosslinked with pyromellitic dianhydride, citric acid, and carbonyldiimidazole, were fabricated. The carbonate nanosponge synthesized by carbonyldiimidazole presented the highest naringenin loading capacity (≈19.42%) and exerted significantly higher antiproliferative effects against MCF-7 cancer cells compared to free naringenin. Additionally, this carbonate nanosponge formed a stable nanosuspension, providing several advantages over the naringenin/hydroxypropyl-β-cyclodextrin host–guest complex, including an increase of about 3.62-fold in the loading capacity percentage, sustained released pattern (versus the burst pattern of host–guest complex), and up to an 8.3-fold increase in antiproliferative effects against MCF-7 cancer cells. Both naringenin-loaded carriers were less toxic to L929 murine fibroblast normal cells than MCF-7 cancer cells. These findings suggest that hydroxypropyl-β-cyclodextrin-based carbonate nanosponges could be a good candidate as a drug delivery system with potential applications in cancer treatment