edoc

Stimuli-responsive amphiphilic peptides for biomedical applications

Sigg, Severin J.. Stimuli-responsive amphiphilic peptides for biomedical applications. 2016, PhD Thesis, University of Basel, Faculty of Science.

[img]
Preview
PDF
33Mb

Official URL: http://edoc.unibas.ch/diss/DissB_11712

Downloads: Statistics Overview

Abstract

The overarching goal of the present thesis entitled “Stimuli-Responsive Amphiphilic Peptides for Biomedical Applications” was the de novo design and synthesis of responsive and functional amphiphilic peptides as molecular building blocks to self-assemble into smart nanoparticles for biomedical applications. These encompass two functional classes: diagnostic nanoparticles and therapeutic nanoparticles.
In the past decades numerous drug- and gene-delivery carriers have been developed to increase therapeutic efficacy, decrease drug doses, and minimize side effects. While drug delivery carriers for small molecule drugs became well established, noncytotoxic gene delivery remains a major challenge. Additionally, emerging beneficial synergistic effects, combining therapeutic drugs and/or genes created a tremendous demand for sophisticated and responsive codelivery systems. Similarly, current diagnostic nanoparticles still lack high sensitivity and specificity. There is, for instance, a great need for highly sensitive and responsive MRI contrast agents for early diagnosis of diseases.
A first project aimed for the production of peptide nanoparticles for theragnostic purposes, i.e. condensing diagnostic and therapeutic requirements down into one nanoparticle design. Therefore, we created composite peptide–gold nanoparticle superstructures. The high optical density and thermoplasmonic properties of the gold nanoparticles within the self-assemblies allow diagnostic imaging triggered release of entrapped payload upon external stimuli, such as near infrared light. The obtained densely packed gold nanoparticle superstructures contain individual gold nanoparticles separated by a peptide bilayer. We proved that these amphiphilic peptides are capable of serving as scaffolds for gold nanoparticles, highlighting the strong driving forces to self-assemble in aqueous solution. These nanoparticles mighty find application in diagnostics, being used for probing cellular uptake pathways, or for real-time drug delivery imaging.
A second project focused on creating a codelivery carrier for antisense oligonucleotides and small molecule drugs. Such systems are crucial for combined treatments to combat multidrug resistance or to exploit synergistic effects of drug–gene or drug–drug combinations. Therefore, we engineered amphiphilic peptides bearing moieties to condense nucleic acid payloads and/or hydrophilic payloads and a hydrophobic region able to entrap small drugs upon self-assembly. The peptides were further equipped with a reduction-sensitive linker for triggered decomposition and cargo release in physiologic conditions at diseases sites. Straightforward rational design combining desired features within one peptide sequence led to noncytotoxic peptide nanoparticles with sizes optimal for biomedical applications (100–150 nm). The created nanoassemblies were able to carry hydrophilic, nucleic acid, and hydrophobic payloads. Further, they revealed high coloading efficiency and were highly sensitive to reductive trigger releasing both payloads in a fast manner. This novel codelivery system is further characterized by effective cell uptake and high therapeutic efficacy delivering the hydrophilic model drug DoxHCl.
A third project addressed the development of amphiphilic peptides bearing polylysine hydrophilic regions to achieve gene transfection in vitro. The created peptides showed good plasmid DNA condensing abilities and formed nanoparticles in appropriate sizes for biomedical applications. Subsequent transfection experiments revealed high efficiencies. The developed purely peptidic nanoparticles show very promising potential towards highly potent gene transfection agents.
A fourth project aimed at the development of a highly sensitive MRI contrast agent. Therefore, we used an amphiphilic block copolymer bearing a hydrophilic block of heparin, known to possess high affinity to trivalent lanthanides such as gadolinium. Gadolinium is widely used as a positive contrast agent to increase contrast in MRI due to its high paramagnetism. The constructed contrast agent revealed relaxivities of more than one order of magnitude higher (44 mM 1s 1) compared to commercially available contrast agents (~4 mM 1s 1). For achieving triggered contrast enhancement, the copolymer was coassembled with a reduction-responsive amphiphilic peptide. Physiologic amounts of reducing agent resulted in a relaxivity increase from 44 to 54 mM-1s-1, which is about 20%. Important properties such as its nontoxicity, lack of anticoagulation activity, and stability over seven months regarding gadolinium release suggest this reduction-responsive highly sensitive MRI contrast agent as very promising candidate for selective contrast enhancement at disease sites.
The present dissertation demonstrates, that rational design of amphiphilic peptides can lead to multifunctional, biocompatible, and biodegradable nanoarchitectures self-assembled in a well-defined manner. Functionality is introduced by point mutations in the peptide sequence. The projects presented here provide an array of tailor-made amphiphilic peptides, tuned to distinct properties required for their intended applications.
Advisors:Meier, Wolfgang P. and Bruns, Nico
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Makromolekulare Chemie (Meier)
Item Type:Thesis
Thesis no:11712
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (XVIII, 132 Seiten)
Language:English
Identification Number:
Last Modified:02 Sep 2016 09:34
Deposited On:02 Sep 2016 09:33

Repository Staff Only: item control page