CLINICAL NANOBIOCHEMISTRY GROUPS
The research of the group is focused into the design, synthesis, characterization and validation of red biotech systems and bio-inspired particles for treatment and diagnosis of human diseases, in particular those affecting the Central Nervous System
Staff: Massimo Masserini , Francesca Re, Claudia Corbo, Silvia Sesana
Non permanent staff: Roberta Dal Magro, Beatrice Formicola
1) DESIGN OF BIOTECH NANOSIZED DEVICES FOR THE THERAPY OF CENTRAL NERVOUS SYSTEM DISEASES
This activity is finalized to the production of NPs able to cross the BBB for therapy and diagnosis of neurodegenerative diseases. The focus of the research is mainly on Alzheimer disease, on glioblastoma and on amyotrophic lateral sclerosis.
a) BBB crossing. NP made of different materials, e.g. Lipid based –liposomes, SLN/ polymeric/ Gold, are functionalized with an arsenal of ligands and tested to boost the crossing of BBB, mainly relying on receptor-mediated transcytosis mechanisms. Noteworthy, one line of research is exploiting the functionalization with blood-borne proteins . The efficacy of BBB crossing is followed either in vivo, on healthy mouse or TG mouse models or in vitro on cellular BBB transwell models. When designed for therapy purposes, NP are loaded with drugs , e.g. Doxorubicin or proprietary therapeutic peptides. However, the lab is also developing nanoparticles with original functionalizations that are able at the same time to promote the BBB crossing and interact with diseased cells.
b) Alzheimer disease. Within the FP7 European project “NAD” Nanoparticles for therapy and diagnosis of Alzheimer’s disease” coordinated by our group, we have developed multi-functionalized liposomes able to destroy Abeta plaques (present in Alzheimer diseased brain), or to prevent their formation and to restore the impaired cognitive function in transgenic mouse models of the disease. These NP have been patented and liposomes registered under the trade mark “Amyposomes”. Relying on the patents, a Spin off company, Amypopharma, has been founded (2015).
c) Glioblastoma multiforme, GBM. GBM also called grade IV astrocytoma is one of the most deadly brain tumors, with a short median patient survival and a very limited response to therapies. Our research aim is to specifically deliver chemotherapeutics to tumour cells, reducing their side effects, through smart bionanotech system. The results show that the product developed is able to reach the brain and to selectively trigger apoptosis in patientderived xenografts (PDXs) rodent model.
d) Amyotrophic lateral sclerosis (SLA). Despite more than 100 disease-modifying or neuroprotective agents have been tested in clinical trials, no cure has yet been found. Our research aim is to validate targeted lipid-based particles as carrier for HK1-Nterminal based peptide (NHK1), which is able to restore the cell viability of motor neuron-like NSC-34 cells. The results show that these particles are able to deliver NHK1 peptide across the BBB, preserving its ability to counteract the oxidative stress in a ALS cellular model.
e) Brain oxidative stress. Different neurological disorders are strongly interwined with reactive oxygen species (ROS) production and oxidative stress, which are considered
common effectors in the cascade of degenerative and pathological events in the brain. Our research aim is to test the antioxidant properties of Cerium oxide nanoparticles (CeONPs), thanks to theri ability known to act as strong, recyclable ROS scavengers by shuttling between Ce3+ (reduced) and Ce4+ (oxidized) oxidation states. The results show that CeONPs are able to strongly reduce the oxidative stress associated to beta-amyloid aggregates, typical hallmarks of Alzheimer’s disease
2) DESIGN OF BIOMIMETIC AND BIO-INSPIRED SYSTEMS FOR DIAGNOSIS AND THERAPY OF HUMAN DISORDERS
a) Bio-inspired nanoparticles for drug delivery. Nature offers a wide-range of sources of inspiration for the synthesis of more effective drug delivery platforms. Because the nano-bio-interface is the key driver of nanoparticle behavior and function, the modification of nanoparticles’ surfaces allows the transfer of biological properties to synthetic carriers by imparting them with a biological identity. Modulation of these surface characteristics governs nanoparticle interactions with the biological barriers they encounter.By mimicking these biological entities, we will learn how to more efficiently interact with the human body and refine our ability to negotiate with the biological barriers that impair the therapeutic efficacy of nanoparticles.
b) Bio-hybrid Nanoparticles to CROSS Biological Barriers. Incapability of effective cross-talk with biological environments has partly impaired the in vivo functionality of nanoparticles (NPs). Homing, biodistribution, and function of NPs could be engineered through regulating their interactions with in vivo niches. Inspired by communications in biological systems, endowing a “biological identity” to synthetic NPs is one approach to control their biodistribution, and immunonegotiation profiles. This synthetic-biological combination is referred to as biohybrid NPs, which comprise both i) engineerable, readily producible, and trackable synthetic NPs as well as ii) biological moieties with the capability to cross-talk with immunological barriers.
c) Protein corona on nanoparticles for personalized diagnostics. It is now well understood that once in contact with biological fluids, nanoscale objects lose their original identity and acquire a new biological character, referred to as a protein corona. Recently it has been shown that the protein corona is strongly affected by the patient’s specific disease. Therefore, the same nanomaterial incubated with plasma proteins of patients with different pathologies adsorb protein coronas with different compositions, giving rise to the concept of personalized protein corona.
d) Nanodiscs inspired to human discoidal lipoproteins (HDL). Plasma levels of high-density lipoproteins (HDL) and apoA-I, the major protein component of plasma HDL, inversely correlate with the development of many disorders, including cardiovascular diseases, diabetes, obesity, cancer, infectious diseases and neurodegenerative diseases. We recently found that apoA-I-based nanodiscs are able to cross the blood-brain barrier and strongly destabilize the conformation of Aβ aggregates, compared to spherical HDL.
3) ADVANCED IN VITRO CELLULAR MODELS OF BRAIN BIOLOGICAL BARRIERS
As a support of the activity finalized to the production of NPs able to cross the BBB for therapy and diagnosis of neurodegenerative diseases, in vitro transwell cellular models of the blood brain barrier (BBB) or the blood cerebrospinal- fluid barrier (BCB) are currently available at UNIMIB, in order to minimize the need for animals in high throughput preclinical studies. The models allow to evaluate quickly and in a reproducible way the predictive in vivo permeability of compounds and nano-based drug delivery systems under development and to identify specific transport mechanisms, for neurotoxicity and neuroprotection studies. Examples of our models are based on rat brain endothelial cell lines, rat choroidal epithelial cell lines and human micro-endothelial cell lines.
The development of realistic in vitro blood-brain barrier (BBB) models that recapitulate the physiological parameters and molecular aspect of the neurovascular unit (NVU) is of fundamental importance not only in CNS drug discovery but also in translational research. We have different BBB platforms, starting from unicellular models to advanced multicellular models of functional BBB in vitro. We are also working on advanced 3D printing technologies for engineering BBB models, which use is now fast expanding among researchers.
- FRRB Lombardy 2019 New frontiers of engineered nanovectors to improve treatment efficacy and safety in neurological disorders (NEVERMIND) – 630.000,00 €
- H2020 JPND 2016 Development of novel multicellular in vitro models of Alzheimer disease-like BBB – total cost 982.409,00 €; UNIMIB 293.160,00 €
- H2020-MSCA-ITN-2014, Design and development of advanced NAnomedicines to overcome Biological BArriers and to treat severe diseases”, NABBA 900000 €
- NAD Nanoparticles for therapy and diagnosis of Alzheimer Disease 2009-2014- total cost 14.900.000,00 €, UNIMIB 3.600.000 €
- Lombardy Region . 2014 Project :Network Enabled Drug Design – 300.000,00 €
- European Center Nanomedicine CEN 2014 Smart Nanoparticles For Boosted Drug Brain Targeting – 90.000,00 €
- European Center Nanomedicine CEN 2014 mApoE-Functionalized Lipidic -and Polymeric- Nanocomposite for Human Glioblastoma Imaging and Treatment – 100.000,00 €
- Lombardy Region. 2013 Project: Scouting of Technology Transfer 100.000,00 €
- Fondazione Banca del Monte di Lombardia 2013: Evaluation of toxicity of nanoparticles designed for therapy of neurodegenerative diseases – 50.000,00 €
- Italian Ministry of University: Role of lipid rafts in the processing of Prion protein
- Cariplo Bank Foundation. 2011 Project: Novel strategies for synthesis and functionalization of nano-and microparticles for biomedical use – 500.000,00 €
- WO 2009/150686E “Liposomes capable of effectively binding the beta-amyloid peptide” Inventors: Massimo Masserini; Francesca Re, M. Silvia Sesana
- WO 2014/00857 “Liposomes for treatment of Alzheimer Disease” Inventors; Massimo Masserini; Francesca Re;
- Greek Patent n. 20100100563/30.09.2010Novel curcumin derivatives with improved physicochemical properties and surface-decorated Nanoliposomes (with the derivatives) with very high affinity for Amyloid beta1-42 peptide Inventors : Antimisiaris S., Nicotra F., La Ferla B. Masserini M..
- Italian patent n. RM2011A000264/30.06.2011. Nuovi composti triciclici glicofusi, procedimento per la loro produzione e loro impiego quali ligandi dei peptidi β amiloidi (Aβ), Inventors : Nicotra F. La Ferla B., Masserini M.
____________________________________________________________________________________________________________________________________________________________RECENT PUBLICATIONS ( from 2017 )
– Formicola, B., Dal Magro, R., Cox, A., Masserini, M., Re, F. “Nanomedicine for Alzheimer disease” Journal of Biomedical Nanotechnology 2019
– Cox, A., Vinciguerra, D., Re, F., Dal Magro, R., Mura, S., Masserini, M., Couvreur, P., Nicolas, J. “Protein-Functionalized Nanoparticles Derived from End-Functional Polymers and Polymer Prodrugs for Crossing the Blood-Brain Barrier” Eur J Pharm Biopharm. 2019 Jun 6.
– Figuereido, I., Paiotta, A., Dal Magro, R., Tinelli, F., Corti, R., Re, F., Cassina, V., Caneva, E., Nicotra, F., Russo, L. “A new approach for glyco-functionalization of collagen-based biomaterials” International Journal of Molecular Sciences Volume 20, Issue 7, 1 April 2019, Article number 1747
– Andrieu, J., Re, F., Russo, L., Nicotra, F. “Phage-displayed peptides targeting specific tissues and organs” (Review) Journal of Drug Targeting Volume 27, Issue 5-6, 3 July 2019, Pages 555-565
– Dal Magro, R., Simonelli, S., Cox, A., Formicola, B., Corti, R., Cassina, V., Nardo, L., Mantegazza, F., Salerno, D., Grasso, G., Deriu, M.A., Danani, A., Calabresi, L., Re, F. “The Extent of Human Apolipoprotein A-I Lipidation Strongly Affects the β-Amyloid Efflux Across the Blood-Brain Barrier in vitro” Front Neurosci. 2019 May 16;13:419.
– Cox A, et al. Protein-Functionalized Nanoparticles Derived from End-Functional Polymers and Polymer Prodrugs for Crossing the Blood-Brain Barrier.
EUR J PHARM BIOPHARM. 2019 Jun 6. pii: S0939-6411(19)30319-4. doi: 10.1016/j.ejpb.2019.06.004.
– Binda A, et al. Modulation of the intrinsic neuronal excitability by multifunctional liposomes tailored for the treatment of Alzheimer’s disease. INT J NANOMEDICINE. 2018 Jul 11;13:4059 4071. doi: 10.2147/IJN.S161563.
– Picciolini S et al. Detection and Characterization of Different Brain-Derived Subpopulations of Plasma Exosomes by Surface Plasmon Resonance Imaging. ANAL CHEM. 2018 Aug 7;90(15):8873-8880. doi: 10.1021/acs.analchem.8b00941.
– Cox A, et al. Evolution of Nanoparticle Protein Corona across the Blood-Brain Barrier. ACS Nano. 2018 Jul 24;12(7):7292-7300. doi: 10.1021/acsnano.8b03500.
– Mancini S, Nardo L, Gregori M, Ribeiro I, Mantegazza F, Delerue-Matos C, Masserini M, Grosso C. Functionalized liposomes and phytosomes loading Annona muricata L. aqueous extract:
Potential nanoshuttles for brain-delivery of phenolic compounds. PHYTOMEDICINE. 2018 Mar 15;42:233-244. doi: 10.1016/j.phymed.2018.03.053. Epub 2018 Mar 19.
– Magro RD, Cox A, Zambelli V, Mancini S, Masserini M, Re F. The ability of liposomes, tailored for blood-brain barrier targeting, to reach the brain is
dramatically affected by the disease state. NANOMEDICINE (LOND). 2018 Mar;13(6):585-594. doi: 10.2217/nnm-2017-0317. Epub
2018 Jan 29
– Carradori D, Balducci C, Re F, Brambilla D, Le Droumaguet B, Flores O, Gaudin A, Mura S, Forloni G, Ordoñez-Gutierrez L, Wandosell F, Masserini M, Couvreur P, Nicolas J,
Andrieux K. Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer’s disease-like transgenic mouse model. NANOMEDICINE. 2018 Feb;14(2):609-618. doi: 10.1016/j.nano.2017.12.006. Epub 2017 Dec 15.
– Ugolini GF, Occhetta P, Saccani A, Re F, Krol S, Rasponi M, Redaelli A. Design and validation of a microfluidic device for blood–brain barrier monitoring and
transport studies. J. Micromech. Microeng. 2018, 28: 044001 (9pp) DOI: 10.1088/1361-6439/aaa816.
– Molinaro, R., Evangelopoulos, M., Hoffman, J., Corbo, C., Taraballi, F., Martinez, J., et al. (2018). Design and Development of Biomimetic Nanovesicles Using a Microfluidic Approach. ADVANCED MATERIALS, 30(15).
– Molinaro, R., Corbo, C., Livingston, M., Evangelopoulos, M., Parodi, A., Boada, C., et al. (2018). Inflammation and Cancer: In Medio Stat Nano. CURRENT MEDICINAL CHEMISTRY, 25(34), 4208-4223.
– Arrighetti, N., Corbo, C., Evangelopoulos, M., Pasto, A., Zuco, V., & Tasciotti, E. (2018). Exosome-like nanovectors for drug delivery in cancer. CURRENT MEDICINAL CHEMISTRY, 25.
– Behzadi, S., Vatan, N., Lema, K., Nwaobasi, D., Zenkov, I., Abadi, P., et al. (2018). Flat Cell Culturing Surface May Cause Misinterpretation of Cellular Uptake of Nanoparticles. ADVANCED BIOSYSTEMS, 2(6).
– Corbo, C., Cevenini, A., & Salvatore, F. (2017). Biomarker discovery by proteomics-based approaches for early detection and personalized medicine in colorectal cancer.
PROTEOMICS. CLINICAL APPLICATIONS, 11(5-6).
– Parodi, A., Molinaro, R., Sushnitha, M., Evangelopoulos, M., Martinez, J., Arrighetti, N., et al. (2017). Bio-inspired engineering of cell- and virus-like nanoparticles for drug delivery. BIOMATERIALS, 147, 155-168.
– Corradetti, B., Taraballi, F., Corbo, C., Cabrera, F., Pandolfi, L., Minardi, S., et al. (2017). Immune tuning scaffold for the local induction of a pro-regenerative environment. SCIENTIFIC REPORTS, 7(1).
– Corradetti, B., Taraballi, F., Martinez, J., Minardi, S., Basu, N., Bauza, G., et al. (2017). Hyaluronic acid coatings as a simple and efficient approach to improve MSC homing
toward the site of inflammation. SCIENTIFIC REPORTS, 7(1).
– Corbo, C., Molinaro, R., Tabatabaei, M., Farokhzad, O., & Mahmoudi, M. (2017). Personalized protein corona on nanoparticles and its clinical implications. BIOMATERIALS SCIENCE, 5(3), 378-387.
– Corbo, C., Molinaro, R., Taraballi, F., Toledano Furman, N., Hartman, K., Sherman, M., et al. (2017). Unveiling the in Vivo Protein Corona of Circulating Leukocyte-like Carriers. ACS NANO, 11(3), 3262-3273.
– Corbo, C., Cromer, W., Molinaro, R., Toledano Furman, N., Hartman, K., De Rosa, E., et al. (2017). Engineered biomimetic nanovesicles show intrinsic anti-inflammatory properties for the treatment of inflammatory bowel diseases. NANOSCALE, 9(38), 14581-14591.
– Gualerzi A, Niada S, Giannasi C, Picciolini S, Morasso C, Vanna R, Rossella V, Masserini M, Bedoni M, Ciceri F, Bernardo ME, Brini AT, Gramatica F. Raman spectroscopy uncovers biochemical tissue-related features of extracellular vesicles from mesenchymal stromal cells. SCI REP. 2017 Aug 29;7(1):9820. doi: 10.1038/s41598-017-10448-1.
– Snellman, A., Rokka, J., Lopez-Picona, F., Helin, S., Re, F., Löyttyniemi, E., et al. (2017). Applicability of [11C]PIB micro-PET imaging for in vivo follow-up of anti-amyloid treatment effects in APP23 mouse model. NEUROBIOLOGY OF AGING May 15;57:84-94. doi: 10.1016/j.neurobiolaging.2017.05.008
– Conti, E., Gregori, M., Radice, I., Da Re, F., Grana, D., Re, F., et al. (2017). Multifunctional liposomes interact with Abeta in human biological fluids: Therapeutic implications for Alzheimer’s disease. NEUROCHEM INT. 2017 Feb 24. pii: S0197-0186(16)30345-X. doi: 10.1016/j.neuint.2017.02.012
– Mancini, S., Balducci, C., Micotti, E., Tolomeo, D., Forloni, G., Masserini, M., et al. (2017). Multifunctional liposomes delay phenotype progression and prevent memory impairment in a presymptomatic stage mouse model of Alzheimer disease. JOURNAL OF CONTROLLED RELEASE Jul 28;258:121-129. doi: 10.1016/j.jconrel.2017.05.013
– Gregori, M., Taylor, M., Salvati, E., Re, F., Mancini, S., Balducci, C., et al. (2017). Retroinverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer’s Aβ peptide. NANOMEDICINE 2017 Feb;13(2):723-732. doi: 10.1016/j.nano.2016.10.006..
– Orlando A, Cazzaniga E, Tringali M, Gullo F, Becchetti A, Minniti S, Taraballi F, Tasciotti E, Re F.Mesoporous silica nanoparticles trigger mitophagy in endothelial cells and perturb neuronal network activity in a size- and time-dependent manner.Int J Nanomedicine 2017;12:3547-3559.