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Article ; Online: Precise and systematic end group chemistry modifications on PAMAM and poly(l-lysine) dendrimers to improve cytosolic delivery of mRNA

Joubert, Fanny / Munson, Michael J. / Sabirsh, Alan / England, Richard M. / Hemmerling, Martin / Alexander, Cameron / Ashford, Marianne B.

Journal of Controlled Release. 2023 Apr., v. 356 p.580-594

2023

Abstract: Here, we aimed to chemically modify PAMAM dendrimers using lysine as a site-selective anchor for successfully delivering mRNA while maintaining a low toxicity profile. PAMAM dendrimers were multi-functionalised by amidation reactions in a regioselective, ...

Abstract	Here, we aimed to chemically modify PAMAM dendrimers using lysine as a site-selective anchor for successfully delivering mRNA while maintaining a low toxicity profile. PAMAM dendrimers were multi-functionalised by amidation reactions in a regioselective, quantitative and stepwise manner with carefully selected property-modifying surface groups. Alternatively, novel lysine-based dendrimers were prepared in the same manner with the aim to unlock their potential in gene delivery. The modified dendrimers were then formulated with Cy5-EGFP mRNA by bulk mixing via liquid handling robotics across different nitrogen to phosphate ratios. The resulting dendriplexes were characterised by size, charge, mRNA encapsulation, and mRNA binding affinity. Finally, their in-vitro delivery activity was systematically investigated across key cellular trafficking stages to relate chemical design to cellular effect. We demonstrate our findings in different cell lines and benchmarked relative to a commercially available transfection agent, jetPEI®. We demonstrate that specific surface modifications are required to generate small, reliable and well-encapsulated positively charged dendriplex complexes. Furthermore, we show that introduction of fusogenic groups is essential for driving endosomal escape and achieving cellular delivery and translation of mRNA in these cell lines.
Keywords	dendrimers ; encapsulation ; liquids ; lysine ; nitrogen ; phosphates ; regioselectivity ; toxicity ; transfection ; Dendrimer ; mRNA ; PAMAM ; Functional delivery ; Chemistry ; Formulation ; GAL9 ; pDNA ; PCA
Language	English
Dates of publication	2023-04
Size	p. 580-594.
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2023.03.011
Database	NAL-Catalogue (AGRICOLA)

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Article: Designing Highly Stable Poly(sarcosine)-Based Telodendrimer Micelles with High Drug Content Exemplified with Fulvestrant

Yu, Qing / England, Richard M. / Gunnarsson, Anders / Luxenhofer, Robert / Treacher, Kevin / Ashford, Marianne B.

Macromolecules. 2022 Jan. 07, v. 55, no. 2

2022

Abstract: Polymeric micelles have been extensively used as nanocarriers for the delivery of chemotherapeutic agents, aiming to improve their efficacy in cancer treatment. However, the poor loading capacity, premature drug release, non-uniformity, and ... ...

Abstract	Polymeric micelles have been extensively used as nanocarriers for the delivery of chemotherapeutic agents, aiming to improve their efficacy in cancer treatment. However, the poor loading capacity, premature drug release, non-uniformity, and reproducibility still remain the major challenges. To create a stable polymeric micelle with high drug loading, a telodendrimer micelle was developed as a nanocarrier for fulvestrant, as an example of a drug that has extremely poor water solubility (sub-nanomolar range). Telodendrimers were prepared by the synthesis of hydrophilic linear poly(sarcosine) and growing a lysine dendron from the chain terminal amine by divergent synthesis. At the periphery of the dendritic block, either 4, 8, or 16 fulvestrant molecules were conjugated to the lysine dendron creating a hydrophobic block. Having drug molecules as a part of the carrier not only reduces the usage of the inert carrier materials but also prevents the drugs from leakage and premature release by diffusion. The self-assembled telodendrimer micelles demonstrated good colloidal stability (cmc < 2 μM) in buffer and were uniform in size. In addition, these telodendrimer micelles could solubilize additional fulvestrant yielding an excellent overall drug loading capacity of up to 77 wt % total drug load (summation of conjugated and encapsulated). Importantly, the size of the micelles could be tuned between 25 and 150 nm by controlling (i) the ratio between hydrophilic and hydrophobic blocks and (ii) the amount of encapsulated fulvestrant. The versatility of these telodendrimer-based micelle systems to both conjugated and encapsulated drugs with high efficiency and stability, in addition to possessing other tuneable properties, makes it a promising drug delivery system for a range of active pharmaceutical ingredients and therapeutic targets.
Keywords	cancer therapy ; drug therapy ; drugs ; encapsulation ; hydrophilicity ; hydrophobicity ; lysine ; micelles ; nanocarriers ; polymers ; sarcosines ; water solubility
Language	English
Dates of publication	2022-0107
Size	p. 401-412.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1491942-4
ISSN	1520-5835 ; 0024-9297
ISSN (online)	1520-5835
ISSN	0024-9297
DOI	10.1021/acs.macromol.1c02086
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Precise and systematic end group chemistry modifications on PAMAM and poly(l-lysine) dendrimers to improve cytosolic delivery of mRNA.

Joubert, Fanny / Munson, Michael J / Sabirsh, Alan / England, Richard M / Hemmerling, Martin / Alexander, Cameron / Ashford, Marianne B

Journal of controlled release : official journal of the Controlled Release Society

2023 Volume 356, Page(s) 580–594

Abstract	Here, we aimed to chemically modify PAMAM dendrimers using lysine as a site-selective anchor for successfully delivering mRNA while maintaining a low toxicity profile. PAMAM dendrimers were multi-functionalised by amidation reactions in a regioselective, quantitative and stepwise manner with carefully selected property-modifying surface groups. Alternatively, novel lysine-based dendrimers were prepared in the same manner with the aim to unlock their potential in gene delivery. The modified dendrimers were then formulated with Cy5-EGFP mRNA by bulk mixing via liquid handling robotics across different nitrogen to phosphate ratios. The resulting dendriplexes were characterised by size, charge, mRNA encapsulation, and mRNA binding affinity. Finally, their in-vitro delivery activity was systematically investigated across key cellular trafficking stages to relate chemical design to cellular effect. We demonstrate our findings in different cell lines and benchmarked relative to a commercially available transfection agent, jetPEI®. We demonstrate that specific surface modifications are required to generate small, reliable and well-encapsulated positively charged dendriplex complexes. Furthermore, we show that introduction of fusogenic groups is essential for driving endosomal escape and achieving cellular delivery and translation of mRNA in these cell lines.
MeSH term(s)	Dendrimers/chemistry ; Polylysine ; Transfection ; Gene Transfer Techniques
Chemical Substances	Dendrimers ; Polylysine (25104-18-1)
Language	English
Publishing date	2023-03-17
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2023.03.011
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Free drug and ROS-responsive nanoparticle delivery of synergistic doxorubicin and olaparib combinations to triple negative breast cancer models.

Cavanagh, Robert J / Monteiro, Patrícia F / Moloney, Cara / Travanut, Alessandra / Mehradnia, Fatemeh / Taresco, Vincenzo / Rahman, Ruman / Martin, Stewart G / Grabowska, Anna M / Ashford, Marianne B / Alexander, Cameron

Biomaterials science

2024 Volume 12, Issue 7, Page(s) 1822–1840

Abstract: Combinations of the topoisomerase II inhibitor doxorubicin and the poly (ADP-ribose) polymerase inhibitor olaparib offer potential drug-drug synergy for the treatment of triple negative breast cancers (TNBC). In this study we ... ...

Abstract	Combinations of the topoisomerase II inhibitor doxorubicin and the poly (ADP-ribose) polymerase inhibitor olaparib offer potential drug-drug synergy for the treatment of triple negative breast cancers (TNBC). In this study we performed
MeSH term(s)	Humans ; Triple Negative Breast Neoplasms/metabolism ; Reactive Oxygen Species ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Doxorubicin/pharmacology ; Doxorubicin/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Drug Combinations ; Nanoparticles ; Cell Line, Tumor ; Phthalazines ; Piperazines
Chemical Substances	olaparib (WOH1JD9AR8) ; Reactive Oxygen Species ; Antineoplastic Agents ; Doxorubicin (80168379AG) ; Poly(ADP-ribose) Polymerase Inhibitors ; Drug Combinations ; Phthalazines ; Piperazines
Language	English
Publishing date	2024-03-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d3bm01931d
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Synthesis and Characterization of Dendrimer-Based Polysarcosine Star Polymers: Well-Defined, Versatile Platforms Designed for Drug-Delivery Applications

England, Richard M / Moss, Jennifer I / Gunnarsson, Anders / Parker, Jeremy S / Ashford, Marianne B

Biomacromolecules. 2020 July 16, v. 21, no. 8

2020

Abstract: This paper describes the synthesis of star polymers designed for future drug-delivery applications. A generation-5 lysine dendrimer was used as a macroinitiator for the ring-opening polymerization of the sarcosine N-carboxyanhydride monomer to produce 32- ...

Abstract	This paper describes the synthesis of star polymers designed for future drug-delivery applications. A generation-5 lysine dendrimer was used as a macroinitiator for the ring-opening polymerization of the sarcosine N-carboxyanhydride monomer to produce 32-arm star polymers with narrow molar mass distributions and desirable hydrodynamic size control. Fluorescent dye-labeled polymers were dosed in mice to measure plasma pharmacokinetics. Long circulation times were observed, representing ideal properties for biophysical targeting of tumors. In vivo efficacy of one of these star polymers conjugated to the therapeutic molecule SN-38 was evaluated in mice bearing SW620 xenografted tumors to demonstrate high antitumor activity and low body weight loss compared to the SN-38 prodrug irinotecan and this shows the potential of these delivery systems. As a further build, we demonstrated that these star polymers can be easily chain-end-functionalized with useful chemical moieties, giving opportunities for future receptor-targeting strategies. Finally, we describe the synthetic advantages of these star polymers that make them attractive from a pharmaceutical manufacturing perspective and report characterization of the polymers with a variety of techniques.
Keywords	antineoplastic activity ; body weight changes ; dendrimers ; fluorescence ; hydrodynamics ; lysine ; molecular weight ; pharmacokinetics ; polymerization ; sarcosines
Language	English
Dates of publication	2020-0716
Size	p. 3332-3341.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ISSN	1526-4602
DOI	10.1021/acs.biomac.0c00768
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Synthesis and Characterization of Dendrimer-Based Polysarcosine Star Polymers: Well-Defined, Versatile Platforms Designed for Drug-Delivery Applications.

England, Richard M / Moss, Jennifer I / Gunnarsson, Anders / Parker, Jeremy S / Ashford, Marianne B

Biomacromolecules

2020 Volume 21, Issue 8, Page(s) 3332–3341

Abstract	This paper describes the synthesis of star polymers designed for future drug-delivery applications. A generation-5 lysine dendrimer was used as a macroinitiator for the ring-opening polymerization of the sarcosine
MeSH term(s)	Animals ; Dendrimers ; Mice ; Peptides ; Pharmaceutical Preparations ; Polymers ; Sarcosine/analogs & derivatives
Chemical Substances	Dendrimers ; Peptides ; Pharmaceutical Preparations ; Polymers ; polysarcosine (25951-24-0) ; Sarcosine (Z711V88R5F)
Language	English
Publishing date	2020-07-28
Publishing country	United States
Document type	Journal Article
ISSN	1526-4602
ISSN (online)	1526-4602
DOI	10.1021/acs.biomac.0c00768
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evaluating liver uptake and distribution of different poly(2-methyl-2-oxazoline) modified lysine dendrimers following intravenous administration.

England, Richard M / Moss, Jennifer I / Hill, Kathryn J / Elvevold, Kjetil / Smedsrød, Bård / Ashford, Marianne B

Biomaterials science

2019 Volume 7, Issue 8, Page(s) 3418–3424

Abstract: We report on the synthesis of four poly(2-methyl-2-oxazoline) modified lysine dendrimers with different residual groups or modifications on the dendrimer core, including: amino groups (positive charge), carboxyl groups (negative charge), and two drug ... ...

Abstract	We report on the synthesis of four poly(2-methyl-2-oxazoline) modified lysine dendrimers with different residual groups or modifications on the dendrimer core, including: amino groups (positive charge), carboxyl groups (negative charge), and two drug molecules, one of which has a high log P. We looked at the in vivo distribution amongst three main liver cell types: hepatocytes, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) and found differences in cell distribution and uptake concentrations dependent on these residual groups. In particular, the amino-functional polymer showed greater uptake by the hepatocytes whilst the carboxyl-functionalised polymer exhibited greater uptake by KCs and LSECs. These findings provide insight into which professional scavenger cells of the liver remove these types of nanoparticles from the bloodstream and we describe some of the design criteria to consider when creating novel drug delivery systems.
MeSH term(s)	Administration, Intravenous ; Animals ; Biological Transport ; Dendrimers/chemistry ; Female ; Hydrophobic and Hydrophilic Interactions ; Liver/metabolism ; Lysine/administration & dosage ; Lysine/chemistry ; Lysine/metabolism ; Lysine/pharmacokinetics ; Mice ; Polyamines/chemistry ; Rhodamines/chemistry ; Tissue Distribution
Chemical Substances	Dendrimers ; Polyamines ; Rhodamines ; poly(2-methyl-2-oxazoline) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2019-07-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/c9bm00385a
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Histopathological biomarkers for predicting the tumour accumulation of nanomedicines.

May, Jan-Niklas / Moss, Jennifer I / Mueller, Florian / Golombek, Susanne K / Biancacci, Ilaria / Rizzo, Larissa / Elshafei, Asmaa Said / Gremse, Felix / Pola, Robert / Pechar, Michal / Etrych, Tomáš / Becker, Svea / Trautwein, Christian / Bülow, Roman D / Boor, Peter / Knuechel, Ruth / von Stillfried, Saskia / Storm, Gert / Puri, Sanyogitta /

Barry, Simon T / Schulz, Volkmar / Kiessling, Fabian / Ashford, Marianne B / Lammers, Twan

Nature biomedical engineering

2024

Abstract: The clinical prospects of cancer nanomedicines depend on effective patient stratification. Here we report the identification of predictive biomarkers of the accumulation of nanomedicines in tumour tissue. By using supervised machine learning on data of ... ...

Abstract	The clinical prospects of cancer nanomedicines depend on effective patient stratification. Here we report the identification of predictive biomarkers of the accumulation of nanomedicines in tumour tissue. By using supervised machine learning on data of the accumulation of nanomedicines in tumour models in mice, we identified the densities of blood vessels and of tumour-associated macrophages as key predictive features. On the basis of these two features, we derived a biomarker score correlating with the concentration of liposomal doxorubicin in tumours and validated it in three syngeneic tumour models in immunocompetent mice and in four cell-line-derived and six patient-derived tumour xenografts in mice. The score effectively discriminated tumours according to the accumulation of nanomedicines (high versus low), with an area under the receiver operating characteristic curve of 0.91. Histopathological assessment of 30 tumour specimens from patients and of 28 corresponding primary tumour biopsies confirmed the score's effectiveness in predicting the tumour accumulation of liposomal doxorubicin. Biomarkers of the tumour accumulation of nanomedicines may aid the stratification of patients in clinical trials of cancer nanomedicines.
Language	English
Publishing date	2024-04-08
Publishing country	England
Document type	Journal Article
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-024-01197-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Subcutaneous administration of AZD0466, a dendrimer-based Bcl-2/Bcl-xL inhibitor increases lymphatic exposure and survival in B-cell lymphoma

Feeney, Orlagh M. / Ardipradja, Katherine / Noi, Ka Fung / Mehta, Dharmini / De Rose, Robert / Yuen, Daniel / Johnston, Angus P.R. / Kingston, Lee / Ericsson, Cecilia / Elmore, Charles S. / Hufton, Richard / Owen, David J. / Ashford, Marianne B. / Porter, Christopher J.H.

Journal of controlled release. 2022 May 24,

2022

Abstract: As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and lymphatics while avoiding off-target toxicity. Subcutaneous ( ... ...

Abstract	As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas. Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a ‘DEP®’ G5 poly-l-lysine dendrimer. PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400 mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC). These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.
Keywords	B-cell lymphoma ; bioavailability ; dendrimers ; drugs ; half life ; lymph ; models ; nanocarriers ; nanomedicine ; pharmacokinetics ; subcutaneous injection ; toxicity
Language	English
Dates of publication	2022-0524
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2022.05.041
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 2055: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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Jg. 1995 - 2021: Lesesall (1.OG)
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Article: Evaluating liver uptake and distribution of different poly(2-methyl-2-oxazoline) modified lysine dendrimers following intravenous administration

England, Richard M / Ashford, Marianne B / Elvevold, Kjetil / Hill, Kathryn J / Moss, Jennifer I / Smedsrød, Bård

Biomaterials science. 2019 July 23, v. 7, no. 8

2019

Abstract	We report on the synthesis of four poly(2-methyl-2-oxazoline) modified lysine dendrimers with different residual groups or modifications on the dendrimer core, including: amino groups (positive charge), carboxyl groups (negative charge), and two drug molecules, one of which has a high log P. We looked at the in vivo distribution amongst three main liver cell types: hepatocytes, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) and found differences in cell distribution and uptake concentrations dependent on these residual groups. In particular, the amino-functional polymer showed greater uptake by the hepatocytes whilst the carboxyl-functionalised polymer exhibited greater uptake by KCs and LSECs. These findings provide insight into which professional scavenger cells of the liver remove these types of nanoparticles from the bloodstream and we describe some of the design criteria to consider when creating novel drug delivery systems.
Keywords	blood flow ; dendrimers ; drug delivery systems ; drugs ; endothelial cells ; hepatocytes ; intravenous injection ; Kupffer cells ; liver ; lysine ; moieties ; nanoparticles
Language	English
Dates of publication	2019-0723
Size	p. 3418-3424.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/c9bm00385a
Database	NAL-Catalogue (AGRICOLA)

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