Novel inulin-based mucoadhesive micelles loaded with corticosteroids as potential transcorneal permeation enhancers

In this work a new copolymer of inulin (INU) derivatized with ethylendiamine (EDA) and retinoic acid (RA), named INU-EDA-RA, was synthetized, characterized and employed to produce micelles as carriers for topical administration of corticosteroids for the potential treatment of diseases of posterior eye segment. Spectroscopic analysis confirmed a molar derivatization degree of 11.30 and 4.30% in EDA and RA, respectively. INU-EDA-RA micelles are capable of strong mucoadhesive interactions which result time-independent and stable over time but concentration depending. Moreover micelles are able to encapsulate efficiently from 3 to 13% (w/w) of lipophilic drugs, as dexamethasone, triamcinolone …

Multi-Functional Nanogels for Tumor Targeting and Redox-Sensitive Drug and siRNA Delivery

(1) Background: A new family of nanosystems able to discern between normal and tumor cells and to release a therapeutic agent in controlled way were synthetized by e-beam irradiation. This technique permits to obtain biocompatible, sterile, carboxyl-functionalized polyvinylpyrrolidone (PVP-co-acrylic acid) nanogels (NGs); (2) Methods: Here, we performed a targeting strategy based on the recognition of over-expressed proteins on tumor cells, like the folate receptor. The selective targeting was demonstrated by co-culture studies and flow cytometry analysis, using folate conjugated NGs. Moreover, nanoparticles were conjugated to a chemotherapeutic drug or to a pro-apoptotic siRNA through a gl…

Sviluppo di nanocarriers per il “drug release” controllato di biomolecole nella terapia antitumorale

Una nuova generazione di nanogels (NGs) in poly(N-vinyl pyrrolidone) (PVP) è stata ottenuta mediante beta–irraggiamento (e-beam) ad alta energia mediante elettroni accelerati, che permette in tempi brevi la reticolazione di polimeri in soluzione acquosa, utilizzando acceleratori di particelle lineari. Oltre al controllo dimensionale, l’aspetto innovativo di tale tecnica è la possibilità di ottenere nanogels sterili, la cui funzionalizzazione di superficie avviene in un unico step. Inizialmente, è stata provata la loro biocompatibilità e non genotossicità in sistemi biologici, caratteristiche fondamentali per la loro applicazione in campo biomedico. Inoltre, sono stati messi a punto dei prot…

Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population

Minimalism in radiation synthesis of biomedical functional nanogels.

A scalable, single-step, synthetic approach for the manufacture of biocompatible, functionalized micro- and nanogels is presented. In particular, poly(N-vinyl pyrrolidone)-grafted-(aminopropyl)methacrylamide microgels and nanogels were generated through e-beam irradiation of PVP aqueous solutions in the presence of a primary amino-group-carrying monomer. Particles with different hydrodynamic diameters and surface charge densities were obtained at the variance of the irradiation conditions. Chemical structure was investigated by different spectroscopic techniques. Fluorescent variants were generated through fluorescein isothiocyanate attachment to the primary amino groups grafted to PVP, to …

Impact of the flame retardant 2,2'4,4'-tetrabromodiphenyl ether (PBDE-47) in THP-1 macrophage-like cell function via small extracellular vesicles

2,2’4,4’-tetrabromodiphenyl ether (PBDE-47) is one of the most widespread environmental brominated flame-retardant congeners which has also been detected in animal and human tissues. Several studies have reported the effects of PBDEs on different health issues, including neurobehavioral and developmental disorders, reproductive health, and alterations of thyroid function. Much less is known about its immunotoxicity. The aim of our study was to investigate the effects that treatment of THP-1 macrophage-like cells with PBDE-47 could have on the content of small extracellular vesicles’ (sEVs) microRNA (miRNA) cargo and their downstream effects on bystander macrophages. To achieve this, we puri…

PHEA-Dox nanoparticles as pH-sensitive model for drug delivery in tumour treatment.

PHEA-Dox nanoparticles as pH-sensitive model for drug delivery in tumour treatment. S. Camporaa, G. Adamoa, N. Maurob, C. Scialabbab, M. Licciardib, G. Giammonab and G. Ghersia. aDipartmento di “Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche” (STEBICEF), Università di Palermo, Viale delle Scienze Ed. 16, 90128 Palermo, Italy. bLaboratory of Biocompatible Polymers, Dipartmento di “Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche” (STEBICEF), Università di Palermo, Via Archirafi, 32 90123 Palermo, Italy. Classical chemotherapeutic applications, using molecules such as doxorubicin (Dox), have side effects due to an unspecific action. In order to obtain a specific release of…

Functionalization of nanoparticles in specific targeting and mechanism release

The development of various nanotechnologies have provided a new field of research, which allows the manipulation of molecular components of matter and covers a vast array of nanodevices. The “smart” multifunctional nanostructures should work as customizable, targeted drug-delivery vehicles capable of carrying large doses of therapeutic agents into malignant cells. Some nanomedical approaches are based on the use of functionalized nanoparticles (NPs), not only to reduce toxicity and side effects of drugs but, also in potential the biological barriers crossing on, such as: the blood–brain barrier, different cellular compartments, including the nucleus. Currently, many materials are used for n…

Polyaminoacid–doxorubicin prodrug micelles as highly selective therapeutics for targeted cancer therapy

An amphiphilic copolymer carrying high-dose doxorubicin (21% on a weight basis), PHEA–EDA–P,C–Doxo, was prepared by coupling doxorubicin with a biocompatible polyaminoacid through a pH-sensitive spacer. Additional derivatization with 4-pentynoic acid endows it with self-assembling properties by means of π–π stacking. These micelles can be triggered to promptly release drug in lysosomes (∼40% in 12 h) through pH-dependent micelle hydrolysis after uptake. In vitro tests on co-cultures of cancer (MDA-MB 231) and normal (HB-2) breast cells proved that the conjugate was selectively internalized into the former rather than normal cells, exploiting the caveolae-dependent endocytosis pathway, expla…

Nano-structured myelin: new nanovesicles for targeted delivery to white matter and microglia, from brain-to-brain

Neurodegenerative diseases affect millions of people worldwide and the presence of various physiological barriers limits the accessibility to the brain and reduces the efficacy of various therapies. Moreover, new carriers having targeting properties to specific brain regions and cells are needed in order to improve therapies for the brain disorder treatment. In this study, for the first time, Myelin nanoVesicles (hereafter defined MyVes) from brain-extracted myelin were produced. The MyVes have an average diameter of 100–150 ​nm, negative zeta potential, spheroidal morphology, and contain lipids and the key proteins of the myelin sheath. Furthermore, they exhibit good cytocompatibility. The…

Self-organized environment-sensitive inulin–doxorubicin conjugate with a selective cytotoxic effect towards cancer cells

An inulin-based random copolymer bearing high dose doxorubicin (18.45% on a weight basis), INU-EDA-P, C-DOXO, was prepared by coupling doxorubicin with inulin though a citraconylamide bridge used as a pH sensitive spacer. A further conjugation with pentynoic acid via an amidic bond led to the hydrophobization of the copolymer which allows the acquisition of a self-assembling ability at low concentration (0.33 mg mL(-1)) combining both Pi-Pi stacking and London interactions. Drug release studies were carried out at different pH demonstrating a remarkable pH dependency, where the maximum release rate was observed at pH mimicking cancer tissue and lysosomal environments. Besides, by measuring …

Water-borne e-beam crosslinked nanogels as nanomaterials platform for drug delivery

FOLATE-DECORATED E-BEAM CROSSLINKED NANOGELS TO ENHANCE UPTAKE BY TUMOR CELLS

E-Beam Crosslinked Polymeric and Bio-Hybrid Nanocarriers for Drug Delivery and Bioimaging

Mucoadhesive micelles based on inulin derivative for ocular release of corticosteroids

Large-scale radiation manufacturing of hierarchically assembled nanogels

Nanogels (NGs), or small particles formed by physically or chemically crosslinked polymer networks, represent a niche in the development of "smart" nanoparticles for drug delivery and diagnostics. They offer unique advantages over other systems, including a large and flexible surface for multivalent bio-conjugation; an internal 3D aqueous environment for incorporation and protection of (bio)molecular drugs; the possibility to entrap active metal or mineral cores for imaging or phototherapeutic purposes; stimuli-responsiveness to achieve temporal and/or site control of the release function and biocompatibility. The availability of inexpensive and robust preparation methodologies is at the ba…

Large-scale Radiation Manufacturing of Hierarchically Assembled Nanogels

Nanogels (NGs), or small particles formed by physically or chemically crosslinked polymer networks, represent a niche in the development of “smart” nanoparticles for drug delivery and diagnostics. They offer unique advantages over other systems, including a large and flexible surface for multivalent bio-conjugation; an internal 3D aqueous environment for incorporation and protection of (bio)molecular drugs; the possibility to entrap active metal or mineral cores for imaging or phototherapeutic purposes; stimuli-responsiveness to achieve temporal and/or site control of the release function and biocompatibility. The availability of inexpensive and robust preparation methodologies is at the ba…

Oligonucleotides-decorated-poly(N-vinyl pyrrolidone) nanogels for gene delivery

Pulsed electron-beam irradiation of a semi-dilute poly(N-vinyl pyrrolidone) (PVP) aqueous solution in the presence of acrylic acid has led to a carboxyl functionalized nanogel system. Nanoparticles hydrodynamic size and surface charge density, in water and as a function of pH, were investigated by dynamic light scattering and laser doppler velocimetry, respectively. Nanogels (NGs) were proved not to be cytotoxic at the cellular level. Indeed, they rapidly bypass the cellular membrane to accumulate in specific cell portions of the cytoplasm, in the perinuclear area. The availability of pendant carboxyl groups on the crosslinked PVP NGs core prompted us to attempt their decoration with a sing…

E-beam crosslinked nanogels conjugated with monoclonal antibodies in targeting strategies

Abstract Poly(N-vinyl pyrrolidone)-based-nanogels (NGs), produced by e-beam irradiation, are conjugated with monoclonal antibodies (mAb) for active targeting purposes. The uptake of immuno-functionalized nanogels is tested in an endothelial cell line, ECV304, using confocal and epifluorescence microscopy. Intracellular localization studies reveal a faster uptake of the immuno-nanogel conjugate with respect to the ‘bare’ nanogel. The specific internalization pathway of these immuno-nanogels is clarified by selective endocytosis inhibition experiments, flow cytometry and confocal microscopy. Active targeting ability is also verified by conjugating a monoclonal antibody which recognizes the αv…

The nucleic acid-binding protein PcCNBP is transcriptionally regulated during the immune response in red swamp crayfish Procambarus clarkii

Gene family encoding cellular nucleic acid binding proteins (CNBP) is well conserved among vertebrates; however, there is limited knowledge in lower organisms. In this study, a CNBP homolog from the red swamp crayfish Procambarus clarkii was characterised. The full-length cDNA of PcCNBP was of 1257 bp with a 5′-untranslated region (UTR) of 63 bp and a 3′-UTR of 331 bp with a poly (A) tail, and an open-reading frame (ORF) of 864 bp encoding a polypeptide of 287 amino acids with the predicted molecular weight of about 33 kDa. The predicted protein possesses 7 tandem repeats of 14 amino acids containing the CCHC zinc finger consensus sequence, two RGG-rich single-stranded RNA-binding domain an…