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RICCARDO CARAFFI

Didattica integrativa
Dipartimento di Scienze della Vita sede ex-Scienze Farmaceutiche

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Pubblicazioni

2024 - The key role of public health in renovating Italian biomedical doctoral programs [Articolo su rivista]
Palandri, Lucia; Urbano, Teresa; Pezzuoli, Carla; Miselli, Francesca; Caraffi, Riccardo; Filippini, Tommaso; Bargellini, Annalisa; Righi, Elena; Mazzi, Davide; Vigezzi, Giacomo Pietro; Odone, Anna; Marmiroli, Sandra; Boriani, Giuseppe; Vinceti, Marco
abstract

Background: A key renovation of doctoral programs is currently ongoing in Italy. Public health and its competencies may play a pivotal role in high-level training to scientific research, including interdisciplinary and methodological abilities. Methods: As a case study, we used the ongoing renovation of the Clinical and Experimental Medicine doctoral program at the University of Modena and Reggio Emilia. We focused on how the program is designed to meet national requirements as well as students' needs, thus improving educational standards for scientific research in the biomedical field, and on the specific contribution of public health and epidemiology in such an effort. Results: The renovation process of doctoral programs in Italy, with specific reference to the biomedical field, focuses on epidemiologic-statistical methodology, ethics, language and communication skills, and open science from an interdisciplinary and international perspective. In the specific context of the doctoral program assessed in the study and from a broader perspective, public health appears to play a key role, taking advantage of most recent methodological advancements, and contributing to the renovation of the learning process and its systematic quality monitoring. Conclusions: From a comparative assessment of this case study and Italian legislation, the key role of public health has emerged in the renovation process of doctoral programs in the biomedical field.

2023 - "Combo" Multi-Target Pharmacological Therapy and New Formulations to Reduce Inflammation and Improve Endogenous Remyelination in Traumatic Spinal Cord Injury [Articolo su rivista]
Moretti, Marzia; Caraffi, Riccardo; Lorenzini, Luca; Ottonelli, Ilaria; Sannia, Michele; Alastra, Giuseppe; Baldassarro, Vito Antonio; Giuliani, Alessandro; Duskey, Jason Thomas; Cescatti, Maura; Ruozi, Barbara; Aloe, Luigi; Vandelli, Maria Angela; Giardino, Luciana; Tosi, Giovanni; Calzà, Laura
abstract

Spinal cord injury (SCI) is characterized by a cascade of events that lead to sensory and motor disabilities. To date, this condition is irreversible, and no cure exists. To improve myelin repair and limit secondary degeneration, we developed a multitherapy based on nanomedicines (NMeds) loaded with the promyelinating agent triiodothyronine (T3), used in combination with systemic ibuprofen and mouse nerve growth factor (mNGF). Poly-L-lactic-co-glycolic acid (PLGA) NMeds were optimized and loaded with T3 to promote sustained release. In vitro experiments confirmed the efficacy of T3-NMeds to differentiate oligodendrocyte precursor cells. In vivo rat experiments were performed in contusion SCI to explore the NMed biodistribution and efficacy of combo drugs at short- and long-term post-lesion. A strong anti-inflammatory effect was observed in the short term with a reduction of type M1 microglia and glutamate levels, but with a subsequent increase of TREM2. In the long term, an improvement of myelination in NG2-IR, an increase in MBP content, and a reduction of the demyelination area were observed. These data demonstrated that NMeds can successfully be used to obtain more controlled local drug delivery and that this multiple treatment could be effective in improving the outcome of SCIs.

2023 - Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease [Articolo su rivista]
Birolini, Giulia; Valenza, Marta; Ottonelli, Ilaria; Talpo, Francesca; Minoli, Lucia; Cappelleri, Andrea; Bombaci, Mauro; Caccia, Claudio; Canevari, Caterina; Trucco, Arianna; Leoni, Valerio; Passoni, Alice; Favagrossa, Monica; Nucera, Maria Rosaria; Colombo, Laura; Paltrinieri, Saverio; Bagnati, Renzo; Duskey, Jason Thomas; Caraffi, Riccardo; Vandelli, Maria Angela; Taroni, Franco; Salmona, Mario; Scanziani, Eugenio; Biella, Gerardo; Ruozi, Barbara; Tosi, Giovanni; Cattaneo, Elena
abstract

: Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.

2023 - Corrigendum to “Quantitative comparison of the protein corona of nanoparticles with different matrices” [Int J Pharm X 2022 Oct 21;4: 100136] (International Journal of Pharmaceutics: X (2022) 4, (S2590156722000251), (10.1016/j.ijpx.2022.100136)) [Articolo su rivista]
Ottonelli, I.; Duskey, J. T.; Genovese, F.; Pederzoli, F.; Caraffi, R.; Valenza, M.; Tosi, G.; Vandelli, M. A.; Ruozi, B.
abstract

: [This corrects the article DOI: 10.1016/j.ijpx.2022.100136.].

2023 - Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles [Articolo su rivista]
Ottonelli, I.; Bighinati, A.; Adani, E.; Loll, F.; Caraffi, R.; Vandelli, M. A.; Boury, F.; Tosi, G.; Duskey, J. T.; Marigo, V.; Ruozi, B.
abstract

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments.

2023 - Recent Advances on Surface-Modified GBM Targeted Nanoparticles: Targeting Strategies and Surface Characterization [Articolo su rivista]
Rodà, Francesca; Caraffi, Riccardo; Picciolini, Silvia; Tosi, Giovanni; Vandelli, Maria Angela; Ruozi, Barbara; Bedoni, Marzia; Ottonelli, Ilaria; Duskey, Jason Thomas
abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor, associated with low long-term survival. Nanoparticles (NPs) developed against GBM are a promising strategy to improve current therapies, by enhancing the brain delivery of active molecules and reducing off-target effects. In particular, NPs hold high potential for the targeted delivery of chemotherapeutics both across the blood-brain barrier (BBB) and specifically to GBM cell receptors, pathways, or the tumor microenvironment (TME). In this review, the most recent strategies to deliver drugs to GBM are explored. The main focus is on how surface functionalizations are essential for BBB crossing and for tumor specific targeting. We give a critical analysis of the various ligand-based approaches that have been used to target specific cancer cell receptors and the TME, or to interfere with the signaling pathways of GBM. Despite the increasing application of NPs in the clinical setting, new methods for ligand and surface characterization are needed to optimize the synthesis, as well as to predict their in vivo behavior. An expert opinion is given on the future of this research and what is still missing to create and characterize a functional NP system for improved GBM targeting.

2022 - Applications of the ROS-Responsive Thioketal Linker for the Production of Smart Nanomedicines [Articolo su rivista]
Rinaldi, A.; Caraffi, R.; Grazioli, M. V.; Oddone, N.; Giardino, L.; Tosi, G.; Vandelli, M. A.; Calza, L.; Ruozi, B.; Duskey, J. T.
abstract

Reactive oxygen species (ROS)-sensitive drug delivery systems (DDS) specifically responding to altered levels of ROS in the pathological microenvironment have emerged as an effective means to enhance the pharmaceutical efficacy of conventional nanomedicines, while simultaneously reducing side effects. In particular, the use of the biocompatible, biodegradable, and non-toxic ROS-responsive thioketal (TK) functional group in the design of smart DDS has grown exponentially in recent years. In the design of TK-based DDS, different technological uses of TK have been proposed to overcome the major limitations of conventional DDS counterparts including uncontrolled drug release and off-target effects. This review will focus on the different technological uses of TK-based biomaterials in smart nanomedicines by using it as a linker to connect a drug on the surface of nanoparticles, form prodrugs, as a core component of the DDS to directly control its structure, to control the opening of drug-releasing gates or to change the conformation of the nano-systems. A comprehensive view of the various uses of TK may allow researchers to exploit this reactive linker more consciously while designing nanomedicines to be more effective with improved disease-targeting ability, providing novel therapeutic opportunities in the treatment of many diseases.

2022 - Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments [Articolo su rivista]
Duskey, J. T.; Rinaldi, A.; Ottonelli, I.; Caraffi, R.; De Benedictis, C. A.; Sauer, A. K.; Tosi, G.; Vandelli, M. A.; Ruozi, B.; Grabrucker, A. M.
abstract

Glioblastoma Multiforme (GBM) is a devastating disease with a low survival rate and few efficacious treatment options. The fast growth, late diagnostics, and off-target toxicity of currently used drugs represent major barriers that need to be overcome to provide a viable cure. Nanomedicines (NMeds) offer a way to overcome these pitfalls by protecting and loading drugs, increasing blood half-life, and being targetable with specific ligands on their surface. In this study, the FDA-approved polymer poly (lactic-co-glycolic) acid was used to optimise NMeds that were surface modified with a series of potential GBM-specific ligands. The NMeds were fully characterised for their physical and chemical properties, and then in vitro testing was performed to evaluate cell uptake and GBM cell specificity. While all targeted NMeds showed improved uptake, only those decorated with the-cell surface vimentin antibody M08 showed specificity for GBM over healthy cells. Finally, the most promising targeted NMed candidate was loaded with the well-known chemotherapeutic, paclitaxel, to confirm targeting and therapeutic effects in C6 GBM cells. These results demonstrate the importance of using well-optimised NMeds targeted with novel ligands to advance delivery and pharmaceutical effects against diseased cells while minimising the risk for nearby healthy cells.

2022 - Quantitative comparison of the protein corona of nanoparticles with different matrices [Articolo su rivista]
Ottonelli, Ilaria; Duskey, Jason Thomas; Genovese, Filippo; Pederzoli, Francesca; Caraffi, Riccardo; Valenza, Marta; Tosi, Giovanni; Vandelli, Maria Angela; Ruozi, Barbara
abstract

: Nanoparticles (NPs) are paving the way for improved treatments for difficult to treat diseases diseases; however, much is unknown about their fate in the body. One important factor is the interaction between NPs and blood proteins leading to the formation known as the "protein corona" (PC). The PC, consisting of the Hard (HC) and Soft Corona (SC), varies greatly based on the NP composition, size, and surface properties. This highlights the need for specific studies to differentiate the PC formation for each individual NP system. This work focused on comparing the HC and SC of three NPs with different matrix compositions: a) polymeric NPs based on poly(lactic-co-glycolic) acid (PLGA), b) hybrid NPs consisting of PLGA and Cholesterol, and c) lipidic NPs made only of Cholesterol. NPs were formulated and characterized for their physico-chemical characteristics and composition, and then were incubated in human plasma. In-depth purification, identification, and statistical analysis were then performed to identify the HC and SC components. Finally, similar investigations demonstrated whether the presence of a targeting ligand on the NP surface would affect the PC makeup. These results highlighted the different PC fingerprints of these NPs, which will be critical to better understand the biological influences of the PC and improve future NP designs.

2022 - Tunneling Nanotubes: A New Target for Nanomedicine? [Articolo su rivista]
Ottonelli, I.; Caraffi, R.; Tosi, G.; Vandelli, M. A.; Duskey, J. T.; Ruozi, B.
abstract

Tunneling nanotubes (TNTs), discovered in 2004, are thin, long protrusions between cells utilized for intercellular transfer and communication. These newly discovered structures have been demonstrated to play a crucial role in homeostasis, but also in the spreading of diseases, infections, and metastases. Gaining much interest in the medical research field, TNTs have been shown to transport nanomedicines (NMeds) between cells. NMeds have been studied thanks to their advantageous features in terms of reduced toxicity of drugs, enhanced solubility, protection of the payload, prolonged release, and more interestingly, cell-targeted delivery. Nevertheless, their transfer between cells via TNTs makes their true fate unknown. If better understood, TNTs could help control NMed delivery. In fact, TNTs can represent the possibility both to improve the biodistribution of NMeds throughout a diseased tissue by increasing their formation, or to minimize their formation to block the transfer of dangerous material. To date, few studies have investigated the interaction between NMeds and TNTs. In this work, we will explain what TNTs are and how they form and then review what has been published regarding their potential use in nanomedicine research. We will highlight possible future approaches to better exploit TNT intercellular communication in the field of nanomedicine.