Falanga, Andrea Patrizia (2016) Effect of peptide functionalization on nanoparticle transport across brain endothelium in a microfluidic chip. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Effect of peptide functionalization on nanoparticle transport across brain endothelium in a microfluidic chip
Falanga, Andrea Patriziaandreapatrizia.falanga@unina.it
Date: 29 March 2016
Number of Pages: 100
Institution: Università degli Studi di Napoli Federico II
Department: Ingegneria Chimica, dei Materiali e della Produzione Industriale
Scuola di dottorato: Ingegneria industriale
Dottorato: Ingegneria dei materiali e delle strutture
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
Mensitieri, Giuseppegiuseppe.mensitieri@unina.it
Netti, Paolo AntonioUNSPECIFIED
Date: 29 March 2016
Number of Pages: 100
Uncontrolled Keywords: nanoparticles,targeting, crossing, blood-brain barrier
Settori scientifico-disciplinari del MIUR: Area 09 - Ingegneria industriale e dell'informazione > ING-IND/34 - Bioingegneria industriale
Date Deposited: 12 Apr 2016 23:19
Last Modified: 04 May 2017 01:00
URI: http://www.fedoa.unina.it/id/eprint/10770


Despite the effort of medicine, many potential drugs, during the development for clinical use, prove not to be able in achieving the central nervous system (CNS), due to the low permeability of the blood-brain barrier (BBB). In consequence, most CNS diseases are untreated. For that reason, there is an increasing interest towards nanotechnology applied to medicine in order to improve the treatments of brain diseases. An important field of nanotechnology applications to CNS is the development of nano-tools for drugs delivering, such as nanoparticles (NPs). In recent years, researchers have been working on several strategies to deliver drugs into the brain. They take advantage of the chance to modulate the chemical-physical surface properties of NPs, improving cell-NP interaction in order to adsorb, to carry compounds and to enhance drug delivery across the BBB. Nevertheless, current drug delivery systems are still associated with the low efficiency of targeting and crossing of the BBB. In this work, peptide functionalized NPs have been synthesized and characterized in order to target and cross the cerebral endothelium. The iron-mimicry moiety CRTIGPSVC (CRT) has been chosen as BBB targeting peptide, exploiting its ability to recognize the transferrin receptor overexpressed on the brain endothelium. Staquicini et al. reported the advanced specific transport ability of CRT through the BBB. Therefore in this work, biocompatible NPs made up of poly (D,L-lactic-co-glycolic acid) (PLGA)-block-polyethylene glycol (PEG) copolymer (namely PELGA) and functionalized with CRT has been synthesized and characterized. The behavior in targeting and transport ability of the NPs in mouse brain endothelial cells has been investigated, under flow conditions. In order to improve the translocation across the BBB, decreasing the lysosomal storage of CRT-NPs, gH625 peptide has been chosen as cell-penetrating peptide (CPP). gH625 is a membranotropic peptide, well known for its ability to penetrate cell membranes and transport a large variety of cargo molecules/materials inside the cells. We speculated that the conjugation of CRT and gH625 to nanoparticle, may improves its translocation efficiency across the BBB. To test this hypothesis, PELGA NPs functionalized with CRT targeting peptide and with the CPP gH625 has been designed. NP efficiency to target the BBB under static and flow conditions and to penetrate across the in vitro BBB has been evaluated. Results demonstrated the cooperative effect of NP functionalization with gH625 and CRT 1:2 in static and flow conditions with a relevant impact on NP transport across the cerebral endothelium. In order to investigate the effect of functionalized NP on transport across the cerebral endothelium, a flow-based in vitro BBB on chip has been engineered. The system more closely mimics in vivo environment and represents a valid BBB in vitro model since exerts the barrier function. Therefore, a study platform for drug delivery systems has been developed. The BBB model system is able to investigate the effects of dynamic conditions on specific targeting and transport across the brain endothelium of active molecules conjugated to nanocarriers.

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