| 1. |
- Andrén, Oliver, 1987-
(författare)
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Exploring bis-MPA Based Dendritic Structures in Biomedicine
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the last decades there has been significant advances in polymer chemistry. New coupling chemistries, polymerization techniques and accelerated approaches enable researches to push the limits of structural control. One outcome of such development is the field of linear dendritic (LD) and dendritic linear dendritic (DLD) hybrid materials, drawing benefit from both linear and dendritic material properties. LD-hybrids with their high density of functional groups and customizability offer much promise for use in biological applications. This thesis deals with the potential use of sophisticated LD-hybrid materials focusing on the field of biomedicine and biomedical applications. The linear component is manly poly(ethylene glycol) (PEG) while the dendritic part consists of 2,2-Bis(hydroxymethyl)propionic (bis-MPA) building blocks.Initially a family of unsymmetrical LD amphiphiles was constructed and evaluated as carriers for drug delivery of chemotherapeutics. Through self-assembly driven by their amphiphilic nature nanocarriers (NC) were constructed with a hydrophobic core and hydrophilic corona. NC were found to enhance the effect of conventional therapeutics by relocating the drug from just the nucleus to the mitochondria among other organelles. Their versatile nature allowed for dual loading of a combination of chemotherapeutics and circumvented the resistance mechanism of resistant cancer cells.Dendrimers containing a disulfide in the backbone were also constructed, these enabled the selective fragmentation of the dendrimer by reduction to small molecular thiols. The fragments were also envisioned to disrupt the delicate thiol-disulfide balance intracellularly causing reactive oxygen species (ROS). Dendrimers were elaborated by conjugation to linear PEG creating LD-hybrids and evaluated in vitro and where found to cause high degree of ROS in cancerous cells.Thiol functional polymers were created, including linear polymers, dendrimers and DLD-hybrids. The DLD-hybrids were utilized as hydrogels through two efficient chemistries relying on the versatility of the thiol. By varying the generation of the LD-hybrid and the cross-linking chemistry the modulus could be tuned.Amine functional LD-hybrids were constructed utilizing the amino acid alanine. Scaffolds were utilized as antimicrobial hydrogels for prophylaxis during surgical intervention. LD-hybrids were initially evaluated in planktonic mode, and were found to have broad spectrum effect and were highly effective against resistant bacteria. Gelation was studied relying on N-hydroxysuccinimide (NHS) esters as cross-linkers, enabling instantaneous gelation under biological conditions. The gels moduli could be varied to match various tissues including stromal and muscle. The effect of the antimicrobial coatings was investigated with promising results both in vitro and in vivo.Finally, more industrially applicable hyperbranched LD-hybrids were constructed. The synthetic strategy relied on a convenient pseudo one-pot approach using Fisher esterification along with sequential monomer addition. Materials were found to have properties and characteristics similar to those of perfect dendritic LD-hybrids. And the scaffolds were evaluated in a range of applications such as hydrogels and isopourous films with promising results.
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| 2. |
- Arnáiz, Eduardo, et al.
(författare)
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Synthesis of cationic carbosilane dendrimers via click chemistry and their use as effective carriers for DNA transfection into cancerous cells.
- 2012
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 9:3, s. 433-47
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Tidskriftsartikel (refereegranskat)abstract
- New amine-terminated carbosilane dendrimers have been prepared by a Huisgen cycloaddition ("click chemistry" reaction) of azide-terminated carbosilane dendrimers with two different propargyl amines. The corresponding cationic derivatives with peripheral ammonium groups were obtained by subsequent addition of MeI. Quaternized dendrimers are soluble and stable in water or other protic solvents for long time periods, and have been studied as nonviral vectors for the transfection of DNA to cancer cells. In this study DNA-dendrimeric nanoparticles (dendriplexes) formulated with two different families of cationic carbosilane dendrimers (family 1 (G1, G2 and G3) and family 2 (G1, G2)) were characterized and evaluated for their ability to transfect cells in vitro and in vivo. Dendriplex derived from second generation dendrimer of family 1 (F1G2 5/1 (+/-)) increased the efficiency of plasmid-mediated gene transfer in HepG2 cells as compared to naked DNA and the commercial control dendrimer. Also, intravenously administered dendriplex F1G3 20/1 (+/-) is superior in terms of gene transfer efficiency in vivo.
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| 3. |
- Garcia Gallego, Sandra, et al.
(författare)
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Accelerated Chemoselective Reactions to Sequence-Controlled Heterolayered Dendrimers
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126.
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Tidskriftsartikel (refereegranskat)abstract
- Chemoselective reactions are a highly desirable approach to generate well-defined functional macromolecules. Their extraordinary efficiency and selectivity enable the development of flawless structures, such as dendrimers, with unprecedented structure-to-property capacity but with typically tedious synthetic protocols. Here we demonstrate the potency of chemoselective reactions to accomplish sequence-controlled heterolayered dendrimers. An accurate accelerated design of bis-MPA monomers with orthogonally complementary moieties and a wisely selected chemical toolbox generated highly complex monodisperse dendrimers through simplified protocols. The versatility of the strategy was proved by obtaining different dendritic families with different properties after altering the order of addition of the monomers. Moreover, we evaluated the feasibility of the one-pot approach toward these heterolayered dendrimers as proof-of-concept.
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| 4. |
- García-Gallego, Sandra, et al.
(författare)
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Anionic sulfonated and carboxylated PPI dendrimers with the EDA core : synthesis and characterization of selective metal complexing agents.
- 2013
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry. - 1477-9226 .- 1477-9234. ; 42:16, s. 5874-89
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Tidskriftsartikel (refereegranskat)abstract
- Herein we describe the synthesis and characterization of new sulfonated and carboxylated poly(propyleneimino) (PPI) dendrimers with the ethylenediamino (EDA) core, at generations 1, 2 and 3. By means of UV-Vis and EPR spectroscopy, using Cu(2+) as a probe, we concluded that these dendrimers show a specific pattern in the coordination of metal ions. In agreement with the UV-Vis studies, EPR spectra of carboxylated compounds are constituted by 3 different signals which appear and then disappear with increasing copper concentration, corresponding to the saturation of different copper complexation sites. At the lowest copper concentration up to a 1:1 molar ratio between Cu(II) and the dendrimer, the spectrum is characteristic of a CuN2O2 coordination at the core of the dendrimer. The spectrum appearing at higher Cu(II) concentrations indicates a peripheral location of the ions coordinating one nitrogen and 3 oxygen atoms in a square planar geometry in restricted mobility conditions. For the highest concentrations tested, copper ions are confined at the external dendrimer surface with CuO4 coordination. For sulfonate systems, the EPR results are in line with a weaker interaction of Cu(II) with the nitrogen sites and a stronger interaction with the oxygen (SO3(-)) groups with respect to the interactions measured by EPR for carboxylate systems.
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| 5. |
- García-Gallego, Sandra, et al.
(författare)
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Carbon-monoxide-releasing molecules for the delivery of therapeutic co in vivo
- 2014
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 53:37, s. 9712-9721
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Tidskriftsartikel (refereegranskat)abstract
- The development of carbon-monoxide-releasing molecules (CORMs) as pharmaceutical agents represents an attractive and safer alternative to administration of gaseous CO. Most CORMs developed to date are transition-metal carbonyl complexes. Although such CORMs have showed promising results in the treatment of a number of animal models of disease, they still lack the necessary attributes for clinical development. Described in this Minireview are the methods used for CORM selection, to date, and how new insights into the reactivity of metal-carbonyl complexes in vivo, together with advances in methods for live-cell CO detection, are driving the design and synthesis of new CORMs, CORMs that will enable controlled CO release in vivo in a spatial and temporal manner without affecting oxygen transport by hemoglobin.
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| 6. |
- Garcia Gallego, Sandra, et al.
(författare)
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Chemistry of multifunctional polymers based on bis-MPA and their cutting-edge applications
- 2015
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Ingår i: Progress in polymer science. - : Elsevier. - 0079-6700 .- 1873-1619. ; 48, s. 85-110
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Forskningsöversikt (refereegranskat)abstract
- Polymers play an important role in the advancement of materials for use in cutting-edge applications. A direct consequence of an increased demand for more sophisticated materials has been a drive toward developing polymers that exhibit a higher level of structural control, especially in terms of the number and type of functionalities provided within the polymer framework. A family of polymers that meets such a challenge is based on the readily available AB2 monomer 2,2-bismethylolpropionic acid (bis-MPA) building block. Due to the ease with which the monomers can be synthesized, an array of multifunctional polymers have been produced including monodisperse dendrimers and dendrons and well-defined linear polymers as well as linear-dendritic hybridizations. This review outlines the evolution of the synthetic strategies for developing novel polymeric architectures based on bis-MPA and their assessment in both solution and substrate-based innovative applications.
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| 7. |
- Garcia Gallego, Sandra, et al.
(författare)
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Fluoride-Promoted Esterification with Imidazolide-Activated Compounds : A Modular and Sustainable Approach to Dendrimers
- 2015
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 54:8, s. 2416-2419
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Tidskriftsartikel (refereegranskat)abstract
- Based on the growing demand for facile and sustainable synthetic methods to structurally perfect polymers, we herein describe a significant improvement of esterification reactions capitalizing on 1,1-carbonyldiimidazole (CDI). Cesium fluoride was shown to be an essential catalyst for these reactions to reach completion. This approach was successfully applied to the synthesis of structurally flawless and highly functional polyester dendrimers employing traditional and accelerated growth strategies. A sixth generation bis-MPA dendrimer with a molecular weight of 22.080Da and 192 peripheral hydroxy groups was isolated in less than one day of total reaction time. Large quantities of dendrimerswere obtained in high yields (>90%) using simple purification steps under sustainable conditions. The fluoride-promoted esterification (FPE) via imidazolide-activated compounds is wide in scope and constitutes a potentially new approach toward functional polymers and other materials.
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| 8. |
- García-Gallego, Sandra, et al.
(författare)
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Function Oriented Molecular Design : Dendrimers as Novel Antimicrobials.
- 2017
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Ingår i: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 22:10
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Tidskriftsartikel (refereegranskat)abstract
- In recent years innovative nanostructures are attracting increasing interest and, among them, dendrimers have shown several fields of application. Dendrimers can be designed and modified in plentiful ways giving rise to hundreds of different molecules with specific characteristics and functionalities. Biomedicine is probably the field where these molecules find extraordinary applicability, and this is probably due to their multi-valency and to the fact that several other chemicals can be coupled to them to obtain desired compounds. In this review we will describe the different production strategies and the tools and technologies for the study of their characteristics. Finally, we provide a panoramic overview of their applications to meet biomedical needs, especially their use as novel antimicrobials.
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| 9. |
- García-Gallego, Sandra, et al.
(författare)
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HIV-1 antiviral behavior of anionic PPI metallo-dendrimers with EDA core
- 2015
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 98, s. 139-148
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Tidskriftsartikel (refereegranskat)abstract
- The development of novel strategies to prevent HIV-1 infection is of outstanding relevance. Metal complexes of Cu2+, Ni2+, Co2+ and Zn2+ derived from sulfonated and carboxylated poly(propylene imine) dendrimers with ethylenediamine core were evaluated as tunable antiviral agents against HIV-1. After demonstrating their biocompatibility, specific trends in the antiviral properties were found, related to both the dendritic scaffold (peripheral group, generation) and the bound metal ions (sort, amount). In HEC-1A and VK-2 cell lines, as model of the first barrier against HIV-1 infection, a high preventive inhibitory action was found, which also avoided virus internalization inside cells and inhibited both CCR5 and CXCR4 HIV-1 strains. In peripheral blood mononuclear cells (PBMC), as model of the second barrier, a dual preventive and therapeutic behavior was observed. A rational design of such metallodendrimers opens new avenues for the production of versatile and efficient treatments against HIV-1 infection.
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| 10. |
- García-Gallego, Sandra, et al.
(författare)
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Polyanionic N-donor ligands as chelating agents in transition metal complexes : synthesis, structural characterization and antiviral properties against HIV
- 2012
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry. - 1477-9226 .- 1477-9234. ; 41:21, s. 6488-99
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Tidskriftsartikel (refereegranskat)abstract
- We describe here the synthesis and characterization of new sulfonated and carboxylated-containing N-donor ligands [Na(4)(edts)]·4H(2)O (2), [Na(2)(dmeddp)]·2H(2)O (3) and [Na(4)(edtp)]·H(2)O (4) (edts = ethylene-diamine- N,N,N',N'-tetraethylenesulfonate ion; dmeddp = dimethyl-ethylene-diamine-N,N,N',N'-tetra-3-propionate ion; edtp = ethylene-diamine-N,N,N',N'-tetra-3-propionate ion) and their corresponding metal (Ni, Co, Cu and Zn) complexes. Mainly, UV-Vis and a computer aided analysis of the EPR spectra provided information on the geometry and structure of the complexes in solution. Some of the metal complexes inhibit HIV replication when treating both pre- and post-infected PBMC cells, and hustle the inhibitory effect compared to the metal salts alone.
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