The development of nickel catalysed coordination polymerisation-induced self assembly (NiCCo-PISA) of helical copolymers for asymmetric organocatalytic nanoreactors

This thesis reports the use of helical polymers for the development of helix containing nano-objects through self-assembly of polyisocyanide block copolymers, and their post-polymerisation modification (PPM) to try and achieve enzyme-like enantioselective nanoreactors. Chapter 2 presents the nickel-catalysed coordination polymerisation-induced self-assembly (NiCCo-PISA) of helical amphiphilic block copolymers of polyisocyanide, the exploration of the resulting morphologies and the effect of the helical core an encapsulated dye. Chapter 3 describes the development of functionalisable NiCCo-PISA micelles and their PPM with primary diamines that contain easily detectable moieties which allow the assessment of the substitution reaction and assess the effect on the nanostructures’ stability of the change in pendant groups’ polarity. In Chapter 4 further investigation into the PPM of NiCCo-PISA micelles by diamine cross-linkers with a view towards the formation of stimulus-responsive nano-objects. Chapter 5 builds upon the previous chapters and presents the PPM of polyisocyanide block copolymers and NiCCo-PISA micelles with DMAP derivatives and their use as catalyst and nanoreactor respectively in acetylation reactions. Chapter 6 provides a summary of the key findings of Chapters 2 – 5 and perspectives for the methodology designed in this thesis. Chapter 7 presents the experimental methods of this thesis. Cette thèse explore l’utilisation de polymère hélicoïdaux pour le développement de nano-objets contenant des hélices par l’autoassemblage de copolymère bloc de polyisocyanures et leur modification post-polymérisation (MPP) pour essayer d’achever des nano-réacteurs imitant les enzymes. Le Chapitre 2 présente l’autoassemblage induit par polymérisation de coordination catalysée au nickel (AAIP-CoCNi) de copolymères bloc amphiphile, l’exploration des morphologies résultante et l’effet du cœur hélicoïdal sur un colorant encapsulé. Le Chapitre 3 décrit le développement de micelles fonctionalisables synthétisées par AAIP-CoCNi et leur MPP avec des diamines primaires qui contiennent qui contiennent des fragments facilement détectables qui permettent d'évaluer la réaction de substitution et d'évaluer l'effet sur la stabilité des nanostructures du changement de polarité des groupes latéraux. Dans le chapitre 4, une étude plus approfondie de la MPP des micelles synthétisées par AAIP-CoCNi par des diamines réticulantes en vue de la formation de nano-objets sensibles au stimulus. Le chapitre 5 s'appuie sur les chapitres précédents et présente la MPP des copolymères blocs de polyisocyanure et des micelles synthétisées par AAIP-CoCNi avec des dérivés DMAP et leur utilisation comme catalyseur et nano-réacteur respectivement dans des réactions d'acétylation. Le chapitre 6 résume les principales conclusions des chapitres 2 à 5 et les perspectives de la méthodologie conçue dans cette thèse. Le chapitre 7 présente les méthodes expérimentales de cette thèse

Functional nanostructures by NiCCo-PISA of helical poly(aryl isocyanide) copolymers

Herein, we present a straightforward and versatile methodology to achieve functional polymeric nano-objects that contain helical cores. Nickel-catalysed coordination polymerisation-induced self-assembly (NiCCo-PISA) of helical poly(aryl isocyanide) amphiphilic diblock copolymers was..

Polymersomes-mediated delivery of CSF1R inhibitor to tumor associated macrophages promotes M2 to M1-like macrophage repolarization

The crosstalk between cancer cells and tumor associated macrophages (TAMs) within the tumor environment modulates tumor progression at all stages of cancer disease. TAMs are predominantly M2-like polarized macrophages with tumor-promoting activities. Nonetheless, they can be repolarized to tumoricidal M1-like macrophages through macrophage colony stimulating factor 1 receptor inhibition (CSF1Ri). CSF1Ri is being explored as multifaced therapeutic approach to suppress TAMs tumor-promoting functions and reduce cancer cell aggressiveness and viability. However, treatment with CSF1Ri results in significant TAMs death, thereby extinguishing the possibility of generating tumoricidal M1-like macrophages. Immunotherapy has improved overall patient's survival in some cancer types, but also caused frequent off-target toxicity. Approaches to balance efficacy versus toxicity are needed. Herein, a CSF1Ri loaded polymersomes (PM) based delivery platform is developed to promote M2-like macrophage repolarization. When testing in vitro on primary human monocyte-derived macrophages (MDMs), CSF1Ri loaded PM are preferentially taken up by M2-like macrophages and enhance M2 to M1-like macrophage repolarization while minimizing cytotoxicity in comparison to the free drug. When testing in a MDMs-MDA-MB-231 breast cancer cell co-culture model, CSF1Ri loaded PM further retain their M2 to M1-like macrophages polarization capacity. This CSF1Ri loaded PM-based platform system represents a promising tool for macrophage-based immunotherapy approaches

Mechanically triggered on-demand degradation of polymers synthesized by radical polymerizations

Polymers that degrade on demand have the potential to facilitate chemical recycling, reduce environmental pollution and are useful in implant immolation, drug delivery or as adhesives that debond on demand. However, polymers made by radical polymerization, which feature all carbon-bond backbones and constitute the most important class of polymers, have proven difficult to render degradable. Here we report cyclobutene-based monomers that can be co-polymerized with conventional monomers and impart the resulting polymers with mechanically triggered degradability. The cyclobutene residues act as mechanophores and can undergo a mechanically triggered ring-opening reaction, which causes a rearrangement that renders the polymer chains cleavable by hydrolysis under basic conditions. These cyclobutene-based monomers are broadly applicable in free radical and controlled radical polymerizations, introduce functional groups into the backbone of polymers and allow the mechanically gated degradation of high-molecular-weight materials or cross-linked polymer networks into low-molecular-weight species. (Figure presented.

Mechanically triggered on-demand degradation of polymers synthesized by radical polymerizations

Polymers that degrade on demand have the potential to facilitate chemical recycling, reduce environmental pollution and are useful in implant immolation, drug delivery or as adhesives that debond on demand. However, polymers made by radical polymerization, which feature all carbon-bond backbones and constitute the most important class of polymers, have proven difficult to render degradable. Here we report cyclobutene-based monomers that can be co-polymerized with conventional monomers and impart the resulting polymers with mechanically triggered degradability. The cyclobutene residues act as mechanophores and can undergo a mechanically triggered ring-opening reaction, which causes a rearrangement that renders the polymer chains cleavable by hydrolysis under basic conditions. These cyclobutene-based monomers are broadly applicable in free radical and controlled radical polymerizations, introduce functional groups into the backbone of polymers and allow the mechanically gated degradation of high-molecular-weight materials or cross-linked polymer networks into low-molecular-weight species.ISSN:1755-4349ISSN:1755-433

Nickel-Catalyzed Coordination Polymerization-Induced Self-Assembly of Helical Poly(aryl isocyanide)s

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Stimuli-responsive and core cross-linked micelles developed by NiCCo-PISA of helical poly(aryl isocyanide)s

International audienceWe report the synthesis of redox- and pH-sensitive block copolymer micelles that contain chiral cores composed of helical poly(aryl isocyanide)s. Pentafluorophenyl (PFP) ester-containing micelles synthesised via nickel-catalysed coordination polymerisation-induced self-assembly (NiCCo-PISA) of helical poly(aryl isocyanide) amphiphilic diblock copolymers are modified post-polymerisation with various diamines to introduce cross-links and/or achieve stimulus-sensitive nanostructures. The successful introduction of the diamines is confirmed by Fourier-transform infrared spectroscopy (FT-IR), while the stabilisation effect of the cross-linking is explored by dynamic light scattering (DLS). The retention of the helicity of the core-forming polymer block is verified by circular dichroism (CD) spectroscopy and the stimuli-responsiveness of the nanoparticles towards a reducing agent (L-glutathione, GSH) and pH is evaluated by following the change in the size of the nanoparticles by DLS. These stimuli-responsive nanoparticles could find use in applications such as drug delivery, nanosensors or biological imaging

Synthesis of artificial cells via biocatalytic polymerisation-induced self-assembly

Artificial cells are biomimetic microstructures that mimic functions of natural cells and find application, e.g., as microreactors, as building blocks for molecular systems engineering, and to host synthetic biology pathways. Here, we report enzymatically synthesised polymer-based artificial cells with the ability to express proteins. They are created by biocatalytic atom transfer radical polymerization-induced self-assembly (bioPISA). The metalloprotein myoglobin synthesises amphiphilic block copolymers that self-assemble into structures ranging from micelles over worm-like micelles to polymersomes and giant unilamellar vesicles (GUVs). The GUVs encapsulate cargo during the polymerisation, including enzymes, nanoparticles, microparticles, plasmids and cell lysate. The resulting artificial cells act as microreactors for enzymatic reactions and for osteoblast-inspired biomineralization, and could express proteins when fed with amino acids, as shown by the expression of the fluorescent protein mClover and of actin. Actin polymerises in the vesicles and alters the artificial cell’s internal structure by creating internal compartments. Thus, bioPISA-derived GUVs mimic bacteria as they are composed of a microscopic reaction compartment that contains genetic information which is able to express proteins upon induction. bioPISA not only is a powerful tool in the pursuit of artificial cells but also for the easy and highly efficient encapsulation of biological molecules under mild conditions and in biologically relevant media. Therefore, it could have significant implications for the development of biomaterials and drug-delivery systems, as well as for cell encapsulation, and the in-situ formation of nano-objects

Artificial cell synthesis using biocatalytic polymerization-induced self-assembly

Artificial cells are biomimetic microstructures that mimic functions of natural cells, can be applied as building blocks for molecular systems engineering, and host synthetic biology pathways. Here we report enzymatically synthesized polymer-based artificial cells with the ability to express proteins. Artificial cells were synthesized using biocatalytic atom transfer radical polymerization-induced self-assembly, in which myoglobin synthesizes amphiphilic block co-polymers that self-assemble into structures such as micelles, worm-like micelles, polymersomes and giant unilamellar vesicles (GUVs). The GUVs encapsulate cargo during the polymerization, including enzymes, nanoparticles, microparticles, plasmids and cell lysate. The resulting artificial cells act as microreactors for enzymatic reactions and for osteoblast-inspired biomineralization. Moreover, they can express proteins such as a fluorescent protein and actin when fed with amino acids. Actin polymerizes in the vesicles and alters the artificial cells’ internal structure by creating internal compartments. Thus, biocatalytic atom transfer radical polymerization-induced self-assembly-derived GUVs can mimic bacteria as they are composed of a microscopic reaction compartment that contains genetic information for protein expression upon induction

Mechanically Triggered On-Demand Degradation of Polymers Synthesized by Radical Polymerizations

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