Publications by authors named "Marck Norret"

20 Publications

  • Page 1 of 1

A dendronised polymer architecture breaks the conventional inverse relationship between porosity and mechanical properties of hydrogels.

Chem Commun (Camb) 2021 Jan;57(6):773-776

School of Molecular Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia.

We present a series of synthetic polymer hydrogels which break the traditional correlation between pore size and mechanical properties. The hydrogels are prepared from a dendronised polymer architecture based on a methacrylate copolymer to which poly(amido amine) dendrons are attached. Our approach will be useful in tailoring hydrogels for tissue engineering, controlled drug release, and flexible electronics.
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http://dx.doi.org/10.1039/d0cc07115cDOI Listing
January 2021

Surface Diffusion of Dendronized Polymers Correlates with Their Transfection Potential.

Langmuir 2020 08 29;36(31):9074-9080. Epub 2020 Jul 29.

School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.

Successful intracellular delivery of therapeutics requires interactions at several liquid-solid interfaces, including cell surface, endosomal membranes, and-depending on the therapeutic-the nuclear membrane. Understanding the dynamics of polymer kinetics at the liquid-solid interface is fundamental for the design of polymers for such biomedical delivery applications. However, the effect of polymer architecture and charge density on polymer kinetics is not readily investigated using routine techniques, and the role of such parameters in the context of gene delivery remains unknown. We adopted a synthetic strategy which enabled the systematic manipulation of charge density, flexibility, and molecular weight using a dendronized linear polymeric architecture. High-speed atomic force microscopy (HS-AFM) was used as a label-free method to directly observe the polymers' dynamic properties, such as velocity, displacement, and diffusion, in physiologically relevant conditions. Importantly, we found that the physical parameters measured by HS-AFM relate to the transfection potential of the individual polymers and may be a valuable tool in screening structural polymer variants.
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http://dx.doi.org/10.1021/acs.langmuir.0c01080DOI Listing
August 2020

A dendronized polymer variant that facilitates safe delivery of a calcium channel antagonist to the heart.

Nanomedicine 2020 10 10;29:102264. Epub 2020 Jul 10.

School of Human Sciences (Physiology), The University of Western Australia, Crawley, WA, Australia; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia. Electronic address:

Therapeutic approaches for myocardial ischemia-reperfusion injury (MI) have been ineffective due to limited bioavailability and poor specificity. We have previously shown that a peptide that targets the α-interaction domain of the cardiac L-type calcium channel (AID-peptide) attenuates MI when tethered to transactivator of transcription sequence (TAT) or spherical nanoparticles. However some reservations remain regarding use of these delivery platforms due to the relationship with human immunodeficiency virus, off-target effects and toxicity. Here we investigate the use of linear dendronized polymers (denpols) to deliver AID-peptide as a potential MI therapy using in vitro, ex vivo and in vivo models. Optimized denpol-complexed AID-peptide facilitated in vitro cardiac uptake of AID-peptide, and reduced MI. Maximal in vivo cardiac uptake was achieved within the 2 h therapeutic time window for acute myocardial infarction. Importantly, optimized denpol-complexed AID-peptide was not toxic. This platform may represent an alternative therapeutic approach for the prevention of MI.
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http://dx.doi.org/10.1016/j.nano.2020.102264DOI Listing
October 2020

Macromolecular approach for targeted radioimmunotherapy in non-Hodgkin's lymphoma.

Chem Commun (Camb) 2019 Nov;55(96):14506-14509

School of Molecular Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia.

Polymers are an attractive anchoring platform for the synthesis of radioimmunoconjugates. They enable independent control over the amount of radioisotope loading and antibody attachment, which is pivotal in developing tailorable formulations for personalised medicine. Herein, we report the synthesis of p(HEMA-ran-GMA) for the conjugation of lutetium ions and rituximab as a functional platform for radioimmunotherapy. We demonstrate the suitability of this platform using non-Hodgkin's lymphoma cells.
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http://dx.doi.org/10.1039/c9cc06603aDOI Listing
November 2019

Novel Hydrophilic Copolymer-Based Nanoparticle Enhances the Therapeutic Efficiency of Doxorubicin in Cultured MCF-7 Cells.

ACS Omega 2019 Oct 11;4(17):17083-17089. Epub 2019 Oct 11.

School of Molecular Sciences and School of Biological Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.

Nanoparticle drug delivery applications have predominantly focused on the entrapment and delivery of hydrophobic molecules with poor water solubility. However, benefits can also be obtained from nanoparticle-based delivery of hydrophilic therapeutics. This study reports on the development of a p(HEMA--GMA)-based nanoparticle synthesized via a spontaneous water-in-oil inverse nanoemulsion to deliver doxorubicin, a water-soluble chemotherapeutic. High drug loading efficiency and sustained release of doxorubicin from Cy5-functionalized p(HEMA--GMA) nanoparticles enabled effective inhibition of the MCF-7 human breast cancer derived cell line. Direct comparative analyses with a hydrophobic PGMA nanoparticle demonstrated enhanced capabilities of the p(HEMA--GMA)-based nanoparticle in vitro. The results suggest that p(HEMA--GMA)-based nanoparticles, which are better suited for hydrophilic drug loading and delivery, may have the potential for the improved therapeutic effect in vivo by enhanced permeation and retention of the nanoparticles by avoidance of off-site side effects of the chemotherapeutic.
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http://dx.doi.org/10.1021/acsomega.8b02894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811859PMC
October 2019

Tumour suppression by targeted intravenous non-viral CRISPRa using dendritic polymers.

Chem Sci 2019 Sep 27;10(33):7718-7727. Epub 2019 Jun 27.

Harry Perkins Institute of Medical Research , 6 Verdun St , Nedlands , WA 6009 , Australia . Email:

Aberrant gene expression is a hallmark of cancer. Although transcription is traditionally considered 'undruggable', the development of CRISPR-associated protein 9 (Cas9) systems offers enormous potential to rectify cancer-associated transcriptional abnormalities in malignant cells. However delivery of this technology presents a critical challenge to overcome in order to realize clinical translation for cancer therapy. In this article we demonstrate for the first time, a fully synthetic strategy to enable CRISPR-mediated activation (CRISPRa) of tumour suppressor genes using a targeted intravenous approach. We show this highly efficient transcriptional activation of two model tumour suppressor genes, Mammary Serine Protease Inhibitor (MASPIN, ) and cysteine-rich 61/connective tissue growth factor/nephroblastoma-overexpressed 6 (, ), in a mouse model of breast cancer. In particular, we demonstrate that targeted intravenous delivery of can be achieved using a novel nanoscale dendritic macromolecular delivery agent, with negligible toxicity and long lasting therapeutic effects, outlining a targeted effective formulation with potential to treat aggressive malignancies.
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http://dx.doi.org/10.1039/c9sc01432bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761875PMC
September 2019

Elucidating the Inability of Functionalized Nanoparticles to Cross the Blood-Brain Barrier and Target Specific Cells in Vivo.

ACS Appl Mater Interfaces 2019 Jun 12;11(25):22085-22095. Epub 2019 Jun 12.

Curtin Health Innovation Research Institute , Curtin University , Bentley 6102 , Australia.

The adsorption of serum proteins on the surface of nanoparticles (NPs) delivered into a biological environment has been known to alter NP surface properties and consequently their targeting efficiency. In this paper, we use random copolymer (p(HEMA- ran-GMA))-based NPs synthesized using 2-hydroxyethyl methacrylate (HEMA) and glycidyl methacrylate (GMA). We show that serum proteins bind to the NP and that functionalization with antibodies and peptides designed to facilitate NP passage across the blood-brain barrier (BBB) to bind specific cell types is ineffective. In particular, we use systematic in vitro and in vivo analyses to demonstrate that p(HEMA- ran-GMA) NPs functionalized with HIV-1 trans-activating transcriptor peptide (known to cross the BBB) and α neural/glial antigen 2 (NG2) (known for targeting oligodendrocyte precursor cells (OPCs)), individually and in combination, do not specifically target OPCs and are unable to cross the BBB, likely due to the serum protein binding to the NPs.
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http://dx.doi.org/10.1021/acsami.9b01356DOI Listing
June 2019

Intracellular speciation of gold nanorods alters the conformational dynamics of genomic DNA.

Nat Nanotechnol 2018 12 8;13(12):1148-1153. Epub 2018 Oct 8.

School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, Australia.

Gold nanorods are one of the most widely explored inorganic materials in nanomedicine for diagnostics, therapeutics and sensing. It has been shown that gold nanorods are not cytotoxic and localize within cytoplasmic vesicles following endocytosis, with no nuclear localization, but other studies have reported alterations in gene expression profiles in cells following exposure to gold nanorods, via unknown mechanisms. In this work we describe a pathway that can contribute to this phenomenon. By mapping the intracellular chemical speciation process of gold nanorods, we show that the commonly used Au-thiol conjugation, which is important for maintaining the noble (inert) properties of gold nanostructures, is altered following endocytosis, resulting in the formation of Au(I)-thiolates that localize in the nucleus. Furthermore, we show that nuclear localization of the gold species perturbs the dynamic microenvironment within the nucleus and triggers alteration of gene expression in human cells. We demonstrate this using quantitative visualization of ubiquitous DNA G-quadruplex structures, which are sensitive to ionic imbalances, as an indicator of the formation of structural alterations in genomic DNA.
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http://dx.doi.org/10.1038/s41565-018-0272-2DOI Listing
December 2018

Multicarbazole scaffolds for selective G-quadruplex binding.

Chem Commun (Camb) 2018 Aug;54(69):9647-9650

School of Molecular Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia.

Herein we report a new class of G-quadruplex stabilising ligands, multicarbazoles, which display high G-quadruplex DNA selectivity in the presence of 250 times excess duplex DNA. We report the synthesis of these compounds in moderate to high yields. Ligands in the series with optimal G-quadruplex selectivity contain an N-propylamino chain length where the amino functionalities are either pyrrolidine or piperidine.
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http://dx.doi.org/10.1039/c8cc03945cDOI Listing
August 2018

Non-viral Methodology for Efficient Co-transfection.

Methods Mol Biol 2018 ;1767:241-254

School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia.

The potential impact of CRISPR/Cas9, TALE, and zinc finger technology is immense, both with respect to their use as tools for understanding the roles and functions of the genomic elements and epigenome modifications in an endogenous context and as new methods for treatment of diseases. Application of such technologies has drawn attention, however, to the prevailing lack of effective delivery methods. Promising viral and non-viral methods both currently fall short when the efficient delivery of large plasmids or multiple plasmids is required. Therefore, the use of TALE and CRISPR platforms has been severely limited in applications where selection methods to increase the relative proportion of treated cells are not applicable, and it represents a significant bottleneck in the further application of these tools as therapeutics.The protocol presented here describes the synthesis of a dendronized polymer as a highly efficient and nontoxic transfection agent. Furthermore, the optimization of the polymer as a co-transfection reagent for large and multiple plasmids in cell lines is described, in addition to general considerations for co-transfection experiments. Usage of this method has allowed for significantly improved large plasmid co-transfection efficiency over Lipofectamine 2000 in multiple cell lines, allowing an improved delivery of CRISPR/dCas9 and TALE systems.
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http://dx.doi.org/10.1007/978-1-4939-7774-1_13DOI Listing
February 2019

The Protein Corona of PEGylated PGMA-Based Nanoparticles is Preferentially Enriched with Specific Serum Proteins of Varied Biological Function.

Langmuir 2017 11 30;33(45):12926-12933. Epub 2017 Oct 30.

Curtin Health Innovation Research Institute, Curtin University and the Perron Institute for Neurological and Translational Science, Sarich Neuroscience Research Institute, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.

The composition of the protein corona formed on poly(ethylene glycol)-functionalized (PEGylated) poly(glycidyl methacrylate) (PGMA) nanoparticles (NPs) was qualitatively and quantitatively compared to the protein corona on non-PEGylated PGMA NPs. Despite the reputation of PEGylated NPs for stealth functionality, we demonstrate the preferential enrichment of specific serum proteins of varied biological function in the protein corona on PEGylated NPs when compared to non-PEGylated NPs. Additionally, we suggest that the base material of polymeric NPs plays a role in the preferential enrichment of select serum proteins to the hard corona.
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http://dx.doi.org/10.1021/acs.langmuir.7b02568DOI Listing
November 2017

Maternal-placental-fetal biodistribution of multimodal polymeric nanoparticles in a pregnant rat model in mid and late gestation.

Sci Rep 2017 06 6;7(1):2866. Epub 2017 Jun 6.

Division of Obstetrics & Gynaecology, The University of Western Australia, Perth, WA, 6009, Australia.

Multimodal polymeric nanoparticles have many exciting diagnostic and therapeutic applications, yet their uptake and passage by the placenta, and applications in the treatment of pregnancy complications have not been thoroughly investigated. In this work, the maternal-fetal-placental biodistribution of anionic and cationic multimodal poly(glycidyl methacrylate) (PGMA) nanoparticles in pregnant rats at mid (ED10) and late (ED20) gestation was examined. Fluorescently-labelled and superparamagnetic PGMA nanoparticles functionalized with/without poly(ethyleneimine) (PEI) were administered to pregnant rats at a clinically-relevant dose and biodistribution and tissue uptake assessed. Quantitative measurement of fluorescence intensity or magnetic resonance relaxometry in tissue homogenates lacked the sensitivity to quantify tissue uptake. Confocal microscopy, however, identified uptake by maternal organs and the decidua (ectoplacental cone) and trophoblast giant cells of conceptuses at ED10. At ED20, preferential accumulation of cationic vs. anionic nanoparticles was observed in the placenta, with PGMA-PEI nanoparticles localised mainly within the chorionic plate. These findings highlight the significant impact of surface charge and gestational age in the biodistribution of nanoparticles in pregnancy, and demonstrate the importance of using highly sensitive measurement techniques to evaluate nanomaterial biodistribution and maternal-fetal exposure.
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http://dx.doi.org/10.1038/s41598-017-03128-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460222PMC
June 2017

Synthetically controlling dendrimer flexibility improves delivery of large plasmid DNA.

Chem Sci 2017 Apr 27;8(4):2923-2930. Epub 2017 Jan 27.

School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia . Email: ; Email:

Tools for editing the genome and epigenome have revolutionised the field of molecular biology and represent a new frontier in targeted therapeutic intervention. Although efficiencies and specificities of genome editing technologies have improved with the development of TALEs and CRISPR platforms, intracellular delivery of these larger constructs still remains a challenge using existing delivery agents. Viral vectors, including lentiviruses and adeno-associated viruses, as well as some non-viral strategies, such as cationic polymers and liposomes, are limited by packaging capacity, poor delivery, toxicity, and immunogenicity. We report a highly controlled synthetic strategy to engineer a flexible dendritic polymer using click chemistry to overcome the aforementioned delivery challenges associated with genome engineering technologies. Using a systematic approach, we demonstrate that high transfection efficiencies and packaging capacity can be achieved using this non-viral delivery methodology to deliver zinc fingers, TALEs and CRISPR/dCas9 platforms.
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http://dx.doi.org/10.1039/c7sc00097aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376716PMC
April 2017

An Unexpected Transient Breakdown of the Blood Brain Barrier Triggers Passage of Large Intravenously Administered Nanoparticles.

Sci Rep 2016 Mar 4;6:22595. Epub 2016 Mar 4.

Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Perth, WA 6009, Australia.

The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining brain homeostasis and is pivotal for proper neuronal function. The BBB is currently considered the main limiting factor restricting the passage of large (up to 200 nm) intravenously administered nanoparticles to the brain. Breakdown of the barrier occurs as a consequence of cerebrovascular diseases and traumatic brain injury. In this article, we report that remote injuries in the CNS are also associated with BBB dysfunction. In particular, we show that a focal partial transection of the optic nerve triggers a previously unknown transient opening of the mammalian BBB that occurs in the visual centres. Importantly, we demonstrate that this transient BBB breakdown results in a dramatic change in the biodistribution of intravenously administered large polymeric nanoparticles which were previously deemed as BBB-impermeable.
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http://dx.doi.org/10.1038/srep22595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778073PMC
March 2016

Dose-Dependent Therapeutic Distinction between Active and Passive Targeting Revealed Using Transferrin-Coated PGMA Nanoparticles.

Small 2016 Jan 30;12(3):351-9. Epub 2015 Nov 30.

School of Chemistry and Biochemistry, The University of Western Australia, Crawley, W. A., 6009, Australia.

The paradigm of using nanoparticle-based formulations for drug delivery relies on their enhanced passive accumulation in the tumor interstitium. Nanoparticles with active targeting capabilities attempt to further enhance specific delivery of drugs to the tumors via interaction with overexpressed cellular receptors. Consequently, it is widely accepted that drug delivery using actively targeted nanoparticles maximizes the therapeutic benefit and minimizes the off-target effects. However, the process of nanoparticle mediated active targeting initially relies on their passive accumulation in tumors. In this article, it is demonstrated that these two tumor-targeted drug delivery mechanisms are interrelated and dosage dependent. It is reported that at lower doses, actively targeted nanoparticles have distinctly higher efficacy in tumor inhibition than their passively targeted counterparts. However, the enhanced permeability and retention effect of the tumor tissue becomes the dominant factor influencing the efficacy of both passively and actively targeted nanoparticles when they are administered at higher doses. Importantly, it is demonstrated that dosage is a pivotal parameter that needs to be taken into account in the assessment of nanoparticle mediated targeted drug delivery.
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http://dx.doi.org/10.1002/smll.201502730DOI Listing
January 2016

A Domino Diels-Alder Approach toward the Tetracyclic Nicandrenone Framework.

Org Lett 2015 Nov 2;17(22):5517-9. Epub 2015 Nov 2.

Research School of Chemistry, Australian National University , Canberra, ACT 2601, Australia.

The tetracarbocyclic framework of the nicandrenone natural products is formed in one step from a linear precursor via a domino intramolecular Diels-Alder/intramolecular furan Diels-Alder/aromatization sequence. The approach represents a new 0 → ABCD strategy for the preparation of aromatic steroids.
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http://dx.doi.org/10.1021/acs.orglett.5b02412DOI Listing
November 2015

Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands.

Org Biomol Chem 2011 Sep 13;9(17):6154-62. Epub 2011 Jul 13.

Centre for Strategic Nano-Fabrication, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, WA-6009, Australia.

A series of novel 2,4,6-triarylpyridines have been synthesized and their interactions with intramolecular G-quadruplexes have been measured by Förster Resonance Energy Transfer (FRET) melting and Fluorescent Intercalator Displacement (FID) assays. A few of these compounds exhibit stabilization of G4-DNA that is comparable to other benchmark G4-DNA ligands with fair to excellent G4-DNA vs. duplex selectivity and significant cytotoxicity towards HeLa cells. The nature of the 4-aryl substituents along with side chain length governs the G4-DNA stabilization ability of the compounds. In addition, we demonstrate that there is a strong correlation between the ability of the compounds to stabilize the same G4-DNA sequence in K(+) and Na(+) conditions and a strong correlation between the ability of the compounds to stabilize different G4-DNA sequences in K(+) or Na(+) buffer.
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http://dx.doi.org/10.1039/c1ob05560gDOI Listing
September 2011

Loading molecular hydrogen cargo within viruslike nanocontainers.

Angew Chem Int Ed Engl 2008 ;47(34):6362-6

Centre for Strategic Nano-Fabrication, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, WA-6009, Australia.

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http://dx.doi.org/10.1002/anie.200802441DOI Listing
September 2008

The Zipper-Mode Domino Intramolecular Diels-Alder Reaction: A New 0→ABCD Strategy for Steroids and Related Compounds.

Angew Chem Int Ed Engl 2001 Nov;40(21):4074-4076

School of Chemistry University of Sydney Sydney, NSW 2006 (Australia) Fax: (+61) 2-9351-6650.

Four C-C bonds, four rings, and eight contiguous stereocenters in one go! Tetracyclic product 2, which results on warming simple acyclic precursor 1 with a mild Lewis acid, is formed through an efficient and highly stereoselective domino sequence of two intramolecular Diels-Alder reactions. Pharmacologically important norsteroids are just one potential application of this extremely effective approach to fused polycyclic systems.
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http://dx.doi.org/10.1002/1521-3773(20011105)40:21<4074::AID-ANIE4074>3.0.CO;2-JDOI Listing
November 2001