1,721,088 research outputs found
Encapsulation of all-trans-retinoic acid in polymeric micelles
No full textAll-trans-retinoic acid (ATRA) is being increasingly included in antitumor therapeutical schemes for the treatment of various type of tumors; however the difficulty of increasing plasma concentrations of ATRA in vivo hindered, until now, a correct evaluation of its possible pro-apoptotic effect towards both the proliferating and non proliferating neuroblastic cells.
Recent approaches to enhance the solubility of hydrophobic drugs considered polymeric micelles particularly interesting for their efficiency in trapping lipophilic drugs within their internal core, the possibility to provide small and flexible structures able to easily extravasate in the solid tumor and a propensity to evade scavenging by the mononuclear phagocyte system. Our studies focus on micelles prepared from a water soluble polymer, PVA, conjugated with lipid alkyl chains, thus achieving amphiphilicity, such as that of A-B type block co-polymers. The core of the polymer serves as a non-aqueous reservoir, where the drug is entrapped, but also stabilized against chemical modifications by the physiological environment [1].
All-trans-retinoic acid (ATRA) is now included in many anti-tumour therapeutic schemes. Unfortunately its poor aqueous solubility hampers its parenteral formulation. To date, there is no parenteral formulation of ATRA commercially available, while oral administration of ATRA is associated with progressively diminishing ATRA levels in plasma. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects [2]. To this purpose we prepared an amphiphilic polymer by poly-vinylalcohol (PVA) substitution with oleyl amine at 1.5% substitution degree and evaluated its functional properties with regard to ATRA complexation.
EXPERIMENTAL PART
The new amphiphile polymer, PVA-co-oleyl-vinyl carbamate, obtained by PVA partial substitution with oleylamine, contains a carbamate bond, rather than an ester bond, as a spacer between the hydrophilic PVA and the hydrophobic oleyl chains. The polymer thus obtained holds enhanced aqueous solubility in the presence of enhanced substitution degree. The solubilizing ability of the substituted polymer was evaluated towards ATRA in aqueous solutions of the polymer and of drug–polymer mixtures obtained by spray-drying hydro-alcoholic solutions of ATRA and polymer at 1:3, 1:5 and 1:10 drug–polymer weight ratios.
RESULTS AND DISCUSSION
The spray-dried complexes rapidly dissolve in water, providing high levels of ATRA solubilization as a function of the drug–polymer weight ratio. The complexes characterized by 1:5 drug–polymer weight ratio (▲) provided higher levels of ATRA solubilization than 1:3 (▄) and 1:10 (▬) drug–polymer weight ratios respectively. Pre-formed polymeric micelles in water, equilibrated in the presence of excess solid ATRA, provided lower levels of solubilization (●). The drug release from the complexes was very slow in PBS, indicating their suitability in anti-tumour drug targeting, where a fundamental requirement is stability towards drug release for at least 24 h, corresponding to the average circulation time period of macromolecular carriers.
A comparison between the present polymer, containing a polyvinyl backbone linked to oleyl chains by carbamate bonds and a previously studied polymer, based on the same polyvinyl backbone linked to oleyl chains by ester bonds, indicates that the nature of the bond between the main backbone and the oleyl chains strongly influence the physico-chemical characteristics of the final polymer. In the presence of the ester bond the highest polymer aqueous solubility obtained was 30 mg/ml at 37°C at a substitution degree not exceeding 1%. The increase in the substitution degree decreased the polymer solubility.
In the presence of the carbamate bond it was possible to increase both the substitution degree and the aqueous pol..
Oxidative Stress, Antioxidant Capabilities, and Bioavailability: Ellagic Acid or Urolithins?
No full textOxidative stress (OS), triggered by overproduction of reactive oxygen and nitrogen
species, is the main mechanism responsible for several human diseases. The available one-target
drugs often face such illnesses, by softening symptoms without eradicating the cause. Differently,
natural polyphenols from fruits and vegetables possess multi-target abilities for counteracting OS,
thus representing promising therapeutic alternatives and adjuvants. Although in several in vitro
experiments, ellagitannins (ETs), ellagic acid (EA), and its metabolites urolithins (UROs) have
shown similar great potential for the treatment of OS-mediated human diseases, only UROs have
demonstrated in vivo the ability to reach tissues to a greater extent, thus appearing as the main
molecules responsible for beneficial activities. Unfortunately, UROs production depends on individual
metabotypes, and the consequent extreme variability limits their potentiality as novel therapeutics, as
well as dietary assumption of EA, EA-enriched functional foods, and food supplements. This review
focuses on the pathophysiology of OS; on EA and UROs chemical features and on the mechanisms of
their antioxidant activity. A discussion on the clinical applicability of the debated UROs in place of
EA and on the effectiveness of EA-enriched products is also includedOxidative stress (OS), triggered by overproduction of reactive oxygen and nitrogen species, is the main mechanism responsible for several human diseases. The available one‐target drugs often face such illnesses, by softening symptoms without eradicating the cause. Differently, natural polyphenols from fruits and vegetables possess multi‐target abilities for counteracting OS, thus representing promising therapeutic alternatives and adjuvants. Although in several in vitro experiments, ellagitannins (ETs), ellagic acid (EA), and its metabolites urolithins (UROs) have shown similar great potential for the treatment of OS‐mediated human diseases, only UROs have demonstrated in vivo the ability to reach tissues to a greater extent, thus appearing as the main molecules responsible for beneficial activities. Unfortunately, UROs production depends on individual metabotypes, and the consequent extreme variability limits their potentiality as novel therapeutics, as well as dietary assumption of EA, EA‐enriched functional foods, and food supplements. This review focuses on the pathophysiology of OS; on EA and UROs chemical features and on the mechanisms of their antioxidant activity. A discussion on the clinical applicability of the debated UROs in place of EA and on the effectiveness of EA‐enriched products is also included
Nanotechnology application in food packaging: a plethora of opportunities versus pending risks assessment and public concerns
No full textEnvironmental factors, oxidation and microorganisms contamination, are the major causes for food spoilage, which leads
to sensory features alteration, loss of quality, production of harmful chemicals and growth of foodborne pathogens capable
to cause severe illness. Synthetic preservatives, traditional conserving methods and food packaging (FP), although
effective in counteracting food spoilage, do not allow the real-time monitoring of food quality during storage and
transportation and assent a relatively short shelf life. In addition, FP may protect food by the spoilage caused by external
contaminations, but is ineffective against foodborne microorganisms. FP preservative functionalities could be improved
adding edible natural antioxidants and antimicrobials, but such chemicals are easily degradable. Nowadays, thanks to
nanotechnology techniques, it is possible to improve the FP performances, formulating and inserting more stable
antioxidant/antimicrobial ingredients, improving mechanical properties and introducing intelligent functions. The stateof-
the-art in the field of nanomaterial-based improved FP, the advantages that might derive from their extensive
introduction on the market and the main concerns associated to the possible migration and toxicity of nanomaterials,
frequently neglected in existing reviews, have been herein discussed
Development of Phytochemical Delivery Systems by Nano-Suspension and Nano-Emulsion Techniques
No full textThe awareness of the existence of plant bioactive compounds, namely, phytochemicals (PHYs), with health properties is progressively expanding. Therefore, their massive introduction in the normal diet and in food supplements and their use as natural therapeutics to treat several diseases are increasingly emphasized by several sectors. In particular, most PHYs possessing antifungal, antiviral, anti-inflammatory, antibacterial, antiulcer, anti-cholesterol, hypoglycemic, immunomodulatory, and antioxidant properties have been isolated from plants. Additionally, their secondary modification with new functionalities to further improve their intrinsic beneficial effects has been extensively investigated. Unfortunately, although the idea of exploiting PHYs as therapeutics is amazing, its realization is far from simple, and the possibility of employing them as efficient clinically administrable drugs is almost utopic. Most PHYs are insoluble in water, and, especially when introduced orally, they hardly manage to pass through physiological barriers and scarcely reach the site of action in therapeutic concentrations. Their degradation by enzymatic and microbial digestion, as well as their rapid metabolism and excretion, strongly limits their in vivo activity. To overcome these drawbacks, several nanotechnological approaches have been used, and many nanosized PHY-loaded delivery systems have been developed. This paper, by reporting various case studies, reviews the foremost nanosuspension- and nanoemulsion-based techniques developed for formulating the most relevant PHYs into more bioavailable nanoparticles (NPs) that are suitable or promising for clinical application, mainly by oral administration. In addition, the acute and chronic toxic effects due to exposure to NPs reported so far, the possible nanotoxicity that could result from their massive employment, and ongoing actions to improve knowledge in this field are discussed. The state of the art concerning the actual clinical application of both PHYs and the nanotechnologically engineered PHYs is also reviewed
One-Step, Low-Cost, Operator-Friendly, and Scalable Procedure to Synthetize Highly Pure N-(4-ethoxyphenyl)-retinamide in Quantitative Yield without Purification Work-Up
No full textIt is widely reported that N-(4-hydroxyphenyl)-retinamide or fenretinide (4-HPR), which is a synthetic amide of all-trans-retinoic acid (ATRA), inhibits in vitro several types of tumors, including cancer cell lines resistant to ATRA, at 1–10 µM concentrations. Additionally, studies in rats and mice have confirmed the potent anticancer effects of 4-HPR, without evidencing hemolytic toxicity, thus demonstrating its suitability for the development of a new chemo-preventive agent. To this end, the accurate determination of 4-HPR levels in tissues is essential for its pre-clinical training, and for the correct determination of 4-HPR and its metabolites by chromatography, N-(4-ethoxyphenyl)-retinamide (4-EPR) has been suggested as an indispensable internal standard. Unfortunately, only a consultable old patent reports the synthesis of 4-EPR, starting from dangerous and high-cost reagents and using long and tedious purification procedures. To the best of our knowledge, no article existed so far describing the specific synthesis of 4-EPR. Only two vendors worldwide supply 4-ERP, and its characterization was incomplete. Here, a scalable, operator-friendly, and one-step procedure to synthetize highly pure 4-EPR without purification work-up and in quantitative yield is reported. Additionally, a complete characterization of 4-EPR using all possible analytical techniques has been provided
Attempts to Improve Lipophilic Drugs’ Solubility and Bioavailability: A Focus on Fenretinide
No full textThe development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates in early clinical trials with 4-HPR did not confirm the in vitro findings, mainly due to the low bioavailability of the oral capsular formulation that was initially developed. Capsular 4-HPR provided variable and insufficient drug plasma levels attributable to the high hepatic first-pass effect and poor drug water solubility. To improve 4-HPR bioavailability, several approaches have been put forward and tested in preclinical and early-phase clinical trials, demonstrating generally improved plasma levels and minimal systemic toxicities, but also modest antitumor efficacy. The challenge is thus currently still far from being met. To redirect the diminished interest of pharmaceutical companies toward 4-HPR and promote its further clinical development, this manuscript reviewed the attempts made so far by researchers to enhance 4-HPR bioavailability. A comparison of the available data was performed, and future directions were proposed
Ellagic Acid: A Green Multi-Target Weapon That Reduces Oxidative Stress and Inflammation to Prevent and Improve the Condition of Alzheimer’s Disease
No full textOxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer’s disease (AD). AD is a multifactorial chronic neurodegenerative syndrome indicated by a form of progressive dementia associated with aging. While one-target drugs only soften its symptoms while generating drug resistance, multi-target polyphenols from fruits and vegetables, such as ellagitannins (ETs), ellagic acid (EA), and urolithins (UROs), having potent antioxidant and radical scavenging effects capable of counteracting OS, could be new green options to treat human degenerative diseases, thus representing hopeful alternatives and/or adjuvants to one-target drugs to ameliorate AD. Unfortunately, in vivo ETs are not absorbed, while providing mainly ellagic acid (EA), which, due to its trivial water-solubility and first-pass effect, metabolizes in the intestine to yield UROs, or irreversible binding to cellular DNA and proteins, which have very low bioavailability, thus failing as a therapeutic in vivo. Currently, only UROs have confirmed the beneficial effect demonstrated in vitro by reaching tissues to the extent necessary for therapeutic outcomes. Unfortunately, upon the administration of food rich in ETs or ETs and EA, URO formation is affected by extreme interindividual variability that renders them unreliable as novel clinically usable drugs. Significant attention has therefore been paid specifically to multitarget EA, which is incessantly investigated as such or nanotechnologically manipulated to be a potential “lead compound” with protective action toward AD. An overview of the multi-factorial and multi-target aspects that characterize AD and polyphenol activity, respectively, as well as the traditional and/or innovative clinical treatments available to treat AD, constitutes the opening of this work. Upon focus on the pathophysiology of OS and on EA’s chemical features and mechanisms leading to its antioxidant activity, an all-around updated analysis of the current EA-rich foods and EA involvement in the field of AD is provided. The possible clinical usage of EA to treat AD is discussed, reporting results of its applications in vitro, in vivo, and during clinical trials. A critical view of the need for more extensive use of the most rapid diagnostic methods to detect AD from its early symptoms is also included in this work
Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production
No full textThe increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of class A, C, and D, and metal-BLEs (MBLEs) of class B. A current strategy to restore no longer functioning BLAs consists of associating them to β-lactamase enzymes inhibitors (BLEsIs), which, interacting with BLEs, prevent them hydrolyzing to the associated antibiotic. Worryingly, the inhibitors that are clinically approved are very few and inhibit only most of class A and C SBLEs, leaving several class D and all MBLEs of class B untouched. Numerous non-clinically approved new molecules are in development, which have shown broad and ultra-broad spectrum of action, some of them also being active on the New Delhi metal-β-lactamase-1 (NDM-1), which can hydrolyze all available BLAs except for aztreonam. To not duplicate the existing review concerning this topic, we have herein examined BLEsIs by a chemistry approach. To this end, we have reviewed both the long-established synthesis adopted to prepare the old BLEsIs, those proposed to achieve the BLEsIs that are newly approved, and those recently reported to prepare the most relevant molecules yet in development, which have shown high potency, providing for each synthesis the related reaction scheme
Correction: Alfei, S.; Zuccari, G. Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production. Pharmaceuticals 2022, 15, 384
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Last Fifteen Years of Nanotechnology Application with Our Contribute
No full textCurrently, nanotechnology is the most promising science, engineering, and technology conducted at the nanoscale (nm), which is used in several sectors. Collectively, nanotechnology is causing a new industrial revolution, and nano-based products are becoming increasingly important for the global market and economy. The interest in nanomaterials has been strongly augmented during the last two decades, and this fact can be easily evaluated by considering the number of studies present in the literature. In November 2024, they accounted for 764,279 experimental studies developed in the years 2009–2024. During such a period, our group contributed to the field of applicative nanotechnology with several experimental and review articles, which we hope could have relevantly enhanced the knowledge of the scientific community. In this new publication, an exhaustive overview regarding the main types of developed nanomaterials, the characterization techniques, and their applications has been discussed. Particular attention has been paid to nanomaterials employed for the enhancement of bioavailability and delivery of bioactive molecules and to those used for ameliorating traditional food packaging. Then, we briefly reviewed our experimental studies on the development of nanoparticles (NPs), dendrimers, micelles, and liposomes for biomedical applications by collecting inherent details in a reader-friendly table. A brief excursus about our reviews on the topic has also been provided, followed by the stinging question of nanotoxicology. Indeed, although the application of nanotechnology translates into a great improvement in the properties of non-nanosized pristine materials, there may still be a not totally predictable risk for humans, animals, and the environment associated with an extensive application of NPs. Nanotoxicology is a science in rapid expansion, but several sneaky risks are not yet fully disclosed. So, the final part of this study discusses the pending issue related to the possible toxic effects of NPs and their impact on customers’ acceptance in a scenario of limited knowledge
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