Hybrid material | EPFL Graph Search

Hybrid materials are composites consisting of two constituents at the nanometer or molecular level. Commonly one of these compounds is inorganic and the other one organic in nature. Thus, they differ from traditional composites where the constituents are at the macroscopic (micrometer to millimeter) level. Mixing at the microscopic scale leads to a more homogeneous material that either show characteristics in between the two original phases or even new properties. Introduction Hybrid materials in nature Many natural materials consist of inorganic and organic building blocks distributed on the nanoscale. In most cases the inorganic part provides mechanical strength and an overall structure to the natural objects while the organic part delivers bonding between the inorganic building blocks and/or the rest of the tissue. Typical examples include bone and nacre. Development of hybrid materials The first hybrid materials were the paints made from inorganic an

Self-assembly of protein-polymer conjugates for drug delivery

Kuljeet Kaur, Harm-Anton Klok, Corey Alfred Stevens

Protein-polymer conjugates are a class of molecules that combine the stability of polymers with the diversity, specificity, and functionality of biomolecules. These bioconjugates can result in hybrid materials that display properties not found in their individual components and can be particularly relevant for drug delivery applications. Engineering amphiphilicity into these bioconjugate materials can lead to phase separation and the assembly of high-order structures. The assembly, termed self-assembly, of these hierarchical structures entails multiple levels of organization: at each level, new properties emerge, which are, in turn, influenced by lower levels. Here, we provide a critical review of protein-polymer conjugate self-assembly and how these materials can be used for therapeutic applications and drug delivery. In addition, we discuss central bioconjugate design questions and propose future perspectives for the field of protein-polymer conjugate self-assembly.

2021

Peptide-Polymer Conjugates for Therapeutic Applications

Ana Maria Raduta

Over the last ten years the attention of the pharmaceutical industry has shifted away from small molecules to focus on new biologics such as antibodies, proteins and therapeutic peptides. Herein, peptides have emerged as a particularly interesting category that fills a niche between small molecule chemicals and the larger proteins. Although they have great potential for drug development, their use is still limited due to their intrinsic low systemic stability, rapid renal elimination and poor membrane permeability. Various formulations have been developed to take advantage of their therapeutic properties, one of the most promising strategies being chemical conjugation to a polymer. Peptide-polymer conjugates are hybrid materials that consist of one or more synthetic polymers covalently attached to one or more peptide fragments. The aim of this thesis was to provide an insight into the requirements for the design of peptide-polymer conjugates for therapy. Chapter 1 illustrates the state of the art in the development of peptides for therapeutic applications, exemplifies the different architectures and structures of peptide-polymer conjugates and discusses ongoing efforts to improve and diversify the range and applications of these conjugates. Chapter 2 describes a novel synthetic strategy to prepare PHPMA based peptide-polymer conjugates via thiol chemistry starting from poly(pentafluorophenyl methacrylate). By varying the feed composition, the extent of side chain modification could be controlled. Further modification of the reactive copolymer scaffolds led to the site specific attachment of model peptides. This method was used to synthesize stable as well as pH and redox sensitive peptide-polymer conjugates and the release of the peptide from the polymer backbone was studied in acidic and redox conditions. In Chapter 3, the aim was to construct a peptide-polymer conjugate that could serve to promote intracellular delivery and drug release but also play a role in the intracellular trafficking of the drug. To this end, coiled coil peptides E3/K3 was attached to a PHPMA polymer backbone and was used to facilitate release from the backbone at acidic pH and further endosomal escape. Initially, the membrane lytic properties of E3/K3 and three newly designed E3/K3X motifs on model membranes were investigated as a function of pH. Secondly, the potential application of E3/K3 peptide-polymer conjugate for cytoplasmic delivery was evaluated in vitro. Chapter 4 explores the synthesis and in vitro therapeutic activity of synthetic peptide-polymer conjugates focusing on the inhibition of an oncogenic transcription factor (AP-1). To this end, AFosW peptide, a peptide binder that can interfere with AP-1 formation was attached to a polymer backbone via a redox or pH sensitive linker using a strategy developed in Chapter 2. Fluorescent microscopy and flow cytometry provided an insight into the cellular uptake of these conjugates. Their ability to interfere with AP-1 formation in vitro was quantified. Chapter 5 describes the synthesis of a second generation of peptide-polymer conjugates for AP-1 inhibition that along the FosW dominant negative peptide also incorporates a motif that facilitates endosomal escape and a nuclear localization sequence. To investigate the potential application for therapy, the conjugates were evaluated and compared with regard to their ability to inhibit AP-1 formation in living cells.

EPFL2015

Functional polypeptide and hybrid materials: Precision synthesis via alpha-amino acid N-carboxyanhydride polymerization and emerging biomedical applications

Harm-Anton Klok

Polypeptides derived from naturally occurring a-amino acids have emerged as a unique and versatile family of bio-inspired biomaterials that can be tailor-made for varying biomedical applications such as controlled drug release, gene delivery, tissue engineering and regenerative medicine. In contrast to traditional biodegradable polymers such as aliphatic polyesters and polycarbonates, polypeptides are inherently functional, allow precise control over polarity and charges, show excellent stability against hydrolysis, and are prone to rapid biodegradation in vivo by specific enzymes. Ring-opening polymerization (ROP) of alpha-amino acid N-carboxyanhydrides (NCAs) is the most straightforward and practical approach for large-scale production of high molecular weight polypeptides. In the past decade, a remarkable progress has been made in controlled NCA polymerization, which offers an unprecedented access to precision polypeptide and hybrid materials by combining with living radical polymerization, click chemistry, and/or post-polymerization modification. Notably, several micellar anti-cancer drugs based on poly(ethylene glycol)-polypeptides have been already advanced to the clinical evaluation. In this review paper, we give an overview on de novo design, controlled synthesis and emerging biomedical applications of functional polypeptide and hybrid materials. (C) 2013 Elsevier Ltd. All rights reserved.

Elsevier2014

Peptide-Polymer Conjugates for Therapeutic Applications

Ana Maria Raduta

EPFL2015