9 research outputs found
Sviluppo di acaricidi ecologici per un'apicoltura sostenibile
No full textThe honeybee (Apis mellifera) is widely recognized as one of the most crucial pollinators for maintaining biodiversity. However, in recent decades, honeybee populations have experienced a significant decline, primarily due to Varroa destructor, an ectoparasitic mite capable of causing colony collapse within months if left untreated. In addition to mechanical damage, Varroa acts as a vector for severe viral infections, further exacerbating honeybee losses.
Current control measures, while partially effective, are increasingly limited by the development of resistance and environmental contamination. Among these, soft acaricides-natural compounds such as organic acids (e.g., oxalic acid) and essential oils (e.g., thymol, camphor, eucalyptol, and menthol)-are widely used to counteract this parasite. These substances offer advantages in efficacy and safety, with reduced risks of resistance development and hive product contamination compared to synthetic acaricides. However, a common limitation of soft acaricides is their dependence on frequent applications. Long-lasting formulations capable of sustaining active agent release for up to 21 days -the reproductive cycle of varroa- could address these challenges.
This research focused on the development and evaluation of long lasting innovative formulations for the delivery of oxalic acid and essential oils.
For oxalic acid, hydrophilic polymer-based gels incorporating xanthan gum and micronized silica were designed to ensure chemical stability and controlled release under acidic conditions. Preliminary in vivo evaluation studies showed a reduction on Varroa infestation levels (approximately 60%), with the added benefit of making the application easier. Additionally, silica sol-gel matrices were explored as an alternative delivery platform. These matrices achieved sustained release and demonstrated good in vivo efficacy (~70%), combining ecological safety with practical effectiveness. The results obtained are promising, and further in vivo experiments will need to be carried out.
For thymol, silica sol-gel matrices were evaluated to develop a delivery system capable of releasing the compound over 28 days. Formulation studies identified triacetin as a promising cosolvent, mitigating thymol volatilization, and enabling sustained release under hive-like conditions. Initial in vivo trials demonstrated moderate efficacy, with environmental factors such as temperature variability and colony health identified as key determinants. In vivo studies show a good efficacy (~60%). Comparisons with the commercial product Apiguard® highlighted the advantages of single-application formulations.
Mesoporous silica materials were also investigated for the controlled delivery of volatile compounds, including thymol, menthol, camphor, and eucalyptol. Silica-based carriers, particularly SilSol®, proved highly effective in maintaining thymol release. SilSol® emerged as the optimal carrier due to its cost-effectiveness, regulatory approval, and ability to stabilize thymol in its amorphous form. Field trials of thymol-loaded SilSol® formulations demonstrated efficacy (~75%) comparable to that of Apiguard®, with the added benefits of prolonged release from a single application, reduced volatilization losses, and strong acceptance by bees.
The findings presented in this thesis contribute to the advancement of sustainable apicultural practices by offering innovative pest management solutions that prioritize both efficacy and ecological balance. These developments represent a significant step forward to ensure the health and resilience of honeybee populations
10th International Granulation Workshop
No full textAlthough the wet granulation process can be performed with different equipment, the use of high-shear mixers (HSMs) may offer many advantages. Among these, the most relevant is the possibility of performing all the granulation steps (mixing, wetting, and massing phases) on the same equipment, leading to a reduction in dustiness, risk of cross-contamination, and toxic exposure. However, in general, the drying phase is performed in other equipment to reduce the process time (fluid bed) or the cost (ventilated oven). However, drying can be performed in HSM if the instrument is equipped with a heating jacket and a vacuum pump.
The purpose of this research is to evaluate the effect of the type of drying technique on the properties of granules and tablets. In particular, the two techniques evaluated were drying in a ventilated oven (D-O) or inside the HSG using the heating jacket and vacuum pump (D-J/V). The three formulations selected for this study contain: 40% (w/w) microcrystalline cellulose as granulation aid, 34% (w/w) lactose as diluent, 3% (w/w) polyvinylpyrrolidone K30 as binder, 3% (w/w) sodium starch glycolate as disintegrant and 20% (w/w) of three model molecules as actives (caffeine, paracetamol or citric acid). The actives are characterized by different water solubility and particle size. The study started with a rheological characterization performed using a mixer torque rheometer to identify the amount of water necessary for granulation and to predict the growth mechanism. Granules were produced following a standard procedure and dried in a ventilated oven set at 60°C or inside the HSM using the jacket temperature set at 60°C and a vacuum pressure of 200 mbar. The process was carried out until a LOD of 3% was reached.
As expected, the data highlighted that D-J/V allows for a reduction in drying time ranging from 30 to 45%. The granules were then characterized by sieve analysis (PSD), content uniformity, flowability, tensile strength, and compression studies. The results showed that the granules obtained by D-J/V are generally smaller, with a higher yield and a lower crushing strength. As regards the granule structure, the data and SEM imagines show that the effect of the drying type depends on the solubility of the active; in fact, if the active is very soluble in water, faster migration and crystallization of the active can occur on the granule surface. Granules with a particle size <500 m were then compressed using different compression forces and tablets with a tensile strength of approximately 1 MPa were then characterized by mass and content uniformity tests, disintegration and dissolution tests. Results showed that compressibility, tabletability, and compactability of the granules were improved using D-J/V when the active was sparingly soluble in water, but the disintegration and dissolution performances were not modified. On the contrary, when a highly soluble active is present, D-O allows for an increase of compression properties owing to the crystals present on the surface, but it produces a drastic worsening of disintegration and dissolution performances
Semisolid Wet Sol–Gel Silica/Hydroxypropyl Methyl Cellulose Formulation for Slow Release of Serpin B3 Promotes Wound Healing In Vivo
No full textFoot ulcerations are a disabling complication of diabetes and no treatment is currently available based on disease mechanisms. The protein serpin B3 (SB3) was identified as a positive biomarker of successful diabetic wound healing; therefore, its exogenous administration may promote healing. The topical administration of SB3 is challenging due to its protein nature. Physical entrapment in wet sol–gel silica can stabilize the protein’s conformation and permit its sustained delivery. However, irreversible syneresis and poor viscoelastic properties hamper wet sol–gel silica application as a semisolid vehicle. To overcome these limits, a sol–gel silica/hydroxypropylmethylcellulose (HPMC) hydrogel blend was developed. SB3 entrapped in 8% SiO2 wet sol–gel silica preserved its structure, was stabilized against denaturation, and was slowly released for at least three days. Blending a silica gel with an HPMC–glycerol (metolose-G) hydrogel permitted spreadability without affecting the protein’s release kinetics. When administered in vivo, SB3 in silica/metolose-G—but not in solution or in metolose-G alone—accelerated wound healing in SB3 knockout and diabetic mouse models. The results confirmed that SB3 is a new pharmacological option for the treatment of chronic ulcers, especially when formulated in a slow-releasing vehicle. Silica–metolose-G represents a novel type of semisolid dosage form which could also be applied for the formulation of other bioactive proteins
A novel mertansine conjugate for acid-reversible targeted drug delivery validated through the Avidin-Nucleic-Acid-NanoASsembly platform
No full text: In targeted cancer therapy, antibody-drug-conjugates using mertansine (DM1)-based cytotoxic compounds rely on covalent bonds for drug conjugation. Consequently, the cytotoxic DM1 derivative released upon their proteolytic digestion is up to 1000-fold less potent than DM1 and lacks a bystander effect. To overcome these limitations, we developed a DM1 derivative (keto-DM1) suitable for bioconjugation through an acid-reversible hydrazone bond. Its acid-reversible hydrazone conjugate with biotin (B-Hz-DM1) was generated and tested for efficacy using the cetuximab-targeted Avidin-Nucleic-Acid-NanoASsembly (ANANAS) nanoparticle (NP) platform. NP-tethered B-Hz-DM1 is stable at neutral pH and releases its active moiety only in endosome/lysosome mimicking acidic pH. In vitro, the NP/Cetux/B-Hz-DM1 assembly showed high potency on MDA-MB231 breast cancer cells. In vivo both B-Hz-DM1 and NP/Cetux/B-Hz-DM1 reduced tumor growth. A significantly major effect was exerted by the nanoformulation, associated with an increased in situ tumor cell death. Keto-DM1 is a promising acid-reversible mertansine derivative for targeted delivery in cancer therapy
Dissecting the contributions of composition and mesostructure on the release of thymol from silica-based mesopowders
No full textIn pharmaceutics, mesoporous silica (MS)- based powders are used as high capacity sorbents for active agents, sometimes with controlled release properties. In literature, MS powder-adsorbed substances display faster or slower release compared to unformulated compounds. In order to understand this controversial phenomenon, we carried out a comprehensive study by investigating the behavior of thymol (TH, a model compound with acaricide properties against the Varroa destructor bee parasite) in different conditions, as a pure powder and when adsorbed onto four silica-based mesopowders from commercial (Sil-Sol 6035 (R), Neusilin US2 (R), Silica Gel 60737 (R)) and synthetic (MCM-41) origin, and characterized by different chemical composition and nano/mesostructure. All MS-powders displayed high TH loading capacity (between 0.35 and 0.72 g/g SiO2), related to their mesopore volume. Stabilization of physisorbed TH in amorphous form was achieved by all except Neusilin US2 (R). Adsorption onto MCM-41 and SiliSol (R) or Silica Gel 60737 (R) led to tenfold and twofold reduction of sublimation rate at 33 degrees C (the average beehive temperature during treatment), respectively. Adsorption onto the three retentive MS-powders also reduced the energy of activation (Ea) of TH sublimation, providing explanation on the controversial effects on the release of bioactive agents adsorbed onto MS powders described by the literature. In field applications, the effect exerted by the retentive powders should permit to cover the entire Varroa reproduction cycle by a single administration. Reduction of the sublimation Ea brings the additional advantage of reducing sensitivity of the sublimation process to the environment temperature fluctuations
Dexamethasone conjugation to an Avidin-Nucleic-Acid-NanoASsembly eliminates the steroid plasma absorption, enhancing selective lung tropism in a murine model of pulmonary fibrosis
No full textDespite their anti-inflammatory activity, corticosteroids are limited in clinic due to poor selectivity and their side effects. The ability to cross biological barriers makes them powerful yet unspecific, leading to toxicity and a low therapeutic index that limits their chronic use in autoimmune, inflammatory, and infectious diseases. It is needed another approachfor innovative targeted delivery strategies. This study aimed at investigating if the dexamethasone conjugation to Avidin-Nucleic-Acid-NanoASsembly (ANANAS) could allow its selective lung release in the bleomycin-induced pulmonary fibrosis model. Since recent evidence showed a selective ANANAS accumulation in macrophage lysosomes in a liver fibrosis model, an acid-sensitive hydrazone linker was used to facilitate dexamethasone release into pulmonary macrophages, key players in lung fibrosis. Systemic ANANAS-Dex administration in healthy mice showed no dexamethasone release in plasma or peripheral organs, with delivery exclusively targeting the liver, independent of the health status. While this confirmed the nanocarrier safety, it underscored the influence of the administration route, rather than the disease state, on ANANAS-Dex tropism. The study on intranasal administration highlighted that: 1) free Dex circulates in the bloodstream, while ANANAS keeps the drug confined in the lungs; 2) ANANAS-Dex results in sustained drug release in the lungs, enhancing the lungs/plasma-peripheral organs ratio; 3) fibrotic mice exhibited prolonged kinetics and macrophage targeting. Based on the biodistribution and pharmacokinetics studies, it is possible to achieve controlled and safe steroid release in lung disorders, reducing systemic toxicity and potentially enhancing clinical compliance
Efficient SARS-CoV-2 infection antagonization by rhACE2 ectodomain multimerized onto the Avidin-Nucleic-Acid-NanoASsembly
No full textNanodecoy systems based on analogues of viral cellular receptors assembled onto fluid lipid-based membranes of nano/extravescicles are potential new tools to complement classic therapeutic or preventive antiviral approaches. The need for lipid-based membranes for transmembrane receptor anchorage may pose technical challenges along industrial translation, calling for alternative geometries for receptor multimerization. Here we developed a semisynthetic self-assembling SARS-CoV-2 nanodecoy by multimerizing the biotin labelled virus cell receptor -ACE2- ectodomain onto a poly-avidin nanoparticle (NP) based on the Avidin-Nucleic-AcidNanoASsembly-ANANAS. The ability of the assembly to prevent SARS-CoV-2 infection in human lung cells and the affinity of the ACE2:viral receptor-binding domain (RBD) interaction were measured at different ACE2: NP ratios. At ACE2:NP = 30, 90 % SARS-CoV-2 infection inhibition at ACE2 nanomolar concentration was registered on both Wuhan and Omicron variants, with ten-fold higher potency than the monomeric protein. Lower and higher ACE2 densities were less efficient suggesting that functional recognition between multi-ligand NPs and multi-receptor virus surfaces requires optimal geometrical relationships. In vivo studies in mice showed that the biodistribution and safety profiles of the nanodecoy are potentially suitable for preventing viral infection upon nasal instillation. Viral receptor multimerization using ANANAS is a convenient process which, in principle, could be rapidly adapted to counteract also other viral infections
Diagnostic Performance of Magnetic Resonance Imaging for Preoperative Local Staging of Penile Cancer: A Systematic Review and Meta-Analysis
No full textInvasion of the tunica albuginea (TA) and/or urethra are key factors in determining the feasibility of organ-preserving surgery in penile cancer (PC). Magnetic resonance imaging (MRI) appeared to be a promising technique for preoperative local staging. We performed a systematic review (SR) and pooled meta-analysis to investigate the diagnostic performance of MRI in preoperative local staging of primary PC. An SR up to May 2021 was performed according to the PRISMA statement. The diagnostic performance of MRI was evaluated according to TA invasion, urethra invasion, and pT-stage ≥ 2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) from eligible studies were pooled and summary receiver operating characteristic (SROC) curves were constructed. Overall, seven qualified studies were deemed suitable. Diagnostic performance of MRI showed an accuracy of 0.89 for TA invasion (sensitivity 0.78, PPV 0.79, specificity 0.91, and NPV 0.90); an accuracy of 0.88 for urethra invasion (sensitivity 0.65, PPV 0.46, specificity 0.86, and NPV 0.93); an accuracy of 0.90 for pT ≥ 2 (sensitivity 0.86, PPV 0.84, specificity 0.70, and NPV 0.73).Currently available evidence indicates that MRI might be a one-stop shop for local staging of primary PC and play a central role with regard to conservative surgical management
Association between multimorbidity and postoperative mortality in patients undergoing major surgery: a prospective study in 29 countries across Europe
No full textBackgroundMultimorbidity poses a global challenge to healthcare delivery. This study aimed to describe the prevalence of multimorbidity, common disease combinations and outcomes in a contemporary cohort of patients undergoing major abdominal surgery.MethodsThis was a pre-planned analysis of a prospective, multicentre, international study investigating cardiovascular complications after major abdominal surgery conducted in 446 hospitals in 29 countries across Europe. The primary outcome was 30-day postoperative mortality. The secondary outcome measure was the incidence of complications within 30 days of surgery.ResultsOf 24,227 patients, 7006 (28.9%) had one long-term condition and 10,486 (43.9%) had multimorbidity (two or more long-term health conditions). The most common conditions were primary cancer (39.6%); hypertension (37.9%); chronic kidney disease (17.4%); and diabetes (15.4%). Patients with multimorbidity had a higher incidence of frailty compared with patients <= 1 long-term health condition. Mortality was higher in patients with one long-term health condition (adjusted odds ratio 1.93 (95%CI 1.16-3.23)) and multimorbidity (adjusted odds ratio 2.22 (95%CI 1.35-3.64)). Frailty and ASA physical status 3-5 mediated an estimated 31.7% of the 30-day mortality in patients with one long-term health condition (adjusted odds ratio 1.30 (95%CI 1.12-1.51)) and an estimated 36.9% of the 30-day mortality in patients with multimorbidity (adjusted odds ratio 1.61 (95%CI 1.36-1.91)). There was no improvement in 30-day mortality in patients with multimorbidity who received pre-operative medical assessment.ConclusionsMultimorbidity is common and outcomes are poor among surgical patients across Europe. Addressing multimorbidity in elective and emergency patients requires innovative strategies to account for frailty and disease control. The development of such strategies, that integrate care targeting whole surgical pathways to strengthen current systems, is urgently needed for multimorbid patients. Interventional trials are warranted to determine the effectiveness of targeted management for surgical patients with multimorbidity
