Nanoparticles (NPs) made of biodegradable and biocompatible polymers present several advantages as carriers for therapeutics. Targeted polymeric NPs, able to hit specific tissues and cells, can be obtained by synthesis of hybrid or biointegrated nanosystems where the combination of polymers with biomolecules such as peptides, proteins, or monoclonal antibodies offers opportunities to design precise and versatile nanoscale systems. The central challenge towards these “smart” materials is represented by the optimal interplay of biophysicochemical parameters that confer molecular targeting, immune evasion, and optimal drug release, and allow to overcome the physiological barriers in vivo. The epidermal growth factor receptor (EGFR) is a cell-surface receptor of extracellular protein ligands of the epidermal growth factor family. Mutations that lead to EGFR overexpression or overactivity have been associated with a wide spectrum of human cancers of epithelial origin, including breast and colorectal cancers, and with autoimmune disorders like rheumatoid arthritis. Recently, several studies have reported the successful identification, by screening phage display libraries, of a peptide ligand, named GE11 (YHWYGYTPQNVI), with high binding capacity to EGFR but with low mitogenic activity. Poly(gamma-glutamic acid) (gamma-PGA) is an extracellular bacterial water-soluble polymer with variable molecular weight produced by several members of the genus Bacillus, composed of D and/or L-glutamic acid monomers, connected by amide bonds between alpha-amino and gamma-carboxyl groups. gamma-PGA is readily biodegraded by a good number of bacteria, it is non-immunogenic and completely innocuous and so it seems to meet most of the requirements of polymers for drug delivery. In addition, it bears pendant carboxylic groups in α-position which are available for chemical derivatization allowing the modification of its molecular properties or the attachment of biologically active molecules. The use of gamma-PGA, however, presents some inherent and not negligible issues. First of all, chemical modification of the material is very arduous: this is a consequence of its structure but also of its scarce solubility in most organic solvents. Consequently, studies are necessar to find a feasible and efficient way to exploit it for drug delivery purposes. This PhD work aimed to find a way to valorize gamma-PGA peculiar characteristics in drug delivery field, particularly in the preparation of GE11 directed nanocarriers. We operated on two different sides: on one hand we performed intense studies on the biopolymer exploring its chemical-physical properties (mainly MW and solubility), its structure and its reactivity. On the other hand we studied and optimized methods to functionalize a well known and widely used biopolymer, poly lactic-co-glycolic acid (PLGA), with peptides. Starting from these conjugates we also prepared and characterized nanoparticles intended to be used as a drug delivery tools to EGFR overexpressing cells.
PEPTIDE-POLYMER CONJUGATES AS TOOLS TO SELECTIVELY TARGET EGFR / M. Biagiotti ; tutor: G. Speranza ; coordinator: D. Roberto. - Milano : Università degli studi di Milano. Università degli Studi di Milano, 2014 Dec 05. ((27. ciclo, Anno Accademico 2014.
|Titolo:||PEPTIDE-POLYMER CONJUGATES AS TOOLS TO SELECTIVELY TARGET EGFR|
|Supervisori e coordinatori interni:||ROBERTO, DOMINIQUE MARIE|
|Data di pubblicazione:||5-dic-2014|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||PEPTIDE-POLYMER CONJUGATES AS TOOLS TO SELECTIVELY TARGET EGFR / M. Biagiotti ; tutor: G. Speranza ; coordinator: D. Roberto. - Milano : Università degli studi di Milano. Università degli Studi di Milano, 2014 Dec 05. ((27. ciclo, Anno Accademico 2014.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/biagiotti-marco_phd2014-12-05|
|Appare nelle tipologie:||Tesi di dottorato|