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Ling Peng - One of the best experts on this subject based on the ideXlab platform.
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Self-assembling supramolecular Dendrimers for biomedical applications: lessons learned from poly(amidoamine) Dendrimers
Accounts of Chemical Research, 2020Co-Authors: Zhenbin Lyu, Ling Ding, Aura Tintaru, Ling PengAbstract:Dendrimers, notable for their well-defined radial structures with numerous terminal functionalities, hold great promise for biomedical applications such as drug delivery, diagnostics, and therapeutics. However, their translation into clinical use has been greatly impeded by their challenging stepwise synthesis and difficult purification. To circumvent these obstacles, we have pioneered a self-assembly approach to constructing noncovalent supramolecular Dendrimers using small amphiphilic dendrimer building units which can be easily synthesized and purified. By virtue of their amphipathic nature, the small amphiphilic Dendrimers are able to self-assemble and generate large supramolecular Dendrimers via noncovalent weak interactions such as van der Waals forces, H bonds, and electrostatic interactions. The so-created noncovalent Dendrimers can mimic covalent Dendrimers not only in terms of the radial structural feature emanating from a central core but also in their capacity to deliver drugs and imaging agents for biomedical applications. The noncovalent supramolecular Dendrimers can be easily synthesized and modulated with regard to size, shape, and properties by varying the nature of the hydrophobic and hydrophilic entities as well as the dendrimer generation and terminal functionalities, ensuring their adaptability to specific applications. In particular, the dendritic structure of the amphiphilic building units permits the creation of large void spaces within the formed supramolecular Dendrimers for the physical encapsulation of drugs, while the large number of surface functionalities can be exploited for both physical and chemical conjugation of pharmaceutic agents for drug delivery. Poly(amidoamine) (PAMAM) Dendrimers are the most intensively studied for biomedical applications by virtue of their excellent biocompatibility imparted by their peptide-mimicking amide backbones and numerous interior and terminal amine functionalities. We present a short overview of our self-assembly strategy for constructing supramolecular PAMAM Dendrimers for biomedical applications. Specifically, we start with the introduction of Dendrimers and their synthesis, focusing on the innovative self-assembly synthesis of supramolecular Dendrimers. We then detail the representative examples of the noncovalent supramolecular PAMAM Dendrimers established in our group for the delivery of anticancer drugs, nucleic acid therapeutics, and imaging agents, either within the dendrimer interior or at the dendrimer terminals on the surface. Some of the supramolecular dendrimer nanosystems exhibit outstanding performance, excelling the corresponding clinical anticancer therapeutics and imaging agents. This self-assembly approach to creating supramolecular Dendrimers is completely novel in concept yet easy to implement in practice, offering a fresh perspective for exploiting the advantageous features of Dendrimers in biomedical applications.
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Self-Assembling Supramolecular Dendrimers for Biomedical Applications: Lessons Learned from Poly(amidoamine) Dendrimers.
Accounts of chemical research, 2020Co-Authors: Zhenbin Lyu, Ling Ding, Aura Tintaru, Ling PengAbstract:ConspectusDendrimers, notable for their well-defined radial structures with numerous terminal functionalities, hold great promise for biomedical applications such as drug delivery, diagnostics, and therapeutics. However, their translation into clinical use has been greatly impeded by their challenging stepwise synthesis and difficult purification.To circumvent these obstacles, we have pioneered a self-assembly approach to constructing noncovalent supramolecular Dendrimers using small amphiphilic dendrimer building units which can be easily synthesized and purified. By virtue of their amphipathic nature, the small amphiphilic Dendrimers are able to self-assemble and generate large supramolecular Dendrimers via noncovalent weak interactions such as van der Waals forces, H bonds, and electrostatic interactions. The so-created noncovalent Dendrimers can mimic covalent Dendrimers not only in terms of the radial structural feature emanating from a central core but also in their capacity to deliver drugs and imaging agents for biomedical applications. The noncovalent supramolecular Dendrimers can be easily synthesized and modulated with regard to size, shape, and properties by varying the nature of the hydrophobic and hydrophilic entities as well as the dendrimer generation and terminal functionalities, ensuring their adaptability to specific applications. In particular, the dendritic structure of the amphiphilic building units permits the creation of large void spaces within the formed supramolecular Dendrimers for the physical encapsulation of drugs, while the large number of surface functionalities can be exploited for both physical and chemical conjugation of pharmaceutic agents for drug delivery.Poly(amidoamine) (PAMAM) Dendrimers are the most intensively studied for biomedical applications by virtue of their excellent biocompatibility imparted by their peptide-mimicking amide backbones and numerous interior and terminal amine functionalities. We present a short overview of our self-assembly strategy for constructing supramolecular PAMAM Dendrimers for biomedical applications. Specifically, we start with the introduction of Dendrimers and their synthesis, focusing on the innovative self-assembly synthesis of supramolecular Dendrimers. We then detail the representative examples of the noncovalent supramolecular PAMAM Dendrimers established in our group for the delivery of anticancer drugs, nucleic acid therapeutics, and imaging agents, either within the dendrimer interior or at the dendrimer terminals on the surface. Some of the supramolecular dendrimer nanosystems exhibit outstanding performance, excelling the corresponding clinical anticancer therapeutics and imaging agents. This self-assembly approach to creating supramolecular Dendrimers is completely novel in concept yet easy to implement in practice, offering a fresh perspective for exploiting the advantageous features of Dendrimers in biomedical applications.
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Poly(amidoamine) Dendrimers: covalent and supramolecular synthesis
Materials Today Chemistry, 2019Co-Authors: Z. Lyu, L. Ding, A.y.t. Huang, L. Kao, Ling PengAbstract:Dendrimers, a class of synthetic macromolecules which are notable for their well-defined ramified structures and unique multivalent cooperativity, hold great promise for developing various functional materials. Among all the reported Dendrimers, poly(amidoamine) (PAMAM) Dendrimers are the most extensively studied by virtue of their readily availability via robust synthesis as well as their dendritic structure and peptide/protein mimic features. Since the seminal report by Tomalia et al., various strategies have been made available for PAMAM Dendrimers, including divergent and/or convergent synthesis alongside click chemistry. Nevertheless, preparation of high-generation and defect-free PAMAM Dendrimers on a large scale remains challenging. To overcome the limitations, an alternative strategy based on self-assembling approach has emerged for dendrimer synthesis, where small dendritic components form large non-covalent supramolecular structures that mimic high-generation covalent den-drimers. This approach is easy to implement in practice and requires much less synthetic effort. Here, we present a brief overview of the different approaches established for PAMAM dendrimer synthesis. We start with a general introduction to Dendrimers and the common strategies for dendrimer synthesis, and then we illustrate the specific approaches for PAMAM dendrimer synthesis and highlight the related advantages and limitations using representative examples. Although various strategies have been established for PAMAM dendrimer synthesis, innovative concepts and approaches are still in high demand for reliably preparing defect-free and high-generation Dendrimers in large quantity.
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Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencing
Frontiers of Chemical Science and Engineering, 2017Co-Authors: Yu Cao, Xiaoxuan Liu, Ling PengAbstract:Small interfering RNA (siRNA) therapeutics hold great promise to treat a variety of diseases, as long as they can be delivered safely and effectively into cells. Dendrimers are appealing vectors for siRNA delivery by virtue of their well-defined molecular architecture and multivalent cooperativity. However, the clinical translation of RNA therapeutics mediated by dendrimer delivery is hampered by the lack of Dendrimers that are of high quality to meet good manufacturing practice standard. In this context, we have developed small amphiphilic Dendrimers that self-assemble into supramolecular structures, which mimic high-generation Dendrimers synthesized with cova-lent construction, yet are easy to produce in large amount and superior quality. Indeed, the concept of supramolecular Dendrimers has proved to be very promising, and has opened up a new avenue for dendrimer-mediated siRNA delivery. A series of self-assembling supramolecular Dendrimers have consequently been established, some of them out-performing the currently available nonviral vectors in delivering siRNA to various cell types in vitro and in vivo, including human primary cells and stem cells. This short review presents a brief introduction to RNAi therapeutics, the obstacles to their delivery and the advantages of dendrimer delivery vectors as well as our bio-inspired structurally flexible Dendrimers for siRNA delivery. We then highlight our efforts in creating self-assembling amphiphilic Dendrimers to construct supramo-lecular dendrimer nanosystems for effective siRNA delivery as well as the related structural alterations to enhance delivery efficiency. The advent of self-assembling supramolecular dendrimer nanovectors holds great promise and heralds a new era of dendrimer-mediated delivery of RNA therapeutics in biomedical applications.
Christine Paul-roth - One of the best experts on this subject based on the ideXlab platform.
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New porphyrin Dendrimers with fluorenyl-based connectors: a simple way to improving the optical properties over Dendrimers featuring 1,3,5-phenylene connectors
New Journal of Chemistry, 2020Co-Authors: Xu Zhang, Sarra Ben Hassine, Nicolas Richy, Olivier Mongin, Mireille Blanchard-desce, Frédéric Paul, Christine Paul-rothAbstract:Two new meso-tetrafluorenylporphyrin-cored Dendrimers 1 and 2 have been synthesized and characterized. The peripheral fluorenyl units of these Dendrimers are linked to the central tetrafluorenylporphyrin (TFP) core by original fluorene-based connectors instead of the more classic 1,3,5-phenylene unit. Selected linear and non-linear optical (LO and NLO) properties were determined for these Dendrimers via absorption or emission studies and by two-photon excited fluorescence (TPEF) measurements. Dendrimer 1, which has a conjugated and quite rigid structure, exhibits a significantly higher two-photon absorption (2PA) cross-section than dendrimer 2, presenting a non-conjugated and more flexible structure, as well as better luminescence and singlet oxygen activation quantum yields. Both Dendrimers exhibit higher 2PA cross-sections than several closely related TFP-based Dendrimers previously characterized. However, among them, dendrimer 1 is the only one outperforming all these compounds in terms of 2PA brightness and 2PA oxygen sensitization. Thus, the new type of connector (or dendrimeric node) introduced in 1 appears to be quite appealing for the design of photosensitizers aimed at theranostic uses in the future.
Serge Mignani - One of the best experts on this subject based on the ideXlab platform.
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original multivalent gold iii and dual gold iii copper ii conjugated phosphorus Dendrimers as potent antitumoral and antimicrobial agents
Molecular Pharmaceutics, 2017Co-Authors: Serge Mignani, Anne-marie Caminade, Maria Bryszewska, Nabil El Brahmi, Said El Kazzouli, Regis Laurent, Sonia Ladeira, Elzbieta Pedziwiatrwerbicka, Eligia M Szewczyk, Mosto BousminaAbstract:Original metallophosphorus Dendrimers (generation 3, 48 terminal groups) have been prepared via the complexation of phosphorus Dendrimers bearing imino-pyridino end groups with Au(III) or with both Au(III) and Cu(II). The complexation of the dendrimer with Au(III), leading to 1G3-[Au48][AuCl4]48, strongly increased the antiproliferative activities against both KB and HL-60 tumoral cell lines, showing IC50s in the low nanomolar range. It can be noticed also that this gold conjugated phosphorus dendrimer displayed low activity on the quiescent cell line EPC versus its potent antiproliferative activity against actively dividing cells. In order to evaluate the potential synergistic effect between Au(III) and Cu(II) and the influence of the number of Au(III) moieties on the surface of dendrimer against the proliferative activities, nine other original Dendrimers with several surface modifications have been prepared. Whatever the number of Au(III) moieties introduced on the surface of Dendrimers, all the dendri...
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Dendrimer-protein interactions versus dendrimer-based nanomedicine.
Colloids and surfaces. B Biointerfaces, 2017Co-Authors: Dzmitry Shcharbin, Serge Mignani, Natallia Shcharbina, Volha Dzmitruk, Elzbieta Pedziwiatr-werbicka, Maksim Ionov, F. Javier De La Mata, Rafael Gómez, María Ángeles Muñoz-fernández, Jean-pierre MajoralAbstract:Dendrimers are hyperbranched polymers belonging to the huge class of nanomedical devices. Their wide application in biology and medicine requires understanding of the fundamental mechanisms of their interactions with biological systems. Summarizing, electrostatic force plays the predominant role in dendrimer-protein interactions, especially with charged Dendrimers. Other kinds of interactions have been proven, such as H-bonding, van der Waals forces, and even hydrophobic interactions. These interactions depend on the characteristics of both participants: flexibility and surface charge of a dendrimer, rigidity of protein structure and the localization of charged amino acids at its surface. pH and ionic strength of solutions can significantly modulate interactions. Ligands and cofactors attached to a protein can also change dendrimer-protein interactions. Binding of Dendrimers to a protein can change its secondary structure, conformation, intramolecular mobility and functional activity. However, this strongly depends on rigidity versus flexibility of a protein's structure. In addition, the potential applications of Dendrimers to nanomedicine are reviwed related to dendrimer-protein interactions.
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Dendrimer therapeutics: covalent and ionic attachments
New Journal of Chemistry, 2012Co-Authors: Said El Kazzouli, Serge Mignani, Mosto Bousmina, Jean-pierre MajoralAbstract:This concise review focuses on Dendrimers functionalized by different linkers required for covalent and ionic attachments of drugs to the dendrimer’s surface and highlights the importance of the chemical nature of linkers for controlled release of free drugs. The stability of linkers under physiological conditions and their lability under acidic conditions such as those of endosomes and lysosomes or under enzymatic conditions will be discussed. Especially, we review functionality of the most recently reported drug–dendrimer conjugates. Then, we give a short comparison of dendrimer conjugates versus either dendrimer complexes or polymer therapeutics and finally we briefly summarize the importance of both targeted and nontargeted covalently conjugated drugs
Mosto Bousmina - One of the best experts on this subject based on the ideXlab platform.
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original multivalent gold iii and dual gold iii copper ii conjugated phosphorus Dendrimers as potent antitumoral and antimicrobial agents
Molecular Pharmaceutics, 2017Co-Authors: Serge Mignani, Anne-marie Caminade, Maria Bryszewska, Nabil El Brahmi, Said El Kazzouli, Regis Laurent, Sonia Ladeira, Elzbieta Pedziwiatrwerbicka, Eligia M Szewczyk, Mosto BousminaAbstract:Original metallophosphorus Dendrimers (generation 3, 48 terminal groups) have been prepared via the complexation of phosphorus Dendrimers bearing imino-pyridino end groups with Au(III) or with both Au(III) and Cu(II). The complexation of the dendrimer with Au(III), leading to 1G3-[Au48][AuCl4]48, strongly increased the antiproliferative activities against both KB and HL-60 tumoral cell lines, showing IC50s in the low nanomolar range. It can be noticed also that this gold conjugated phosphorus dendrimer displayed low activity on the quiescent cell line EPC versus its potent antiproliferative activity against actively dividing cells. In order to evaluate the potential synergistic effect between Au(III) and Cu(II) and the influence of the number of Au(III) moieties on the surface of dendrimer against the proliferative activities, nine other original Dendrimers with several surface modifications have been prepared. Whatever the number of Au(III) moieties introduced on the surface of Dendrimers, all the dendri...
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Dendrimer therapeutics: covalent and ionic attachments
New Journal of Chemistry, 2012Co-Authors: Said El Kazzouli, Serge Mignani, Mosto Bousmina, Jean-pierre MajoralAbstract:This concise review focuses on Dendrimers functionalized by different linkers required for covalent and ionic attachments of drugs to the dendrimer’s surface and highlights the importance of the chemical nature of linkers for controlled release of free drugs. The stability of linkers under physiological conditions and their lability under acidic conditions such as those of endosomes and lysosomes or under enzymatic conditions will be discussed. Especially, we review functionality of the most recently reported drug–dendrimer conjugates. Then, we give a short comparison of dendrimer conjugates versus either dendrimer complexes or polymer therapeutics and finally we briefly summarize the importance of both targeted and nontargeted covalently conjugated drugs
Tommy Nylander - One of the best experts on this subject based on the ideXlab platform.
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On the ability of PAMAM Dendrimers and dendrimer/DNA aggregates to penetrate POPC model biomembranes.
The journal of physical chemistry. B, 2010Co-Authors: Marie-louise Ainalem, Richard A. Campbell, Syma Khalid, Richard J. Gillams, Adrian R. Rennie, Tommy NylanderAbstract:Poly(amido amine) (PAMAM) Dendrimers have previously been shown, as cationic condensing agents of DNA, to have high potential for nonviral gene delivery. This study addresses two key issues for gene delivery: the interaction of the biomembrane with (i) the condensing agent (the cationic PAMAM dendrimer) and (ii) the corresponding dendrimer/DNA aggregate. Using in situ null ellipsometry and neutron reflection, parallel experiments were carried out involving Dendrimers of generations 2 (G2), 4 (G4), and 6 (G6). The study demonstrates that free Dendrimers of all three generations were able to traverse supported palmitoyloleoylphosphatidylcholine (POPC) bilayers deposited on silica surfaces. The model biomembranes were elevated from the solid surfaces upon dendrimer penetration, which offers a promising new way to generate more realistic model biomembranes where the contact with the supporting surface is reduced and where aqueous cavities are present beneath the bilayer. The largest dendrimer (G6) induced partial bilayer destruction directly upon penetration, whereas the smaller Dendrimers (G2 and G4) leave the bilayer intact, so we propose that lower generation Dendrimers have greater potential as transfection mediators. In addition to the experimental observations, coarse-grained simulations on the interaction between generation 3 (G3) Dendrimers and POPC bilayers were performed in the absence and presence of a bilayer-supporting negatively charged surface that emulates the support. The simulations demonstrate that G3 is transported across free-standing POPC bilayers by direct penetration and not by endocytosis. The penetrability was, however, reduced in the presence of a surface, indicating that the membrane transport observed experimentally was not driven solely by the surface. The experimental reflection techniques were also applied to dendrimer/DNA aggregates of charge ratio = 0.5, and while G2/DNA and G4/DNA aggregates interact with POPC bilayers, G6/DNA displays no such interaction. These results indicate that, in contrast to free dendrimer molecules, dendrimer/DNA aggregates of low charge ratios are not able to traverse a membrane by direct penetration.
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on the ability of pamam Dendrimers and dendrimer dna aggregates to penetrate popc model biomembranes
Journal of Physical Chemistry B, 2010Co-Authors: Marie-louise Ainalem, Richard A. Campbell, Syma Khalid, Richard J. Gillams, Adrian R. Rennie, Tommy NylanderAbstract:Poly(amido amine) (PAMAM) Dendrimers have previously been shown, as cationic condensing agents of DNA, to have high potential for nonviral gene delivery. This study addresses two key issues for gene delivery: the interaction of the biomembrane with (i) the condensing agent (the cationic PAMAM dendrimer) and (ii) the corresponding dendrimer/DNA aggregate. Using in situ null ellipsometry and neutron reflection, parallel experiments were carried out involving Dendrimers of generations 2 (G2), 4 (G4), and 6 (G6). The study demonstrates that free Dendrimers of all three generations were able to traverse supported palmitoyloleoylphosphatidylcholine (POPC) bilayers deposited on silica surfaces. The model biomembranes were elevated from the solid surfaces upon dendrimer penetration, which offers a promising new way to generate more realistic model biomembranes where the contact with the supporting surface is reduced and where aqueous cavities are present beneath the bilayer. The largest dendrimer (G6) induced partial bilayer destruction directly upon penetration, whereas the smaller Dendrimers (G2 and G4) leave the bilayer intact, so we propose that lower generation Dendrimers have greater potential as transfection mediators. In addition to the experimental observations, coarse-grained simulations on the interaction between generation 3 (G3) Dendrimers and POPC bilayers were performed in the absence and presence of a bilayer-supporting negatively charged surface that emulates the support. The simulations demonstrate that G3 is transported across free-standing POPC bilayers by direct penetration and not by endocytosis. The penetrability was, however, reduced in the presence of a surface, indicating that the membrane transport observed experimentally was not driven solely by the surface. The experimental reflection techniques were also applied to dendrimer/DNA aggregates of charge ratio = 0.5, and while G2/DNA and G4/DNA aggregates interact with POPC bilayers, G6/DNA displays no such interaction. These results indicate that, in contrast to free dendrimer molecules, dendrimer/DNA aggregates of low charge ratios are not able to traverse a membrane by direct penetration.