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Water-Soluble Carbosilane Dendrimers: Synthesis Biocompatibility and Complexation with Oligonucleotides; Evaluation for Medical Applications
Abstract
Novel amine- or ammonium-terminated carbosilane dendrimers of type nG-[Si{OCH2(C6H3)-3,5-(OCH2CH2NMe2)2}]x, nG-[Si{O(CH2)2N(Me)(CH2)2NMe2}]x and nG-[Si{(CH2)3NH2}]x or nG-[Si{OCH2(C6H3)-3,5-(OCH2CH2NMe3 +I-)2}]x, nG-[Si{O(CH2)2N(Me)(CH2)2NMe3 +I-}]x, and nG-[Si{(CH2)3NH3 +Cl-}]x have been synthesized and characterized up to the third generation by two strategies: 1) alcoholysis of Si--Cl bonds with amino alcohols and subsequent quaternization with MeI, and 2) hydrosilylation of allylamine with Si--H bonds of the dendritic systems and subsequent quaternization with HCl. Quaternized carbosilane dendrimers are soluble in water, although degradation is apparent due to hydrolysis of Si--O bonds. However, dendrimers containing Si--C bonds are water-stable. The biocompatibility of the second-generation dendrimers in primary cell cultures of peripheral blood mononuclear cells (PBMCs) and erythrocytes have been analyzed, and they show good toxicity profiles over extended periods. In addition, we describe a study on the interactions between the different carbosilane dendrimers and DNA oligodeoxynucleotides (ODNs) and plasmids along with a comparative analysis of their toxicity. They can form complexes with DNA ODNs and plasmids at biocompatible doses via electrostatic interaction. Also a preliminary transfection assay has been accomplished. These results demonstrate that the new ammonium-terminated carbosilane dendrimers are good base molecules to be considered for biomedical applications.
... The Table 2, and the comparsion of the perioues reported [38,39]. that pure R-PE had three subunits and that these findings were consistent with the composition and subunits described in other sources [35,36]. ...
... cm -1 of C-H, and 2198.99 cm -1 of C=C, which correspond to alkyne stretches, 1569.59 and 1418.97 cm -1 of C=C, which correspond to aromatic stretches, 1300.40 and 1031.60 cm -1 C=O ether stretches, 779.20 and 651.44 cm -1 of C-CI, 536.37 cm -1 C-Br, respectively. The band peaks at 3439 cm -1 represents the N-H stretching of ammonium ions, while band of 2981cm -1represents C-H rock alkanes[38,[40][41][42]. ...
... Since the discovery of the "cascade molecule" in 1978 and the first complete dendrimer family that was synthesized from generation 1 to 7 in 1985, nanoparticle development has led to the creation of various dendrimer structures with diverse applications in fields such as light harvesting and energy transfer, nanoscale catalysis, chemical sensors, unimolecular micelles, enzyme mimics, encapsulation of guest molecules, molecular recognition, diagnostic agents and gene and drug delivery [26][27][28] . Due to their unique structural features, dendrimers have received considerable attention for use as potential nucleic acid carriers 18,[29][30][31] . ...
... Due to their unique structural features, dendrimers have received considerable attention for use as potential nucleic acid carriers 18,[29][30][31] . Carbosilane dendrimers were found to be a stable and effective delivery system with high transfection efficiency by Weber et al. 28,32 Advancing research in this area has the potential to overcome the current limitations and challenges of today's therapy methods and unlock the full potential of dendrimers for the treatment of neurodegenerative disorders and other diseases. It is crucial to continue the development and characterization of these extraordinary tools for gene therapy applications. ...
Gene therapy presents an innovative approach to the treatment of previously incurable diseases. The advancement of research in the field of nanotechnology has the potential to overcome the current limitations and challenges of conventional therapy methods, and therefore to unlocking the full potential of dendrimers for use in the gene therapy of neurodegenerative disorders. The blood–brain barrier (BBB) poses a significant challenge when delivering therapeutic agents to the central nervous system. In this study, we investigated the biophysical properties of dendrimers and their complexes with siRNA directed against the apolipoprotein E (APOE) gene to identify an appropriate nanocarrier capable of safely delivering the cargo across the BBB. Our study yielded valuable insights into the complexation process, stability over time, the mechanisms of interaction, the influence of dendrimers on the oligonucleotide's spatial structure, and the potential cytotoxic effects on human cerebral microvascular endothelium cells. Based on our findings, we identified that the dendrimer G3Si PEG6000 was an optimal candidate for further research, potentially serving as a nanocarrier capable of safely delivering therapeutic agents across the BBB for the treatment of neurodegenerative disorders.
... In 1999, Caminade and Majoral Lab used phosphorus (P)-containing dendrimers to deliver DNA [101]. Cationic carbosilanes were employed to deliver DNA and RNA by Muñoz and Bryszewska laboratories in 2005 [102,[118][119][120][121][122], while cationic PPI was used by Sinselmeyer Lab in 2002 [103,123]. Both covalent cationic dendrimers are associated with some of the negative features of cationic liposomes. ...
... Although substantial research is required to accomplish a system like this, we believe that the strategy of 1c-IAJD-DNP is conceptually suitable to accomplish it. Alternative dendrimer fragments such as carbosilane, PPI, and others can also be incorporated into IAJDs [101,102,[118][119][120][121][122]. ...
Viral and synthetic vectors to deliver nucleic acids were key to the rapid development of extraordinarily efficient COVID-19 vaccines. The four-component lipid nanoparticles (LNPs), containing phospholipids, PEG-conjugated lipids, cholesterol, and ionizable lipids, co-assembled with mRNA via a microfluidic technology, are the leading nonviral delivery vector used by BioNTech/Pfizer and Moderna to access COVID-19 mRNA vaccines. LNPs exhibit a statistical distribution of their four components when delivering mRNA. Here, we report a methodology that involves screening libraries to discover the molecular design principles required to realize organ-targeted mRNA delivery and mediate activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer (IAJD) derived from plant phenolic acids. IAJDs co-assemble with mRNA into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions, via the simple injection of their ethanol solution in a buffer. The precise location of the functional groups in one-component IAJDs demonstrated that the targeted organs, including the liver, spleen, lymph nodes, and lung, are selected based on the hydrophilic region, while activity is associated with the hydrophobic domain of IAJDs. These principles, and a mechanistic hypothesis to explain activity, simplify the synthesis of IAJDs, the assembly of DNPs, handling, and storage of vaccines, and reduce price, despite employing renewable plant starting materials. Using simple molecular design principles will lead to increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics.
... Water-soluble cationic dendrimers are useful as non-viral vectors for gene therapy [209][210][211]. These molecules have the ability to bind oligonucleotides and siRNAs together and transport them into the cell, protecting nucleic materials from damage by proteins and nucleases; however, the biggest problem with cationic dendrimers is their inherent toxicity. ...
... These molecules have the ability to bind oligonucleotides and siRNAs together and transport them into the cell, protecting nucleic materials from damage by proteins and nucleases; however, the biggest problem with cationic dendrimers is their inherent toxicity. To solve this problem, they use the connection of PEG sections, which also increases the solubility of macromolecules [210]. In this regard, Sánchez-Nieves et al. [212] synthesized amphiphilic Janus dendrimers consisted of two types of dendrons including PEG and carbosilane with ammonium end groups. ...
Dendrimers are among the most popular multifaceted systems. Conventional dendrimers cannot be used in many specific applications such as simultaneous loading of different drugs due to the presence of identical end-groups. Thus, they are conjugated with other compounds that results in losing their functional groups. Janus dendrimers has emerged to fix these issues. These dendrimers have unique structure and properties with the combinations of different types of end-groups in different parts of the surface. Four main methods have been proposed by combination of divergent and convergent approaches for synthesis of Janus dendrimers. Janus dendrimers have enhanced solubility, electrochemical properties, and ability of self-assembly which distinguish themselves from other dendritic structures. The broken symmetry structure of Janus dendrimers offers new and efficient features for formation of complex materials that conventional dendrimers fail to deliver. These macromolecules are used in a variety of fields including ionic liquids, bioimaging, catalysis, smart systems, drug suspensions, hydrogels, and cancer therapy. Although some studies on Janus dendrimers have been performed by other researchers in the past few years, their main goal was bioapplications of these dendrimers. In this work, we have studied new synthetic methods besides conventional ones and also, all applications of Janus dendrimers have been studied.
... Three families of polyphenolic dendritic compounds G n -[Si(CH 2 ) 3 NHC(O)R] m (R 1 = ferulic: n = 1, m = 4,(1), n = 2, m = 8 (4); R 2 = caffeic: n = 1, m = 4,(2), n = 2, m = 8 (5); R 3 = gallic: n = 1, m = 4,(3), n = 2, m = 8 (6)) ( Figure 1) were prepared using carbosilane dendrimers with amino groups on the periphery G n -[Si(CH 2 ) 3 NH 2 ] m (n = 1, m = 4 (I), n = 2, m = 8 (II)) as precursors [23]. The presence of carboxylic groups in selected polyphenols allows for easy attachment via a covalent bond to the amino groups localized at the surface of the dendrimers through a straightforward amidation reaction. ...
... The NMR spectra of the first-generation polyphenolic dendrimer functionalized with caffeic acid (2) are reported in Figure 2 as an example. [23]. The presence of carboxylic groups in selected polyphenols allows for easy attachment via a covalent bond to the amino groups localized at the surface of the dendrimers through a straightforward amidation reaction. ...
A new family of polyphenolic carbosilane dendrimers functionalized with ferulic, caffeic, and gallic acids has been obtained through a straightforward amidation reaction. Their antioxidant activity has been studied by different techniques such as DPPH (2,2′-diphenyl-1-picrylhydrazyl) radical scavenging assay, FRAP assay (ferric reducing antioxidant power), and cyclic voltammetry. The antioxidant analysis showed that polyphenolic dendrimers exhibited higher activities than free polyphenols in all cases. The first-generation dendrimer decorated with gallic acid stood out as the best antioxidant compound, displaying a correlation between the number of hydroxyl groups in the polyphenol structure and the antioxidant activity of the compounds. Moreover, the antibacterial capacity of these new systems has been screened against Gram-positive (+) and Gram-negative (−) bacteria, and we observed that polyphenolic dendrimers functionalized with caffeic and gallic acids were capable of decreasing bacterial growth. In contrast, ferulic carbosilane dendrimers and free polyphenols showed no effect, establishing a correlation between antioxidant activity and antibacterial capacity. Finally, a viability assay in human skin fibroblasts cells (HFF-1) allowed for corroborating the nontoxicity of the polyphenolic dendrimers at their active antibacterial concentration.
... A widespread kind of nanoparticles (NPs) have shown great results inhibiting several steps of the viral cycle in HSV-1 and HIV-2 infection [33][34][35], as well as in other latent viruses [36][37][38]. They have a controlled synthesis consisting of a core with several sequential branching units, which present several end-groups [39]. The capability to synthesize this hyperbranched polymer with different cores or functional groups provides these NPs a versatile functionalization. ...
... NPs were synthesized according to described procedures by Bermejo et al [39]. The gold NPAuG1-S2, NPAuG2-S4, and NPAuG3-S8 were selected according to the generation number, type and number of peripherical charges and the focal point. ...
Infections caused by HSV-1 and their typical outbreaks invading the nervous system have been related to neurodegenerative diseases. HSV-1 infection may deregulate the balance between the amyloidogenic and non-amyloidogenic pathways, raising the accumulation of amyloid-β peptides, one of the hallmarks in the neurodegenerative diseases. An effective treatment against both, HSV-1 infections and neurodegeneration, is a major therapeutic target. Therefore, gold nanoparticles (NPAus) have been previously studied in immunotherapy, cancer and cellular disruptions with very promising results. Our study demonstrates that a new NPAus family inhibits the HSV-1 infection in a neural-derived SK-N-MC cell line model and that this new NPAus reduces the HSV-1-induced -secretase activity, as well as amyloid- accumulation in SK-APP-D1 modifies cell line. We demonstrated that NPAuG3-S8 crosses the blood-brain barrier (BBB) and does not generate cerebral damage to in vivo CD1 mice model. The NPAuG3-S8 could be a promising treatment against neuronal HSV-1 infections and neuronal disorders related to the Aβ peptides.
... Compounds dicyandiamide, trimethylsilyl chloride (TMSCl), and chlorhexidine digluconate (CLX) were obtained from commercial sources. Compounds G n Si(NH 2 ) m (n = 0, m = 1 (I); n = 1, m = 4 (II), and n = 2, m = 8 (III)) were synthesized as published (Bermejo et al. 2007;Maroto-Díaz et al. 2016). ...
... Different generations of amine-terminated carbosilane dendrimers G n Si(NH 2 ) m (n = 0, m = 1 (I); n = 1, m = 4 (II), and n = 2, m = 8 (III)) (Maroto-Díaz et al. 2016;Bermejo et al. 2007) (Fig. 1) were selected as starting materials to prepare the corresponding biguanide-functionalized dendrimers (biGU-dendrimers) by microwave chemistry. Microwave heating can accelerate reaction time reducing it from days or hours to minutes. ...
The genus Acanthamoeba can cause Acanthamoeba keratitis (AK) and granulomatous amoebic encephalitis (GAE). The treatment of these illnesses is hampered by the existence of a resistance stage that many times causes infection relapses. In an attempt to add new agents to our chemotherapeutic arsenal against acanthamebiasis, two Acanthamoeba isolates were treated in vitro with newly synthesized biguanide dendrimers. Trophozoite viability analysis and ultrastructural studies showed that dendrimers prevent encystment by lysing the cellular membrane of the amoeba. Moreover, one of the dendrimers showed low toxicity when tested on mammalian cell cultures, which suggest that it might be eventually used as an amoebicidal drug or as a disinfection compound in contact lens solutions.
... 10 Their cationic derivatives show a great contrast in properties of the interior and periphery that creates very favourable environment for encapsulation of various molecules within the dendrimer, and it can be exploited in particular for transport of the target material across the cell membrane. 11,12 Up to date, cationic carbosilane dendrimers are represented mainly by derivatives of quaternary ammonium salts (QAS). [11][12][13][14][15][16][17] Disadvantageous for medicinal applications of QAS functionalized macromolecules is their quite high cytotoxicity induced by high concentration of charged groups at the periphery. ...
... 11,12 Up to date, cationic carbosilane dendrimers are represented mainly by derivatives of quaternary ammonium salts (QAS). [11][12][13][14][15][16][17] Disadvantageous for medicinal applications of QAS functionalized macromolecules is their quite high cytotoxicity induced by high concentration of charged groups at the periphery. 18 To obtain dendrimers with similar hydrophobic/hydrophilic core-shell structure but lower toxicity, we decided to substitute QAS at the periphery for commonly more biocompatible phosphonium groups. ...
Macromolecular polyelectrolytes are gaining considerable attention for the application in medicine which implies their detailed characterization. We have successfully applied electrospray ionization mass spectrometry (ESI MS) to the analysis of defects in the structure of three generations of polycationic carbosilane dendrimers bearing series of quarternary phosphonium groups at their periphery. Besides expected defects caused by incomplete conversion of particular reaction steps during the synthesis of dendritic scaffold and subsequent peripheral functionalization, also several products of side reactions were observed together with defects created in the course of measurement (particularly ion exchange products). Defective molecules can be to some extent separated on GPC column which proves that they are not products of in source fragmentation processes. Within the reaction sequence used for the synthesis of dendrimers under study, hydrosilylation was the source of most defects; the effectivity of quarternization depends on the type of phosphine. Results confirm high sensitivity of ESI MS towards defects, stability of the carbosilane skeleton towards fragmentation under the conditions of ESI ionization and capability to detect both lower‐ and higher molecular weight impurities arising from the synthetic sequence in the same m/z range as the target dendrimer, thus providing valuable view of the polydispersity.
... In this work we used various techniques, such as fluorescence spectroscopy, ultrasonic spectroscopy, Langmuir method, Brewster angle microscopy, dynamic light scattering and atomic force microscopy to characterize biophysical properties of lipid vesicles, monolayers and supported lipid bilayers (sBLMs) and to study the interaction of dendrimer/peptide complexes with these model membrane systems composed of zwitterionic and negatively charged PEGylated lipids. We used carbosilane dendrimers [25,26] modified by Nef petide which is important in achieving and maintaining high viral loads both in vivo and in vitro. It is known that Nef has at least two distinct roles: it enhances viral replication and stimulates a reduction in the number of CD4 receptors on the surface of the infected cells [27]. ...
... Second generation water-soluble cationic carbosilane dendrimers containing carbon-silicon bonds and 16 positive charges, BDBR0011 (CBD-CS) have been synthesized as described elsewhere [25,26]. The structure of CBD-CS C 144 H 348 I 16 N 16 Si 13 16+ is presented in Fig. 1. ...
... In this work we used various techniques, such as fluorescence spectroscopy, ultrasonic spectroscopy, Langmuir method, Brewster angle microscopy, dynamic light scattering and atomic force microscopy to characterize biophysical properties of lipid vesicles, monolayers and supported lipid bilayers (sBLMs) and to study the interaction of dendrimer/peptide complexes with these model membrane systems composed of zwitterionic and negatively charged PEGylated lipids. We used carbosilane dendrimers [25,26] modified by Nef petide which is important in achieving and maintaining high viral loads both in vivo and in vitro. It is known that Nef has at least two distinct roles: it enhances viral replication and stimulates a reduction in the number of CD4 receptors on the surface of the infected cells [27]. ...
... Second generation water-soluble cationic carbosilane dendrimers containing carbon-silicon bonds and 16 positive charges, BDBR0011 (CBD-CS) have been synthesized as described elsewhere [25,26]. The structure of CBD-CS C 144 H 348 I 16 N 16 Si 13 16+ is presented in Fig. 1. ...
In this study, dendrimers have been purposed as an alternative approach for delivery of HIV peptides to dendritic cells. We have investigated the interaction of dendriplexes formed from polyanionic HIV peptide Nef and cationic carbosilane dendrimer (CBD) with model lipid membranes - large unilamellar vesicles (LUVs), Langmuir monolayers and supported lipid membranes (sBLMs) containing various molar ratio of zwitterionic 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[Methoxy (polyethylene glycol) - 2000] (DSPE-PEG2000). In our experiments, the lipid membranes represented the model of the plasma membrane of the cell. PEGylated lipids were used in order to model glycocalyx which constitutes the outer leaflet of cellular membranes. The presence of PEGylated lipids resulted in an increase of the phase transition temperature of the lipid bilayer of LUVs, in a decrease of specific volume and adiabatic compressibility. Fluorescence anisotropy study suggests that PEGylated LUVs possessed higher lipid order and decreased fluidity when compared to zwitterionic DMPC vesicles. The interaction of dendriplexes with monolayers was accompanied by the formation of the aggregates as revealed by BAM experiments. This conclusion has been confirmed also by AFM imaging of sBLMs. We have demonstrated that dendriplexes interact with lipid membranes for all types of lipid composition. Moreover, the stronger interaction of cationic dendrimer/peptide complexes with lipid monolayers, vesicles and sBLMs was observed for membranes composed of zwitterionic lipids than for PEGylated lipid membranes. Increased concentration of PEGylated lipids made this interaction weaker.
... It is selective and tolerable to a wide range of compound active groups [1], and it could be catalyzed by a number of transition metal catalysts, including platinum catalysts [22,23].Platinum Karstedt's catalyst [23] and Speier's catalyst [24,25] were used as promoters to participate in the reaction through hydrosilylation. The functionalization of polymethylhydrosiloxane (PMHS) have been carried out utilizing silicone oils with various hydrogen concentrations, olefin structures, and ratios between C = C bonds and H-Si units [26][27][28][29][30][31][32]. ...
The hydrosilylation of polymethyl-hydrosiloxane (PMHS) with alkenes comprising alkyl, epoxy alkyl, and other functional groups under the action of platinum catalysts were investigated in this work. As reported herein, the synthetic routes, reaction conditions, synthetic procedures were studied. Moreover, a more effective preparation method was conceptualized, leading to the formation of modified silicone oil containing alkyl, epoxy alkyl, and other functional groups capped. In addition, we explored the reaction kinetics and thermodynamic processes through online monitoring technology in an attempt to establish the relationship between the monomer structure and the functionalization degree of organosilicon. The chemical reaction rate and the reaction conversion rate were determined using real-time in-situ FT-IR spectroscopy. Nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC) were used to characterize the functionalized polymers. The results indicated the steric structure and electronic effects of the substituents directly attached to the double bond, which play an important role in the creation of the desired products and the reaction’s total conversion time. Furthermore, the steric hindrance leads to the greatest impact on reaction activity and conversion, followed by electronic effects like conjugation and induction. It is worth noting that partially modified polymers with pendant alkoxy groups have promising applications in resin modification, coating, soft finishing, and decontamination.
Graphical abstract
... Different delivery nanocarriers provide a scaffold through which different small RNA molecules have been successfully delivered in diverse studies [12][13][14][15]. We have carried out broad research about various dendrimers in the context of HIV-1 infection [16][17][18][19][20]. Previously, we reported amino-terminated carbosilane dendrimers that provide stability, protection and high transfection efficiency to oligodeoxynucleotides and siRNAs inhibiting HIV-1 replication in peripheral blood mononuclear cells (PBMCs) and CD4 T-cells [21][22][23][24]. Carbosilane dendrimers are three-dimensional hyperbranched molecules capable of forming complexes by electrostatic interactions between the positively charged functional terminal groups and negatively charged backbone of small RNAs, what confers protection and facilitates transfection of bound RNAs [25]. ...
Background
The appearance of resistance against new treatments and the fact that HIV-1 can infect various cell types and develop reservoirs and sanctuaries makes it necessary to develop new therapeutic approaches to overcome those failures.
Results
Studies of cytotoxicity, genotoxicity, complexes formation, stability, resistance, release and particle size distribution confirmed that G2-SN15-PEG, G3-SN31-PEG, G2-SN15-PEG-FITC and G3-SN31-PEG-FITC dendrimers can form complexes with miRNAs being biocompatible, stable and conferring protection to these nucleic acids. Confocal microscopy and flow cytometry showed effective delivery of these four dendrimers into the target cells, confirming their applicability as delivery systems. Dendriplexes formed with the dendrimers and miRNAs significantly inhibited HIV-1 infection in PBMCs.
Conclusions
These dendrimers are efficient delivery systems for miRNAs and they specifically and significantly improved the anti-R5-HIV-1 activity of these RNA molecules.
Graphic Abstract
... Следует отметить, что этот этап в развитии мозга крысы в целом характеризуется интенсивным ростом нейронов [13]. Подобная динамика прогрессивного роста нейронов головного мозга в постнатальном онтогенезе наблюдалась нами ранее в больших пирамидных нейронах изокортекса и клетках Пуркинье мозжечка [14,15]. ...
(ARTICLE IN RUSSIAN). Dendrimers are hyperbranched polymers belonging to the class of nanomaterials. These nanostructures and their derivatives (dendrons and dendronized nanoparticles) are multi-target nanocarriers that can be modified to achieve various tasks. For example, it is possible to increase biocompatibility and stability, to control the release of active substances. Their widespread use in biology and medicine requires an understanding of the basic mechanisms of their interaction with proteins – one of the main biological systems. The interaction of dendrimers with proteins may vary depending on the size of the ones, surface charge, structure and stiffness of the branches. All these interactions in one way or another can affect the structure and functions of proteins. Present article discusses the mechanisms of interactions between dendrimers, dendronized nanoparticles and protein macromolecules. The effect of nanoparticles on the secondary structure, conformation, dynamics and functional activity of proteins is reviewed.
... These include peptide dendrimers, polyester dendrimers, polyamine dendrimers, polyether dendrimers, carbohydrate dendrimers, triazine dendrimers, carbosilane dendrimers and phosphorus dendrimers (Figure 4). [28][29][30][31][32][33][34][35][36] Collectively, the reported dendrimers possess remarkable structural and chemical diversity. ...
Poly(amidoamine) (PAMAM) dendrimers are the most intensively studied class of dendrimers since the seminal report of Tomalia et al. in 1985. PAMAM dendrimers have many outstanding characteristics that make them highly suited to biological applications, including their peptide-mimicking amide backbones, numerous interior and terminal amine functionalities, nanosized three-dimensional architecture, well-defined dendritic structure and intrinsically generated multivalent cooperativity. PAMAM dendrimers can be readily synthesized, and are commercially available at an affordable price. In this chapter, we present an overview of the synthesis of PAMAM dendrimers and their related biological applications as drugs, and as systems for delivering drugs, nucleic acids and imaging agents for therapeutic and diagnostic purposes.
... They demonstrated that the PEG-modified PAMAM dendrimer is an extremely efficient, highly biocompatible, low-cost DNA delivery system, and it can be readily used in basic research laboratories as well as in future clinical applications. On another study [127] water-soluble carbosilane dendrimers were complexed with oligonucleotides via electrostatic interaction. Perrisé-Barrios et al. [40] reported the synthesis of carbosilane dendrimers 2G-NN16 and 2G-03NN24 with the capacity to transfect siRNA to CD4 T lymphocytes, inhibiting HIV-1 replication. ...
The European Medicines Agency (EMA) and the Current Good Manufacturing Practices (cGMP) in the United States of America, define excipient as the constituents of the pharmaceutical form other than the active ingredient, i.e., any component that is intended to furnish pharmacological activity. Although dendrimers do not have a pharmacopoeia monograph and, therefore, cannot be recognized as a pharmaceutical excipient, these nanostructures have received enormous attention from researchers. Due to their unique properties, like the nanoscale uniform size, a high degree of branching, polyvalency, aqueous solubility, internal cavities, and biocompatibility, dendrimers are ideal as active excipients, enhancing the solubility of poorly water-soluble drugs. The fact that the dendrimer’s properties are controllable during their synthesis render them promising agents for drug-delivery applications in several pharmaceutical formulations. Additionally, dendrimers can be used for reducing the drug toxicity and for the enhancement of the drug efficacy. This review aims to discuss the properties that turn dendrimers into pharmaceutical excipients and their potential applications in the pharmaceutical and biomedical fields.
... Furthermore, we wanted to maximize the number of iminopyridine groups and their metal complexes on the dendritic surface, and subsequently the anticancer activity. Using a statistical approach for the heterofunctionalization of the precursor dendrimers G n -[NH 2 ] m (n = 1, m = 4 (I), n = 2, m = 8 (II)) [34], a condensation reaction was carried out between the amino groups present in the precursor dendrimers and 2-pyridinecarboxaldehyde, in a 1:3 ratio for the first-generation derivative, and a 1:7 ratio for the second-generation analogue, resulting in the formation of G n -{[NCPh(o-N)] (m-1) [NH 2 ]}, (n = 1, m = 4 (G 1 -PyN, 1); n = 2, m = 8 (G 2 -PyN, 2)) with one free -NH 2 group (Scheme 1) [30]. ...
Dendrimers exhibit unique interactions with cell membranes, arising from their nanometric size and high surface area. To a great extent, these interactions define their biological activity and can be reported in situ by spin-labelling techniques. Schiff-base carbosilane ruthenium (II) metallodendrimers are promising antitumor agents with a mechanism of action yet to explore. In order to study their in situ interactions with model cell membranes occurring at a molecular level, namely cetyltrimethylammonium bromide micelles (CTAB) and lecithin liposomes (LEC), electron paramagnetic resonance (EPR) was selected. Both a spin probe, 4-(N,N-dimethyl-N-dodecyl)ammonium-2,2,6,6-tetramethylpiperidine-1-oxyl bromide (CAT12), able to enter the model membranes, and a spin label, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) covalently attached at newly synthesized heterofunctional dendrimers, were used to provide complementary information on the dendrimer–membrane interactions. The computer-aided EPR analysis demonstrated a good agreement between the results obtained for the spin probe and spin label experiments. Both points of view suggested the partial insertion of the dendrimer surface groups into the surfactant aggregates, mainly CTAB micelles, and the occurrence of both polar and hydrophobic interactions, while dendrimer–LEC interactions involved more polar interactions between surface groups. We found out that subtle changes in the dendrimer structure greatly modified their interacting abilities and, subsequently, their anticancer activity.
... These systems had good toxicity profiles at < 5 µM concentration (PBMCs cells, T lymphocytic cell line, erythrocytes). They were capable of binding the fluorescent probe ANS, BSA, nucleic acids (forming dendriplexes): DNA, plasmids, oligodeoxynucleotides (ODNs) and siRNAs with anti-HIV activity at biocompatible doses through electrostatic interaction [71][72][73][74][75][76][77]. For efficient gene delivery, these dendriplexes must overcome extracellular and intercellular barriers. ...
The use of nanotechnology in biology and medicine has been marked by rapid progress of these industries due to
the emergence of new devices, supramolecular systems, structures, complexes and composites. One striking
example of nanotech polymers is dendrimers. Their structure is formed by branches of monomeric subunits
diverging in all directions from the central core. In choosing monomers and functional groups in synthesis, one
can precisely set the properties of the resulting macromolecules. Currently, with modifications,>100 types of
dendrimers have been synthesized. Of these, the 5 most common families can be distinguished: (i)
Polyamidoamine (PAMAM) dendrimers are based on the ethylenediamine core and their branches are constructed
from methyl acrylate and ethylene diamine. Currently, there is a large selection of PAMAM dendrimers
with surface groups of many types. (ii) Polypropyleneimine (PPI) dendrimers are based on a butylenediamine
core and polypropyleneimine monomers. In addition to PPI, the second popular abbreviation of these dendrimers
is DAB (diaminobutyl) – from the name of the nucleus. Currently commercially available are (iii)
Phosphorus dendrimers. In phosphorus dendrimers, phosphorus atoms are present in the core and branches of
the dendrimer. (iv) Carbosilane dendrimers are based on a silicon core and have ammonium or amino groups on
the periphery. (v) Poly(lysine) and poly(L-ornithine) dendrimers are a dendrimeric structure composed of amino
acids residues. Characteristic surface groups possessing hydrophobic or hydrophilic components help to encapsulate
the ligands inside or attach them to the surface, ensuring protection from degradation. Drug molecules
complexed with dendrimer can be delivered to target cell where they are released from the complex. Dendrimers
can improve the bioavailability of drugs by increasing their solubility in water, and changing surface charge,
thereby reducing toxicity. In this review, the properties of dendrimers as drug carriers are discussed.
... The core-shell structure enables both encapsulation of hydro- phobic molecules and conjugation of other moieties to the sur- face, leading to promising biological applications, such as drug delivery, 3,4 biosensors, 5 medical diagnostics, 6 and antiangiogenic/ gene therapy. 7,8 Aside from their ability to serve as soluble nanostructures, another intriguing but less explored use of dendrimers is as crosslinkers in hydrogels, which have potential applications in tissue engineering/regenerative medicine, 9 bio- fabrication, 10 and extracellular matrix (ECM) mimics. 11 Despite their potential uses in biology and medicine, dendrimer-based hydrogels are typically made from synthetic dendrimers that are not bio-derived or biodegradable, most notably polyamidoamine (PAMAM). ...
Hydrogels that mimic the native extracellular matrix were prepared from hyaluronic acid (HA) and amine-terminated dendritic elastin-like peptides (denELPs) of generations 1, 2, and 3 (G1, 2, and 3) as crosslinking units. The physical properties of the hydrogels were investigated by rheology, scanning electron microscopy, swelling tests, small-angle X-ray scattering (SAXS), and model drug loading and release assays. Hydrogel properties depended on the generation number of the denELP, which contained structural segments based on the repeating GLPGL pentamer. Hydrogels with higher generation denELPs (G2 and 3) showed similar properties, but those prepared from G1 denELPs were rheologically weaker, had a larger mesh size, absorbed less model drug, and released the drug more quickly. Interestingly, most of the HA-denELP hydrogels studied here remained transparent upon gelation, but after lyophilization and addition of water retained opaque, "solid-like" regions for up to 4 d during rehydration. This rehydration process was carefully evaluated through time-course SAXS studies, and the phenomenon was attributed to the formation of pre-coacervates in the gel-forming step, which slowly swelled in water during rehydration. These findings provide important insights into the behavior of ELP-based hydrogels, in which physical crosslinking of the ELP domains can be controlled to tune mechanical properties, highlighting the potential of HA-denELP hydrogels as biomaterials.
... Hemolysis may involve direct erythrocyte damage and/or an immune-mediated hemolytic process. Generally, positively charged NPs tend to damage erythrocytes in a dose-dependent manner, as found with C60 fullerenes (Bosi et al., 2004), PAMAM (Domański et al., 2004), carbosilane (Bermejo et al., 2007), polypropylene imine (Agashe et al., 2006), and polylysine (Shah et al., 2000) dendrimers. In the case of drug loaded rHDL NPs, several reports indicate no hemolysis when NPs were incubated with red blood cells, perhaps due to the absence of SR-B1 receptor expression by erythrocytes (Oda et al., 2006;Yuan et al., 2013;Lu et al., 2015). ...
Drug delivery to malignant tumors is limited by several factors, including off-target toxicities and suboptimal benefits to cancer patient. Major research efforts have been directed toward developing novel technologies involving nanoparticles (NPs) to overcome these challenges. Major obstacles, however, including, opsonization, transport across cancer cell membranes, multidrug-resistant proteins, and endosomal sequestration of the therapeutic agent continue to limit the efficiency of cancer chemotherapy. Lipoprotein-based drug delivery technology, “nature’s drug delivery system,” while exhibits highly desirable characteristics, it still needs substantial investment from private/government stakeholders to promote its eventual advance to the bedside. Consequently, this review focuses specifically on the synthetic (reconstituted) high-density lipoprotein rHDL NPs, evaluating their potential to overcome specific biological barriers and the challenges of translation toward clinical utilization and commercialization. This highly robust drug transport system provides site-specific, tumor-selective delivery of anti-cancer agents while reducing harmful off-target effects. Utilizing rHDL NPs for anti-cancer therapeutics and tumor imaging revolutionizes the future strategy for the management of a broad range of cancers and other diseases.
... Other applications include catalysis [160,161], biosensing [162,163,164], photonics [165,166,167] and contrast agents in imaging systems (MRI) [168,169], and electronics [170]. In addition, different functionalized PAMAM dendrimers can be used for interfacial self-assembly to form monolayers at the air-water interface [171] or multilayers [172] onto solid substrates including planar substrates [173,174,175] and colloidal particles [176]. ...
A detailed analysis of the physicochemical properties of engineered nanoparticles (NPs) is required to understand on a mechanistic level their interactions/potential toxicity with/towards biotic components of fresh water systems. Such an analysis is further mandatory to achieve a comprehensive evaluation and optimisation of the performance of (ultra)filtration methods developed to prevent NPs release into aquatic media. Within this context, the aim of this PhD thesis was to decipher the basic physico-chemical processes governing the loading of carboxylated-poly(amidoamine) (PAMAM-COOH) nanodendrimers -commonly employed in biomedical applications- into layer-by-layer assembled (poly(diallyl dimethyl ammonium) chloride-poly(acrylic acid))n ((PDADMAC-PAA)n) multilayer films. For that purpose, a systematic investigation of the electrohydrodynamic properties of PAMAM-COOH NPs was first performed as a function of pH and monovalent salt concentration in solution. On the basis of advanced electrokinetic theory for soft particles with zwitterionic functionality, it is demonstrated that the interfacial electrostatic features of the considered NPs are determined both by surface and bulk particle contributions to an extent that depends on electrolyte concentration. This leads to a remarkable NPs mobility reversal with changing monovalent salt concentration and to a marked dependence of the point of zero NPs mobility on electrolyte content. In addition, confrontation between experiments and theory further highlights how pH- and salt-mediated modifications of the NP particle structure affect dendrimer electrokinetic features at large pH and/or low salt concentrations. In a second part, the structure, morphology and mechanical properties of PDADMAC-PAA films, and their evolution over time under natural aging conditions or after thermal treatment, were addressed from atomic force microscopy (AFM) and Raman microspectroscopy analyses. Results evidence that PDADMAC-PAA multilayer films of exponential type exhibit mechanical and structural features that are typical for polyelectrolyte multilayer films with linear growth. In particular, their slow relaxation to equilibrium is accelerated after heating treatment at 60°C and, in line with density functional theory computation, this relaxation dynamics is shown to be intimately connected to instability of film domains rich in PDADMAC, depleted in water and marked by the presence of characteristic donut-like structures. In a final part, the reported dependence of PDADMAC-PAA multilayer films elasticity on concentration of nanodendrimers in bulk solution suggests that these complex multilayer films constitute a promising option to be further investigated for the loading and removal of carboxylated nanodendrimers from aqueous environments
... Carbosilane dendrimers usually possess a C-Si backbone and their bifunctional methylsilane fragments act as the bifurcation/branching points of monomeric unit branches. Several techniques for synthesizing carbosilane dendrimers with a compact tetrafunctional cores (e.g., tetraallylsilane, tetravinylsilane) [45,46] and a more voluminous trifunctional nucleus (trioxybenzene) [47] have been described. Since the core is relatively small, dendrimers of this class have a high density of functional groups at the periphery. ...
The lack of an appropriate intracellular delivery system for therapeutic nucleic acids (TNAs) is a major problem in molecular biology, biotechnology, and medicine. A relatively new class of highly symmetrical hyperbranched polymers, called dendrimers, shows promise for transporting small TNAs into both cells and target tissues. Dendrimers have intrinsic advantages for this purpose: their physico-chemical and biological properties can be controlled during synthesis, and they are able to transport large numbers of TNA molecules that can specifically suppress the expression of single or multiple targeted genes. Numerous chemical modifications of dendrimers extend the biocompatibility of synthetic materials and allow targeted vectors to be designed for particular therapeutic purposes. This review summarizes the latest experimental data and trends in the medical application of various types of dendrimers and dendrimer-based nanoconstructions as delivery systems for short small interfering RNAs (siRNAs) and microRNAs at the cell and organism levels. It provides an overview of the structural features of dendrimers, indicating their advantages over other types of TNA transporters.
... El desarrollo de secuencias mosaico de antígenos diversos también podría suponer un arma a la hora de limitar la variabilidad y evitar el escape inmunológico. La utilización de adyuvantes que aumenten la calidad y la fuerza de la respuesta, sin inducir una activación del sistema inmune específica, también es de gran relevancia para mejorar las técnicas de vacunación actuales (55,61,108). No se deben olvidar los numerosos medios de transmisión del VIH-1 como otra dificultad más en el desarrollo de vacunas efectivas. ...
... El desarrollo de secuencias mosaico de antígenos diversos también podría suponer un arma a la hora de limitar la variabilidad y evitar el escape inmunológico. La utilización de adyuvantes que aumenten la calidad y la fuerza de la respuesta, sin inducir una activación del sistema inmune específica, también es de gran relevancia para mejorar las técnicas de vacunación actuales (55,61,108). No se deben olvidar los numerosos medios de transmisión del VIH-1 como otra dificultad más en el desarrollo de vacunas efectivas. ...
... These scaffolds can be hydrophilic (PAMAM, PPI, polyester), hydrophobic (phosphorus and silicon containing derivatives), hydrolizable (polyester). In the particular case of carbosilane dendrimers, due to their lypophilic nature, which facilitates interaction with lipidic membranes (Wrobel et al., 2012), and an adequate functionalization have shown attractive biomedical applications as gene carriers (Bermejo et al., 2007;Sánchez-Nieves et al., 2014;Serramía et al., 2015), bactericides (Ortega et al., 2011;Rasines et al., 2009) or antivirals (Arnáiz et al., 2014;Vacas-Córdoba et al., 2014;Vacas-Córdoba et al., 2016), being able also to cross the blood brain barrier Serramía et al., 2015). ...
Water soluble silver nanoparticles (AgNPs) capped with cationic carbosilane dendrons have been synthesized by direct reaction in water of dendrons, silver precursor and a reducing agent. These nanoparticles have been characterized by nuclear magnetic resonance (NMR), transmission electron microscopy (TEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA), ultraviolet spectroscopy (UV), elemental analysis, and zeta potential (ZP). The antibacterial and antifungal properties of the cationic dendrons and dendronized AgNPs and AuNPs with these dendrons have been evaluated against Gram-negative and Gram-positive bacterial −including resistant strains- and yeast strains, respectively. The results stand out for the activity of AgNPs covered with first generation dendron compared with this free dendron and corresponding dendronized AuNPs.
... Different kinds of carbosilane-based dendriplexes have shown good toxicity profiles in peripheral blood mononuclear cells and erythrocytes over extended periods of time [159]. ...
Over the last decades, gene therapy has emerged as a pioneering therapeutic approach to treat or prevent several diseases. Among the explored strategies, the short-term silencing of protein coding genes mediated by siRNAs has a good therapeutic potential in a clinical setting. However, the widespread use of siRNA will require the development of clinically suitable, safe and effective vehicles with the ability to complex and deliver siRNA into target cells with minimal toxicity. Lately, dendrimers have gained considerable attention as non-viral vectors in nucleic acid delivery due to their unique structural characteristics (globular, well defined and highly branched structure, multivalency, low polydispersity and tunable nanosize), along with their relevant capacity to complex and protect nucleic acids in compact nanostructures, which can be functionalized with targeting moieties in order to get cell specificity. Here we present an overview of the state-of-the-art of the most significant and recent advances on the use of dendrimers as siRNA delivery vectors, with particular focus on the in vivo applications. We will cover the use of different dendrimers, distinct administration routes, toxicity issues, as well as the target tissue or disease, highlighting the potential of dendrimers as nanocarriers for therapeutic and biomedical applications.
... Novel drug carriers for nontoxic, intelligent, and controlled drug delivery that are currently being developed and improved include liposomes ( Dorasamy et al., 2012) and ultrasmall nanostructured lipid carriers ( Singh et al., 2016), micelles ( Kapoor et al., 2012), nanogels ( Pereira et al., 2013), nanosuspensions ( Endres et al., 2012), quantum dots ( Zhao et al., 2013), dendrimers ( Bermejo et al., 2007;Caminade and Majoral, 2005), and hollow silica nanoparticles ( Zhao et al., 2015). Cyclodextrins are potential candidates for a role of drug carriers; they change physical, chemical, biological, and pharm a cological parameters of included molecules due to the guest-host interaction. ...
Sertraline represents selective serotonin reuptake inhibitors, which lowered blood glucose level and is used in patients with diabetes to treat depression and improve glycemic control. Oral application of sertraline is limited because it is sparingly soluble compound. We enhanced water-solubility of sertraline by complexation with 2-hydroxypropyl-β-cyclodextrin (HPβCD) and evaluated the pharmacological properties of the HPβCD:sertraline complex in rats with alloxan-induced diabetes.Using the methods of UV-V is spectroscopy and isothermal titration calorimetry (ITC) we evaluated the interaction parameters, the enthalpy, entropy, association constant, and Gibbs energy of complex formation between sertraline hydrochloride (SER) and HPβCD in aqueous solution at 298.15 K. Both entalpic and entropic effects concur in SER association with HPβCD.The complexation with HPβCD enhanced the solubility of SER with the association constant for sertraline and HPβCD 6530 ± 54 M⁻¹. The treatment of diabetic rats with the HPβCD:sertraline complex during 2 weeks exerted beneficial effect on pancreatic islet morphology and β-cell survival, which consequently lowered the severity of diabetes that pointed the decrease of blood glucose and glycated hemoglobin contents, the normalization of serum insulin level, and insulin sensitivity (HOMA-IR). The antidiabetic effect of the complex was significantly more pronounced as compared to the similar effect of both the monopreparations, HPβCD and SER. These results are suggested that the complexation of SER with the cyclodextrin derivative improves the pharmacological effect of sertraline, probably due to enhanced drug bioavailability.
... Another biodegradable dendrimer developed so far is carbosilane dendrimer containing interior carbon-silicon bond, which can be hydrolyzed in water between 4 and 24 h [99]. This slow degradation process ensures gradual release of terminal amines and simultaneous release of the condensed nucleic acids, therefore cytotoxicity of carbosilane dendrimers is more significantly reduced than PAMAM [100]. Several studies have applied this kind of polymer in siRNA delivery for brain-related diseases and obtained transfection efficiency similar to that achieved by viral vectors [101,102]. ...
Gene therapies have become a promising strategy for treating neurological disorders, such as brain cancer and neurodegenerative diseases, with the help of molecular biology interpreting the underlying pathological mechanisms. Successful cellular manipulation against these diseases requires efficient delivery of nucleic acids into brain and further into specific neurons or cancer cells. Compared with viral vectors, non-viral polymeric carriers provide a safer and more flexible way of gene delivery, although suffering from significantly lower transfection efficiency. Researchers have been devoted to solving this defect, which is attributed to the multiple barriers existing for gene therapeutics in vivo, such as systemic degradation, blood–brain barrier, and endosome trapping. This review will be mainly focused on systemically administrated brain-targeted polymers developed so far, including PEI, dendrimers, and synthetic polymers with various functions. We will discuss in detail how they are designed to overcome these barriers and how they efficiently deliver therapeutic nucleic acids into targeted cells.
In this study, EpCAM aptamer-activated nanoparticles (Ap-NPs) were synthesized to enhance treatment efficiency in colorectal cancer (CRC). PLGA [poly (D, L-lactide-co-glycolide)] copolymer was fabricated by conjugation of COOH-PEG-NH2 to PLGA-COOH through an EDC/NHS-mediated chemistry. Afterward, 5‐fluorouracil-loaded (FU) nanoparticles were prepared using the water/oil/water double emulsion solvent evaporation method. The in vitro cytotoxicity of formulations was evaluated using the MTT assay in HCT-116, CT-26, and HEK-293 cell lines. For in vivo study, tumor-bearing BALB/c mice were established by subcutaneous injection of CT-26 cell line. The results indicated that fabricated AP-FU-NPs had 101 nm size with a spherical surface, relatively homogeneously and, satisfactory encapsulation efficiency (83.93%). In vitro experiments revealed that Ap-FU-NPs had a superior in vitro cytotoxicity than both FU-NPs and free 5-FU in CT-26 and HCT-116 cells but, were significantly low toxic against HEK-293 cells relative to free 5-FU. Furthermore, in vivo results showed no significant hemolytic effect, hepatic and renal injury, or weight loss. After treatment of various animal groups with formulations, notable tumor growth delay was observed followed the order: Ap-FU-NPs < FU-NPs < 5-FU < PBS. The results suggest that AP-FU-NPs could be an effective and promising carrier for 5-FU delivery to the EpCAM overexpressing CRC cells.
In this work we explored a MW-assisted chlorine-free direct phenol substitution, which was indicated as a key Green Chemistry research area for pharmaceuticals manufacturers. The reaction of β-aminocarbonates (mustard carbonates) with several substituted phenols in the presence of a polar solvent (acetonitrile or butanol) led to the related aminoalkylated products via the anchimeric assistance of the nitrogen incorporated in the organic carbonate backbone. The aminoalkylation required short reaction time (7 minutes) and the related products were isolated in high yield (> 90%) via quick liquid-liquid extraction or column chromatography depending on the solvent employed. Furthermore, MW irradiation also showed to promote the one-pot aminoalkylation of phenol in excellent yield. In this approach a β-aminoalcohol was reacted with phenol in the presence of diethyl carbonate, used for the in-situ formation β-aminocarbonate, key intermediate in the consequent anchimerically driven alkylation. The resulting product, namely N,N-dimethyl-2-phenoxyethanamine, was isolated as pure in almost quantitative yield.
The unique physico-chemical properties of cationic polymers and their ability to be easily modified make them attractive for many biological applications. As a result there is a vast amount of research focussed on designing novel natural or synthetic cationic polymers with specific biological functionality.
Cationic Polymers in Regenerative Medicine brings together the expertise of leading experts in the field to provide a comprehensive overview of the recent advances in cationic polymer synthesis, modification and the design of biomaterials with different structures for therapeutic applications. Chapters cover recent developments in novel cationic polymer based systems including poly(L-lysine), Poly(N,N-dimethylaminoethyl methacrylate) and cationic triazine dendrimers as well as cationic polymer-coated micro- and nanoparticles and cationic cellulose and chitin nanocrystals. Applications discussed in the book include drug and gene delivery, therapeutics in thrombosis and inflammation as well as gene therapy.
Suitable both for an educational perspective for those new to the field and those already active in the field, the book will appeal to postgraduates and researchers. The broad aspects of the topics covered are suitable for polymer chemists interested in the fundamentals of the materials systems as well as pharmaceutical chemists, bioengineering and medical professionals interested in their applications.
N,N‐dialkyl ethylamine moiety can be found in numerous scaffolds of macromolecules, catalysts, and especially pharmaceuticals. Common synthetic procedures for its incorporation in a substrate relies on the use of a nitrogen mustard gas or on multistep syntheses featuring chlorine hazardous/toxic chemistry. Reported herein is a one‐pot synthetic approach for the easy introduction of aminoalkyl chain into different phenolic substrates through dialkyl carbonate (β‐aminocarbonate) chemistry. This new direct alcohol substitution avoids the use of chlorine chemistry, and it is efficient on numerous pharmacophore scaffolds with good to quantitative yield. The cytotoxicity via MTT of the β‐aminocarbonate, key intermediate of this synthetic approach, was also evaluated and compared with its alcohol precursor.
Iminopyridine-decorated carbosilane metallodendrimers have recently emerged as a promising strategy in the treatment of cancer diseases. Their unique features such as the nanometric size, the multivalent nature and the structural perfection offer an extraordinary platform to explore structure-to-property relationships. Herein, we showcase the outstanding impact on the antitumor activity of a parameter not explored before: the iminopyridine substituents in meta position. New Cu(II) carbosilane metallodendrimers, bearing methyl or methoxy substituents in the pyridine ring, were synthesized and thoroughly characterized. Electron paramagnetic resonance (EPR) was exploited to unveil the properties of the metallodendrimers. This study confirmed the presence of different coordination modes of the Cu(II) ion (Cu-N2O2, Cu-N4 and Cu-O4), whose ratios were determined by the structural features of the dendritic molecules. These metallodendrimers exhibited IC50 values in the low micromolar range (<6 μM) in tumor cell lines such as HeLa and MCF-7. The subsequent in vitro assays on both healthy (PBMC) and tumor (U937) myeloid cells revealed two key facts which improved the cytotoxicity and selectivity of the metallodrug: First, maximizing the Cu-N2O2 coordination mode; second, adequately selecting the pair ring-substituent/metal-counterion. The most promising candidates - G1(-CH3)Cl (8) and G1(-OCH3)NO3 (17), exhibited a substantial increase in the antitumor activity in U937 tumor cells, compared to the non-substituted counterparts, probably through two different ROS-production pathways.
In the preceding chapter, different physiological, chemical, and bio-chemical barriers in systemic drug delivery have been introduced. In this chapter, we will talk about the interactions between nanoparticles and blood components, and will delineate strategies to enhance the compatibility of the nanoparticles in blood. In fact, in order to achieve systemic delivery, blood circulation plays an important role because it is the blood that helps deliver the therapeutics to tissues bodywide. A good understanding of the interactions between nanoparticles and various components in blood is, therefore, pivotal to proper design of nanoparticulate systems as effective systemic carriers. The objective of this chapter is to introduce the methods of manipulating the pharmacokinetics and biodistribution of nanoparticulate systems by manipulating the interactions between nanoparticles and blood components during systemic delivery. Strategies to improve the hematocompatibility of the nanoparticulate systems will also be discussed for enhancing the use of the carriers in practical interventions at the preclinical and clinical levels.
Dendrimers are having novel three dimensional, synthetic hyperbranched, nano-polymeric structure. Among all of the dendrimers, Poly-amidoamine (PAMAM) dendrimer are used enormously applying materials in supramolecular chemistry. This review described the structure, characteristic, synthesis, toxicity, and surface modification of PAMAM dendrimer. Various strategies in supramolecular chemistry of PAMAM for synthesizing it at commercial and laboratory scales along with their limitations and applications has also discussed. When compared to other nano polymers, the characteristics of supramolecular PAMAM dendrimers in nanopolymer science has shown significant achievement in transporting drugs for molecular targeted therapy, particularly in host-guest reaction. It also finds its applications in gene transfer devices and imaging of biological systems with minimum cytotoxicity. From that viewpoint, this review has elaborated the structural and safety aspect of PAMAM for targeted drug delivery with pharmaceuticals in addition to the biomedical application.
Protein sample preparation is the bottleneck in the analysis of proteins. The aim of this work is to evaluate the feasibility of carbosilane dendrimers functionalized with cationic groups to make easier this step. Anionic carbosilane dendrimers (sulphonate- and carboxylate-terminated) have already demonstrated their interaction with proteins and their potential in protein sample preparation. In this work, interactions between positively charged carbosilane dendrimers and different model proteins were studied when working under different pH conditions, dendrimer concentrations, and dendrimer generations. Amino- and trimethylammonium-terminated carbosilane dendrimers presented, in some cases, weak interactions with proteins. Unlike them, carbosilane dendrimers with terminal dimethylamino groups could interact, in many cases, with proteins and these interactions were affected by the pH, the dendrimer concentration, and the dendrimer generation. Moreover, dendrimer precipitation was observed at all pHs, although just second and fourth generation (2 G and 4 G) dendrimers resulted in the formation of complexes with proteins. Under experimental conditions promoting dendrimer-protein interactions, 2 G dimethylamino-terminated dendrimers were proposed as an alternative to other methods used in analytical chemistry or analysis in which an organic solvent or a resin are required to enrich/purify proteins in a complex sample.
Aim: To research the synergistic activity of G2-S16 dendrimer and dapivirine (DPV) antiretroviral as microbicide candidate to prevent HIV-1 infection. Materials & methods: We assess the toxicity of DPV on cell lines by MTT assay, the anti-HIV-1 activity of G2-S16 and DPV alone or combined at several fixed ratios. Finally, their ability to inhibit the bacterial growth in vitro was assayed. The analysis of combinatorial effects and the effective concentrations were performed with CalcuSyn software. Conclusion: Our results represent the first proof-of-concept study of G2-S16/DPV combination to develop a safe microbicide.
A polycarbosilane having lactose‐derived structures was synthesized, and its thermal property, cytotoxicity, chemical crosslinking, and protein adsorption properties were investigated. The polycarbosilane (PSB‐Lac) was prepared by a thiol‐ene reaction between precursor poly(1‐(3‐butenyl)‐1‐methylsilacyclubane) (PSB) and heptaacetyl lactose that carried a thiol group at the anomeric position, and the successive deprotection of the acetyl groups. The lactose introduction efficiency determined by 1H NMR measurement was 75%. TGA and DSC revealed that the polymer had a 5 wt% decomposition temperature of 260 °C and glass transition temperature (Tg) of 84 °C, which indicated that PSB‐Lac was a thermally stable polymer. PSB‐Lac had no significant cytotoxicity, which was evaluated by human liver cancer cell line HepG2 cultivation on the polystyrene dishes coated with the polymer. Urethane‐crosslinked PSB‐Lac films were prepared by casting solutions of PSB‐Lac and hexamethylene diisocyanate and heating at 120 °C after evaporation of the solvent. The crosslinked PSB‐Lac showed higher adsorption of bovine serum albumin than the similarly crosslinked polycarbosilane that had a glucose structure (PSB‐Glc). © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 A polycarbosilane having lactose‐derived structures (PSB‐Lac) was synthesized, and its thermal property, cytotoxicity, chemical crosslinking, and protein adsorption properties were investigated. PSB‐Lac had no significant cytotoxicity, which was evaluated by human liver cancer cell line HepG2 cultivation. The crosslinked PSB‐Lac showed higher adsorption of bovine serum albumin than the similarly crosslinked polycarbosilane that had a glucose structure (PSB‐Glc).
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 dendrimers. 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.
The diversity of structures of inorganic dendrimers has been presented in Chapter 5, and the properties of inorganic dendrimers are emphasized in this chapter. However, only two families of inorganic dendrimers have attracted significant attention for their properties: the carbosilane dendrimers and the phosphorhydrazone dendrimers. Different types of properties have been observed for inorganic dendrimers in three main fields: (i) catalysis, (ii) nanomaterials, and (iii) biology/nanomedicine. With regard to catalysis, after an overview of the field, the dendritic effect and the possibility of recovering and reusing the dendritic catalysts will be emphasized. The field of nanomaterials will be divided into three topics: materials exclusively composed of dendrimers; materials incorporating inorganic dendrimers in their structure; and surfaces of materials modified with inorganic dendrimers, in particular for biological purposes. The last part of this chapter will discuss the use of inorganic dendrimers for biology/nanomedicine, with special insights into six topics: for bioimaging, for gene therapy, and for treatment of viral infections, brain diseases, cancers, and inflammatory diseases.
The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is one of the most widely employed “click” chemistry processes due to its ability to produce functional polymers and various architectures of polymers. Some unique properties of CuAAC include high selectivity, near-perfect reliability, high yields, and exceptional tolerance toward a wide range of functional groups and reaction conditions. Furthermore, CuAAC is an extremely chemoselective reaction, which forms triazole; therefore, it can be used for functional polymer materials and also for modifying highly functional biomolecules such as polypeptides, nucleic acids, and polysaccharides. The application of CuAAC ‘‘clicking’’ in polymer chemistry is increasing exponentially, leading to fabrication of a growing family of well-defined polymer materials with novel properties.
Nanobiomaterials can be defined as materials interacting with and influencing the biological microenvironment at a nanointerface. Recently the basic as well as applied research related to nanobiomaterials – a conjugation of nano-, material- and life-sciences – has immensely evolved for therapeutics and related biotechnology areas. The current overview focused on the potential of nanobiomaterial-based substrates towards the generation of biocompatible surfaces, tissue engineering architectures, and regenerative medicine. Emphasis was given to chemomolecular functionalization of nanobiomaterials, nanobiomaterial composites, and morphomechanically modified nanoarchetypes and their inherent chemo-biological interaction with the biological microenvironment. Additionally, recent developments in nanobiomaterial substrate design and structure, chemo-biological interface related bio-systems uses and further evolving applications in health care, therapeutics and nanomedicine were discussed herein. Furthermore, a special emphasis was placed on the nano-chemo-biological interactions inherent to various nanobiomaterial substrates in close vicinity with biological systems.
We report the synthesis and cytotoxicity evaluation of a completely new class of cationic carbosilane dendrimers functionalized with several different phosphonium peripheral groups and an ammonium functionalised one as a reference. The carbosilane dendrimers with NMe3, PMe3, P(Et2)2(CH2)3OH, PBu3, P(C6H4-OMe)3 and P(Ph)3 peripheral substituents were synthesized, thoroughly characterized and modelled by computer simulations. The cytotoxicities of the dendrimers were investigated in vitro on three model cell lines (B14, BRL and NRK cells) by MTT and CV assay methods. Generally, the cytotoxicities of PMe3 carbosilane dendrimers were similar or slightly lower when compared with NMe3 dendrimers. The substitution of methyl groups in PMe3 carbosilane dendrimers with more hydrophobic and bulky alkyl substituents (PBu3 and P(Et2)2(CH2)3OH dendrimers) resulted in an increase of cytotoxicity. The P(C6H4-OMe)3 dendrimer showed exceptionally low cytotoxicity across all cell lines or assay methods used. Generally, p
Carbosilane dendrimers containing vanillin on the surface have been prepared with the purpose of combining the unique antioxidant and anticancer properties of polyphenols and dendrimers. These new compounds exhibit antioxidant potency as free-radical scavengers, as determined by DPPH and ABTS. Remarkably, all synthesized dendrimers exhibit improved antioxidant efficacy compared to vanillin. Anticancer activity has been studied against HeLa cervical and PC3 human prostate cancer cell lines. Proliferation, cell cycle, adhesion and migration in human prostate tumor cells have been studied. Data revealed a general trend indicating that polyphenolic dendrimers are more cytotoxic than their monopolyphenolic counterparts in both cancer cell lines. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
For nanoparticles to be used successfully in biomedical application, their interactions with biological fluids need to be investigated, in which they will react with proteins and other macromolecules. In this case, dendrimers might change their biological properties. Thus, the interaction of 2 generations of carbosilane-viologen-phosphorus and 2 types of carbosilane dendrimers with the 3 proteins – alkaline phosphatase from E.coli, human aspartate transaminase and L-lactate dehydrogenase from rabbit muscles, will be discussed. The techniques used included circular dichroism, zeta potential measurement, fluorescence quenching and transmission electron microscopy. The results show that positively charged hybrid and carbosilane dendrimers can interact with negatively charged regulatory proteins, and are able to form complexes. However, the spatial structure and the flexibility of dendrimer are as important as the protein configuration in complex formation.
IIn order to improve the efficiency of the anti-inflammatory drug ibuprofen, cationic carbosilane dendrimers and dendrons with ibuprofen at their periphery or at their focal point, respectively, have been synthesized and the release of the drug was studied using HPLC. Macrophages were used to evaluate the anti-inflammatory effect of the ibuprofen-conjugated dendritic systems and compared with mixtures of non-ibuprofen dendritic systems in the presence of the drug. The cationic ibuprofen-conjugated dendron was the compound that showed higher anti-inflammatory properties. It reduces the LPS-induced COX-2 expression, decreases the release of several inflammatory cytokines such as TNFα, IL-1β, IL-6 and CCL3. These results open new perspectives in the use of these compounds as drug carriers.
Several cationic carbosilane dendrimers have been synthesized containing two different types of degradable bonds: Si-O and ester bonds. The first type of systems was prepared by reacting carbosilane dendrimers containing peripheral Si-Cl bonds with first generation dendrons presenting a OH function at the focal point and amine peripheral functions. The second type of systems was prepared by esterification between a dendrimer containing acid groups and an alcoholamine. The stability in water of both types of cationic systems was evaluated.
Dendrimers have a number of favorable properties, such as good transfection efficiency and relatively low toxicity, which have promoted their wider investigation as synthetic vectors for gene therapy. Their well-defined branched molecular architecture is highly adaptable thanks to the facile attachment of tunable functional groups that allow a range of chemical modifications. These are, for example, targeted at improving the gene condensation capacity, reducing toxicity, as well as aiming to give stealth or targeting properties after administration.
A DNA-transfection protocol has been developed that makes use of a synthetic cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA). Small unilamellar liposomes containing DOTMA interact spontaneously with DNA to form lipid-DNA complexes with 100% entrapment of the DNA, DOTMA facilitates fusion of the complex with the plasma membrane of tissue culture cells, resulting in both uptake and expression of the DNA. The technique is simple, highly reproducible, and effective for both transient and stable expression of transfected DNA. Depending upon the cell line, lipofection is from 5- to greater than 100-fold more effective than either the calcium phosphate or the DEAE-dextran transfection technique.
Starburst polyamidoamine (PAMAM) dendrimers are a new type of synthetic polymer characterized by a branched spherical shape and a high density surface charge. We have investigated the ability of these dendrimers to function as an effective delivery system for antisense oligonucleotides and 'antisense expression plasmids' for the targeted modulation of gene expression. Dendrimers bind to various forms of nucleic acids on the basis of electrostatic interactions, and the ability of DNA-dendrimer complexes to transfer oligonucleotides and plasmid DNA to mediate antisense inhibition was assessed in an in vitro cell culture system. Cell lines that permanently express luciferase gene were developed using dendrimer mediated transfection. Transfections of antisense oligonucleotides or antisense cDNA plasmids into these cell lines using dendrimers resulted in a specific and dose dependent inhibition of luciferase expression. This inhibition caused approximately 25-50% reduction of baseline luciferase activity. Binding of the phosphodiester oligonucleotides to dendrimers also extended their intracellular survival. While dendrimers were not cytotoxic at the concentrations effective for DNA transfer, some non-specific suppression of luciferase expression was observed. Our results indicate that Starburst dendrimers can be effective carriers for the introduction of regulatory nucleic acids and facilitate the suppression of the specific gene expression.
Phase 1 clinical trials of liposome-mediated gene therapy for cystic fibrosis have been completed and in all cases the expression level achieved has been low and transient. Clearly, improvements in the efficiency of gene transfer are required. It is now being recognised that delivery of high doses of DNA/liposomes to the mouse airway epithelium can achieve reproducible evidence of transgene, but is often associated with an unacceptable level of inflammation/ toxicity. It has recently been shown that instillation of bacterial DNA causes inflammation in the lower respiratory tract of rodents. The increased number and unmethylated status of CpG motifs, particularly when present in a particular base context, was identified as an important factor in this response. It was suggested that the immune system recognises this molecular pattern as 'foreign' thus activating appropriate immune responses. We have found that methylation of DNA decreases the level of several inflammatory cytokines in lavage fluid and surprisingly has a differential effect on expression of the plasmids pCMV CFTR-int6ab and pCMV CAT which only differ in the actual transcription cassette. The severe lung pathology observed did not show a corresponding decrease with methylation suggesting that these cytokines are not the only contributors to the toxicity/inflammation observed. Gene Therapy (2000) 7, 384-392.
To evaluate polypropylenimine dendrimers (generations 1-5: DAB 4, DAB 8, DAB 16, DAB 32, and DAB 64) as gene delivery systems.
DNA binding was evaluated by measuring the reduced fluorescence of ethidium bromide, and molecular modelling of dendrimer-DNA complexes also was performed. Cell cytotoxicity was evaluated against the A431 cell line using the MTT assay. In vitro transfection was evaluated against the A431 cell line using the beta-galactosidase reporter gene and N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulphate (DOTAP) served as a positive control.
Molecular modeling and experimental data revealed that DNA binding increased with dendrimer generation. Cell cytotoxicity was largely generation dependent, and cytotoxicity followed the trend DAB 64 > DAB 32 > DAB 16 > DOTAP > DAB 4 > DAB 8, whereas transfection efficacy followed the trend DAB 8 = DOTAP = DAB 16 > DAB 4 > DAB 32 = DAB 64.
The generation 2 polypropylenimine dendrimer combines a sufficient level of DNA binding with a low level of cell cytoxicity to give it optimum in vitro gene transfer activity.
The formation of particulate systems with well-defined sizes and shapes is of eminent interest in certain medical applications such as drug delivery, gene transfection, and imaging. The high level of control possible over the architectural design of dendrimers; their size, shape, branching length/density, and their surface functionality, clearly distinguishes these structures as unique and optimum carriers in those applications. The bioactive agents may be encapsulated into the interior of the dendrimers or chemically attached/physically adsorbed onto the dendrimer surface, with the option of tailoring the carrier to the specific needs of the active material and its therapeutic applications. In this regard, the high density of exo-presented surface groups allows attachment of targeting groups or functionality that may modify the solution behavior or toxicity of dendrimers. Quite remarkably, modified dendrimers have been shown to act as nano-drugs against tumors, bacteria, and viruses. Recent successes in simplifying and optimizing the synthesis of dendrimers such as the 'lego' and 'click' approaches, provide a large variety of structures while at the same time reducing the cost of their production. The reflections on biomedical applications of dendrimers given in this review clearly demonstrate the potential of this new fourth major class of polymer architecture and indeed substantiate the high hopes for the future of dendrimers.
Dendrimers are characterized by a combination of high end-group functionality and a compact, precisely defined molecular structure. These characteristics can be used in biomedical applications, for example, for the amplification or multiplication of effects on a molecular level, or to create extremely high local concentrations of drugs, molecular labels, or probe moieties. A brief summary of the current state of the art in the field is given, and focuses on the application of dendrimers both in diagnostics as well as in therapy. In diagnostics, dendrimers that bear GdIII complexes are used as contrast agents in magnetic resonance imaging. DNA dendrimers have potential for routine use in high-throughput functional genomic analysis, as well as for DNA biosensors. Dendrimers are also being investigated for therapeutics, for example, as carriers for controlled drug delivery, in gene transfection, as well as in boron neutron-capture therapy. Furthermore, the antimicrobial activity of dendrimers has been studied.
Dendrimers are well-defined hyperbranched macromolecules with characteristic globular structures for the larger systems. These novel polymers have inspired many chemists to develop new materials and several applications have been explored, catalysis being one of them. The recent impressive strides in synthetic procedures increased the accessibility of functionalized dendrimers, resulting in a rapid development of dendrimer chemistry. The position of the catalytic site(s) as well as the spatial separation of the catalysts appears to be of crucial importance. Dendrimers that are functionalized with transition metals in the core potentially can mimic the properties of enzymes, their efficient natural counterparts, whereas the surface-functionalized systems have been proposed to fill the gap between homogeneous and heterogeneous catalysis. This might yield superior catalysts with novel properties, that is, special reactivity or stability. Both the core and periphery strategies lead to catalysts that are sufficiently larger than most substrates and products, thus separation by modern membrane separation techniques can be applied. These novel homogeneous catalysts can be used in continuous membrane reactors, which will have major advantages particularly for reactions that benefit from low substrate concentrations or suffer from side reactions of the product. Here we review the recent progress and breakthroughs made with these promising novel transition metal functionalized dendrimers that are used as catalysts, and we will discuss the architectural concepts that have been applied.
A wide variety of silane dendrimers with up to 972 end groups has been synthesised in excellent yields using repetitive alkenylation–hydrosilylation cycles.
Silane dendrimers have potential for applications such as stable micelles, building blocks for nanotechnology, X-ray beam scattering and cores for star-branched polymers. The Figure shows a first generation silane dendrimer in which the unsaturated terminal groups (the starting points for the production of the second generation) can be seen. The synthesis and properties of these species are discussed.
This article focuses on the preparation of water-soluble carbosiloxane dendrimers by the divergent growth method using repetitive hydrosilylation-alcoholysis cycles as well as ammonolysis and ionexchange reaction steps.
It is proposed that the very important and useful “Speier catalyst” contains the complex H[(C3H6)PtCl3] in a solution of isopropyl alcohol. It is this platinum complex which is the active catalyst ingredient in hydrosilylation reactions. When solvent was removed from an “aged” solution of chloroplatinic acid in isopropyl alcohol, the Zeise type dimer, (C3H6)2Pt2Cl4, was deposited as an orange solid. This dimer underwent solvolysis and dissociated into a monomeric species when it dissolved in isopropyl alcohol. Spectroscopic methods involving 195Pt NMR, 1H NMR (360 MHz), far infrared, IR and ESCA were employed in reaching these conclusions.
Starting with tetravinylsilane as the core molecule, a succession of alternate Pt-catalyzed hydrosilylations of all vinyl groups with HSiCl6 and vinylations of all of the SiCl groups thus introduced with CH2=CHMgBr in THF provided a divergent synthesis of four generations of polycarbosilane dendrimers in which the Si atoms are linked by CH2CH2 groups. The chlorosilane of each generation was reduced with LiAlH4 to the corresponding silicon hydride. The fourth generation hydride 4G-H, contains 324 Si-H bonds. The crystal structure of the second generation hydride, 2G-H, is described: space group P1BAR, a = 13.907 angstrom, b = 15.682 angstrom, c = 16.414 angstrom, alpha = 82.76-degrees, beta = 71.76-degrees, gamma = 82.49-degrees, Z = 2, R = 0.0996, R(w) = 0.1274. The high residuals result from the inherently high thermal activity at the ends of the dendrimer arms.
A series of carbosilane dendritic macromolecules grown from four directions of a tetrahedral central core has been synthesized and characterized. In the synthesis tetravinylsilane is used as the central core molecule and dichloromethylsilane as the propagation unit. Two reactions are involved in the synthesis of each generation: hydrosilylation of vinylsilane with dichloromethylsilane and nucleophilic replacement of silicon chloride by vinylmagnesium bromide. The reaction conditions for hydrosilylation must be well controlled. After purification by chromatography on silica gel pure products for each generation are obtained. The H-1 and C-13 NMR spectra are consistent with the proposed structures. The molecular weights of the resulting carbosilane dendrimers have been determined by vapor pressure osmometry or light scattering. Their experimental values are in very good agreement with the theoretical values. The dilute solution properties of these dendrimers are different from linear polymers.
Nucleophilic reactions between mercapto-substituted amphiphiles and carbosilane dendrimers bearing (chloromethyl)silyl groups on their terminal branches gave, in high yields, amphiphilic dendrimers with hydrophobic carbosilane cores and alcohol, dimethylamino, or sodium sulfonate amphiphilic groups at the periphery. The negatively charged, sulfonate-terminated dendrimers were soluble in water, as were positively charged poly(ammonium) salts prepared from the dimethylamino-terminated derivatives. These new amphiphilic dendrimers were characterized by spectroscopic and mass spectrometric techniques. Preliminary studies of the aqueous solution behavior of the second generation, sulfonate-terminated dendrimer demonstrated its ability to enhance the solubility of lipophilic alkyl-substituted benzene derivatives, a characteristic property of micelles.
(1) Dow Corning Corporation, Midland, Mich. Some silicon hydrides add to the double bond of olefinic compounds in the presence of platinic chloride, platinized carbon, platinum black, ruthenium chloride and iridium. The addition reaction is exothermic and in many cases very rapid at temperatures from below room temperature to about 100°. Pentene-1 and pentene-2 both form n-pentylsilanes under these conditions. Only in the presence of a very active catalyst would cyclohexene react. Silicon hydrides useful in this reaction include trichlorosilane, methyldichlorosilane, dimethylchlorosilane, phenyldichlorosilane, 1,1,3,3-tetramethyldisiloxane. diethoxymethylsilane and others. A wide variety of olefinic compounds are reactive. In some cases allyl acetate and other allyl compounds as well as isopropenyl acetate form propylene.
Eine einzigartige Kombination von genau definierter Partikelstruktur und sehr hoher Oberflächenfunktionalität bieten die zur Zeit sehr aktuellen Dendrimere. Das Ziel vieler Arbeitsgruppen, die sich mit dieser ungewöhnlichen Molekülarchitektur beschäftigen, ist die Entwicklung neuer Anwendungen. In dieser Hinsicht am weitesten fortgeschritten ist ein Kontrastmittel auf Dendrimerbasis (siehe schematische Darstellung), das die Visualisierung von Blutbahnen ermöglicht.
Dendrimere zeichnen sich durch die Kombination von hoher Endgruppendichte und kompakter, präzise definierter Molekülstruktur aus. Diese Eigenschaften lassen sich für biomedizinische Anwendungen nutzen, z. B. zur Verstärkung oder Vervielfachung von Effekten auf molekularer Ebene oder zur Erzeugung hoher lokaler Konzentrationen von Wirkstoffen, Signalfunktionen oder Sondenmolekülen. Es wird ein kurzer Überblick des aktuellen Entwicklungsstandes präsentiert, der sowohl Anwendungen in der Diagnostik als auch Perspektiven für einen therapeutischen Einsatz behandelt. Im Bereich Diagnostik eignen sich Dendrimere auf der Basis von GdIII-Komplexen als Kontrastmittel beim Magnetresonanz-Imaging. DNA-Dendrimere sind vielversprechende Reagentien für die DNA-Biosensorik und für die Hochdurchsatz-Genomanalytik. Für einen Einsatz zu therapeutischen Zwecken, etwa in den Bereichen kontrollierte Wirkstofffreisetzung und Gentransfektion, in der Borneutroneneinfangtherapie oder als antimikrobielle Wirkstoffe, werden Dendrimere ebenfalls in Betracht gezogen.
Dendrimere sind wohldefinierte hochverzweigte Makromoleküle, die bei hinreichender Größe charakteristische globuläre Strukturen aufweisen. Sie haben viele Chemiker zur Entwicklung von neuen Materialien angeregt, und eine Reihe von Anwendungen, auch in der Katalyse, wurde bereits untersucht. Die jüngsten Fortschritte bei den Syntheseverfahren haben den Zugang zu funktionalisierten Dendrimeren sehr vereinfacht, was zu einer raschen Entwicklung der Dendrimerchemie geführt hat. Sowohl die Lage der katalytischen Zentren als auch die räumliche Trennung der Katalysatoren scheinen hier wesentlich zu sein. Dendrimere, die im Kern mit Übergangsmetallen funktionalisiert sind, sind potentielle Enzymmimetika; die an der Oberfläche funktionalisierten hingegen könnten die Lücke zwischen homogener und heterogener Katalyse füllen. Dies könnte vorzügliche Katalysatoren mit neuartigen Eigenschaften – besonderer Reaktivität oder Stabilität – liefern. Sowohl die kern- als auch die peripherieorientierte Strategie ergeben Katalysatoren, die die meisten Substrate und Produkte an Größe deutlich übertreffen, sodass eine Abtrennung durch moderne Membrantrenntechniken möglich ist. Diese neuen homogenen Katalysatoren lassen sich in kontinuierlich betriebenen Membranreaktoren verwenden, was vor allem bei solchen Reaktionen sehr vorteilhaft wäre, die von niedrigen Substratkonzentrationen profitieren oder durch Nebenreaktionen des Produkts beeinträchtigt werden. Wir geben hier einen Überblick über die jüngsten Fortschritte auf dem Gebiet der Übergangsmetall-funktionalisierten Dendrimere, die als Katalysatoren eingesetzt werden; auch die unterschiedlichen Konzepte für ihre Architektur werden besprochen.
Improvement of the methods for oligonucleotide delivery into cells is necessary for the development of antisense therapy. In the present work, a new strategy for oligonucleotide delivery into cells was tested using cationic peptides as a vector. At first, to understand what structure of the peptide is required for binding with an oligonucleotide, several kinds of α-helical and non-α-helical peptides containing cationic amino acids were employed. As a result, the amphiphilic α-helix peptides were best for binding with the oligonucleotide, and the long chain length and large hydrophobic region in the amphiphilic structure of the peptide were necessary for the binding and forming of aggregates with the oligonucleotide. In the case of non-α-helical peptides, no significant binding ability was observed even if their chain lengths and number of cationic amino acid residues were equal to those of the α-helical peptides. The remarkable ability of oligonucleotide delivery into COS-7 cells was observed in the α-helical peptides with a long chain length and large hydrophobic region in the amphiphilic structure, but was not observed in the non-α-helical peptides. It is considered that such α-helical peptides could form optimum aggregates with the ODN for uptake into cells. Based on these results, the α-helical peptide with a long chain length and large hydrophobic region is applicable as a vector for the delivery of oligonucleotides into cells. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.
Two decades ago a repetitive strategy for the synthesis of cascade molecules succeeded for the first time, and a rapid increase in the chemistry of dendrimers began. In the beginning the work was concentrated on the synthesis of dendrimers with new skeletons in high generations, but the tailoring of dendrimers to certain applications soon started. Here we would like to take stock and examine the latest developments in this research field. Therefore, we report on topical works to show the many facets of modern dendrimer chemistry. Dendrimers have also become commercially available, and the first applications have emerged. A contrast agent for magnetic resonance imaging (MRI) to visualize the bloodstream in the body is probably the most spectacular progress. Since specific properties of dendrimers were used for this process, this development could be at the leading edge of new applications. In the future dendrimers will generally be used more as anchor groups than they are hitherto, since dendritic building blocks allow the attachment of many substituents unlike the carbon tetrahedron (four substituents) and the benzene core (six substituents). Thus it is possible to enhance physical properties. As a tree can be full of blossoms and fruit, dendrimers can multiply functions. Undoubtedly it is more difficult to develop new functionalities for desired effects than to obtain new properties by multiplying known functions. When the orderly synthetic attachment of particular, many, selected, or different moieties on fractal central units can be controlled better than hitherto, and when analytical methods can distinguish between very similar dendritic isomers ('dendrimer libraries') and detect structure defects more easily and more precisely, then the progress ought to be even more ingeniously tempestuous than it is currently.
The convergent synthesis of a series of polycationic aryl ether dendrimers has been accomplished by a convenient procedure involving quantitative quaternarization of aryl(poly)amine core molecules. The series has been expanded to the preparation of the first polycationic, mixed core - shell dendrimer. All these dendrimers consist of an apolar core with a peripheral ionic layer which is surrounded by a less polar layer of dendritic wedges. These cationic, macromolecular species have been investigated for their ability to form assemblies with (anionic) guest molecules. The results obtained from UV/Vis and NMR spectroscopies, and MALDI-TOF-MS demonstrate that all the cationic sites throughout the dendrimer core are involved in ion pair formation with anionic guests giving predefined guest/host ratios up to 24. The large NMR spectroscopic shifts of resonances correlated with the groupings located in the core of the dendrimers, together with the relaxation time data indicate that the anionic guests are associated with the cationic core of these dendrimers. The X-ray molecular structure of the octacationic, tetra-arylsilane model derivative [Si(C6H3{CH2NMe3}(2)-3,5)(4)](8+) 81- shows that the iodide counterions are primarily located near the polycationic sphere. The new polycationic dendrimers have been investigated for their catalytic phase-transfer behavior and substrate delivery over a nanofiltration membrane.
An active substance having pesticide properties is linked to the surface of phosphorus-containing dendrimers through a linker. Depending on the chemical stability of the linker towards hydrolysis, the release of the active substance can be controlled. (C) 2001 Published by Elsevier Science Ltd.
In most cases, the water solubility of phosphorus-containing dendrimers is mainly due to the presence of hydrophilic end groups, which bear either positive or negative charges. In the first part of this paper, several methods of synthesis and functionalization of phosphorus dendrimers are described leading to the grafting either of ammonium groups or carboxylate groups, which ensure the water-solubility. The structural conflict between the hydrophobic interior and the hydrophilic exterior of these dendrimers leads to special properties, which are emphasized in a second part. For instance, some of them behave like nanometric sponges toward lipophilic substances; whereas, others form supramolecular arrangements leading to vesicles or hydrogels. Some of these dendrimers also possess interesting biological properties and can be used as in vitro DNA transfecting agents or in vivo anti-prion agents. © 2005 Elsevier Ltd. All rights reserved.
Dendrimers are highly branched macromolecules of low polydispersity that provide many exciting opportunities for design of novel drug-carriers, gene delivery systems and imaging agents. They hold promise in tissue targeting applications, controlled drug release and moreover, their interesting nanoscopic architecture might allow easier passage across biological barriers by transcytosis. However, from the vast array of structures currently emerging from synthetic chemistry it is essential to design molecules that have real potential for in vivo biological use. Here, polyamidoamine (PAMAM, Starburst™), poly(propyleneimine) with either diaminobutane or diaminoethane as core, and poly(ethylene oxide) (PEO) grafted carbosilane (CSi–PEO) dendrimers were used to study systematically the effect of dendrimer generation and surface functionality on biological properties in vitro. Generally, dendrimers bearing -NH2 termini displayed concentration- and in the case of PAMAM dendrimers generation-dependent haemolysis, and changes in red cell morphology were observed after 1 h even at low concentrations (10 μg/ml). At concentrations below 1 mg/ml CSi–PEO dendrimers and those dendrimers with carboxylate (COONa) terminal groups were neither haemolytic nor cytotoxic towards a panel of cell lines in vitro. In general, cationic dendrimers were cytotoxic (72 h incubation), displaying IC50 values=50–300 μg/ml dependent on dendrimer-type, cell-type and generation. Preliminary studies with polyether dendrimers prepared by the convergent route showed that dendrimers with carboxylate and malonate surfaces were not haemolytic at 1 h, but after 24 h, unlike anionic PAMAM dendrimers they were lytic. Cationic 125I-labelled PAMAM dendrimers (gen 3 and 4) administered intravenously (i.v.) to Wistar rats (∼10 μg/ml) were cleared rapidly from the circulation (<2% recovered dose in blood at 1 h). Anionic PAMAM dendrimers (gen 2.5, 3.5 and 5.5) showed longer circulation times (∼20–40% recovered dose in blood at 1 h) with generation-dependent clearance rates; lower generations circulated longer. For both anionic and cationic species blood levels at 1 h correlated with the extent of liver capture observed (30–90% recovered dose at 1 h). 125I-Labelled PAMAM dendrimers injected intraperitoneally were transferred to the bloodstream within an hour and their subsequent biodistribution mirrored that seen following i.v. injection. Inherent toxicity would suggest it unlikely that higher generation cationic dendrimers will be suitable for parenteral administration, especially if they are to be used at a high dose. In addition it is clear that dendrimer structure must also be carefully tailored to avoid rapid hepatic uptake if targeting elsewhere (e.g. tumour targeting) is a primary objective.
Dendrimers and hyperbranched polymers are a relatively new class of materials with unique molecular architectures and dimensions in comparison to traditional linear polymers. This review details recent notable advances in the application of these new polymers in terms of the development of new polymeric delivery systems. Although comparatively young, the developing field of hyperbranched drug delivery devices is a rapidly maturing area and the key discoveries in drug-conjugate systems amongst others are highlighted. As a consequence of their ideal hyperbranched architectures, the utilisation of host–guest chemistries in dendrimers has been included within the scope of this review.
Gene transfer into eukaryotic cells plays an important role in cell biology. Over the last 30 years a number of transfection methods have been developed to mediate gene transfer into eukaryotic cells. Classical methods include co-precipitation of DNA with calcium phosphate, charge-dependent precipitation of DNA with DEAE-dextran, electroporation of nucleic acids, and formation of transfection complexes between DNA and cationic liposomes. Gene transfer technologies based on activated PAMAM-dendrimers provide another class of transfection reagents. PAMAM-dendrimers are highly branched, spherical molecules. Activation of newly synthesized dendrimers involves hydrolytic removal of some of the branches, and results in a molecule with a higher degree of flexibility. Activated dendrimers assemble DNA into compact structures via charge interactions. Activated dendrimer-DNA complexes bind to the cell membrane of eukaryotic cells, and are transported into the cell by non-specific endocytosis. A structural model of the activated dendrimer-DNA complex and a potential mechanism for its uptake into cells will be discussed.
Phospholipids are the major components of most liposomes. Extensive testing of these naturally occurring compounds has revealed them to be remarkably safe for pharmaceutical use. Addition of other constituents to liposomes in order to alter stability or kinetics can result in an increase in toxic potential, particularly on parenteral administration of liposomes. This paper describes some simple in vitro cellular tests for direct toxicity of liposomes, particularly following intravenous (i.v.) or topical administration, including tests for haemolysis, thrombosis and cytotoxicity. In addition, an in vivo test for the effects on phagocytosis and for pyrogenicity are described, together with a brief outline of the requirements for the further toxicity testing of liposomal drugs at a later stage of development.
Cascade polymers also known as Starburst dendrimers are spheroidal polycations that can be synthesized with a well-defined diameter and a precise number of terminal amines per dendrimer. We show, using luciferase and beta-galactosidase containing plasmids, that dendrimers mediate high efficiency transfection of a variety of suspension and adherent cultured mammalian cells. Dendrimer-mediated transfection is a function both of the dendrimer/DNA ratio and the diameter of the dendrimer. Maximal transfection of luciferase are obtained using a diameter of 68 A and a dendrimer to DNA charge ratio of 6/1 (terminal amine to phosphate). Expression is unaffected by lysomotrophic agents such as chloroquine and only modestly affected (2-fold decrease) by the presence of 10% serum in the medium. Cell viability, as assessed by dye reduction assays, decreases by only 30% at 150 micrograms dendrimer/mL in the absence of DNA and about 75% in the presence of DNA. Under similar conditions polylysine causes a complete loss of viability. Gene expression decreased by 3 orders of magnitude when the charge ratio is reduced to 1:1. When GALA, a water soluble, membrane-destabilizing peptide, is covalently attached to the dendrimer via a disulfide linkage, transfection efficiency of the 1:1 complex is increased by 2-3 orders of magnitude. The high transfection efficiency of the dendrimers may not only be due to their diameter and shape but may also be caused by the pKa's (3.9 and 6.9) of the amines in the polymer. The low pKa's permit the dendrimer to buffer the pH change in the endosomal compartment. The characteristics of precise control of structure, favorable pKa's, and low toxicity make the dendrimers suitable for gene-transfer vehicles.
Transfection of cultured cells has been reported using complexes between DNA and spherical cationic polyamidoamine polymers (Starburst dendrimers) that consist of primary amines on the surface and tertiary amines in the interior. The transfection activity of the dendrimers is dramatically enhanced (> 50-fold) by heat treatment in a variety of solvolytic solvents, e.g., water or butanol. Such treatment induces significant degradation of the dendrimer at the amide linkage, resulting in a heterodisperse population of compounds with molecular weights ranging from the very low (< 1500 Da) to several tens of kilodaltons. The compound facilitating transfection is the high molecular weight component of the degraded product and is denoted as a "fractured" dendrimer. Transfection activity is related both to the initial size of the dendrimer and its degree of degradation. Fractured dendrimers exhibit an increased apparent volume change as measured by an increase in the reduced viscosity upon protonation of the terminal amines as pH is reduced from 10.5 to 7.2 whereas intact dendrimers do not. Dendrimers with defective branching have been synthesized and also have improved transfection activity compared to that of the intact dendrimers. For a series of heat-treated dendrimers we observe a correlation between transfection activity and the degree of flexibility, computed with a random cleavage simulation of the degradation process. We suggest that the increased transfection after the heating process is principally due to the increase in flexibility that enables the fractured dendrimer to be compact when complexed with DNA and swell when released from DNA.
DNA and polyamidamine (PAMAM) dendrimers form complexes on the basis of the electrostatic interactions between negatively charged phosphate groups of the nucleic acid and protonated (positively charged) amino groups of the polymers. Charge neutralization of both components and subsequent increases of the net positive charge of the complex result in changes in the physicochemistry and biological properties of the complexes. The formation of soluble, low-density and insoluble, high-density complexes was analyzed using UV light absorption and measurements of radioactive labeled DNA. Formation of high molecular weight and high-density complexes depended mainly on the DNA concentration and was enhanced by increasing the dendrimer-DNA charge ratio. Electrostatic charge related effects (attraction or repulsion of charged particles) appeared to be modulated by the generation of dendrimer (size of the polymer). With the progressive increases in the dendrimer-DNA charge ratio (above 20), an increase in the amount of low-density, soluble complexes was observed. Functional analysis revealed that the great majority (>90%) of transfection is carried by low-density, soluble, complexes which only represent approximately 10-20% of total complexed DNA. The ability of the dendrimer to complex and form aggregates with DNA is crucial for efficient transfection and the function of the complexed DNA.
Improvement of the methods for oligonucleotide delivery into cells is necessary for the development of antisense therapy. In the present work, a new strategy for oligonucleotide delivery into cells was tested using cationic peptides as a vector. At first, to understand what structure of the peptide is required for binding with an oligonucleotide, several kinds of alpha-helical and non-alpha-helical peptides containing cationic amino acids were employed. As a result, the amphiphilic alpha-helix peptides were best for binding with the oligonucleotide, and the long chain length and large hydrophobic region in the amphiphilic structure of the peptide were necessary for the binding and forming of aggregates with the oligonucleotide. In the case of non-alpha-helical peptides, no significant binding ability was observed even if their chain lengths and number of cationic amino acid residues were equal to those of the alpha-helical peptides. The remarkable ability of oligonucleotide delivery into COS-7 cells was observed in the alpha-helical peptides with a long chain length and large hydrophobic region in the amphiphilic structure, but was not observed in the non-alpha-helical peptides. It is considered that such alpha-helical peptides could form optimum aggregates with the ODN for uptake into cells. Based on these results, the alpha-helical peptide with a long chain length and large hydrophobic region is applicable as a vector for the delivery of oligonucleotides into cells.
PAMAM dendrimers are cationic polymers that have been used for the delivery of genes and oligonucleotides to cells. However, little is known about the behavior of dendrimer-nucleic acid complexes once they reach the cell interior. To pursue this issue, we prepared dendrimers conjugated with the fluorescent dye Oregon green 488. These were used in conjunction with oligonucleotides labeled with a red (TAMRA) fluorophore in order to visualize the sub-cellular distribution of the dendrimer-oligonucleotide complex and of its components by two-color digital fluorescence microscopy. The 2'-O:-methyl antisense oligonucleotide sequence used in these studies was designed to correct splicing at an aberrant intron inserted into a luciferase reporter gene; thus effective delivery of the antisense agent results in the expression of the reporter gene product. The dendrimer-oligonucleotide complex remained associated during the process of uptake into vesicular compartments and eventual entry into the nucleus. Since the pharmacological activity of the antisense compound was manifest under these conditions, it suggests that the dendrimer-oligonucleotide complex is functionally active. A surprising result of these studies was that the Oregon green 488-conjugated dendrimer was a much better delivery agent for antisense compounds than unmodified dendrimer. This suggests that coupling of relatively hydrophobic small molecules to PAMAM dendrimers may provide a useful means of enhancing their capabilities as delivery agents for nucleic acids.
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Dendritic catalysts and dendrimers in catalysis were discussed. Dendrimers can combine the advantages of homogeneous and heterogeneous catalysis. Results showed that it is possible to remove the catalyst from the reaction medium after a reaction carried out in the presence of a metallodendritic catalyst.
Developed over the past two decades, the antisense strategy has become a technology of recognised therapeutic potential, and many of the problems raised earlier in its application have been solved to varying extents. However, the adequate delivery of antisense oligodeoxynucleotides to individual cells remains an important and inordinately difficult challenge. Synthetic polymers appeared on this scene in the middle 1980s, and there is a surprisingly large variety used or proposed so far as agents for delivery of oligodeoxynucleotides. After discussing the principles of antisense strategy, certain aspects of the ingestion of macromolecules by cells, and the present situation of delivery procedures, this article analyses in detail the attempts to use synthetic polymers as carrier matrices and or cell membrane permeabilisation agents for delivery of antisense oligodeoxynucleotides. Structural aspects of various polymers, as well as the results, promises and limitations of their use are critically evaluated.
Monodispersed dendritic poly(L-lysine)s (DPKs) of several generations were synthesized, and their characteristics as a gene transfection reagent were then investigated. The agarose gel shift and ethidium bromide titration assay proved that the DPKs of the third generation and higher could form a complex with a plasmid DNA, and the degree of compaction of the DNA was increased by the increasing number of the generation. The DPKs of the fifth and sixth generation, which have 64 and 128 amine groups on the surface of the molecule, respectively, showed efficient gene transfection ability into several cultivated cell lines without significant cytotoxity. In addition, the transfection efficiency of the DPK of the sixth generation was not seriously reduced even if serum was added at 50% of the final concentration into the transfection medium. Because we can strictly synthesize various DPK derivatives, which have several types of branch units, terminal cationic groups, and so on, they are expected to be a good object of study regarding the basic information on the detailed mechanism of gene transfection into cells. We also expect to be able to easily construct DPK-based functional gene carriers, e.g., DPKs modified by ligands such as a sugar chain, which can enable advanced gene delivery in vivo.
The development of efficient methods to transfer genes into eukaryotic cells is important for molecular biotechnology. A number of different technologies to mediate gene transfer have been developed over the last 35 years, but most have drawbacks such as cytotoxicity, low efficiency and/or restricted applicability. Activated polyamidoamine (PAMAM)-dendrimers provide a new technology for gene transfer that offers significant advantages over classical methods. Reagents based on this technology provide high gene transfer efficiencies, minimal cytotoxicity, and can be used with a broad range of cell types. This technology could also be useful for in vivo gene transfer in gene therapy applications.
A comparative in vitro cytotoxicity study with different water-soluble, cationic macromolecules which have been described as gene delivery systems was performed. Cytotoxicity in L929 mouse fibroblasts was monitored using the MTT assay and the release of the cytosolic enzyme lactate dehydrogenase (LDH). Microscopic observations were carried out as indicators for cell viability. Furthermore, hemolysis of erythrocytes was quantified spectrophotometrically. To determine the nature of cell death induced by the polycations, the nuclear morphology after DAPI staining and the inhibition of the toxic effects by the caspase inhibitor zVAD.fmk were investigated. All assays yielded comparable results and allowed the following ranking of the polymers with regard to cytotoxicity: Poly(ethylenimine)=poly(L-lysine)>poly(diallyl-dimethyl-ammonium chloride)>diethylaminoethyl-dextran>poly(vinyl pyridinium bromide)>Starburst dendrimer>cationized albumin>native albumin. The magnitude of the cytotoxic effects of all polymers were found to be time- and concentration dependent. The molecular weight as well as the cationic charge density of the polycations were confirmed as key parameters for the interaction with the cell membranes and consequently, the cell damage. Evaluating the nature of cell death induced by poly(ethylenimine), we did not detect any indication for apoptosis suggesting that the polymer induced a necrotic cell reaction. Cell nuclei retained their size, chromatin was homogenously distributed and cell membranes lost their integrity very rapidly at an early stage. Furthermore, the broad spectrum caspase inhibitor zVAD.fmk did not inhibit poly(ethylenimine)-induced cell damage. Insights into the structure-toxicity relationship are necessary to optimize the cytotoxicity and biocompatibility of non-viral gene delivery systems.
Annette Deichmann, Martijn H Brugman, Cynthia C Bartholomae, Kerstin Schwarzwaelder, Monique MA Verstegen, Steven J Howe, Anne Arens, Marion G Ott, Dieter Hoelzer, Reinhard Seger, Manuel Grez, Salima Hacein-Bey-Abina, Marina Cavazzana-Calvo, Alain Fischer, Anna Paruzynski, Richard Gabriel, Hanno Glimm, Ulrich Abel, Claudia Cattoglio, Fulvio Mavilio, Barbara Cassani, Alessandro Aiuti, Cynthia E Dunbar, Christopher Baum, H Bobby Gaspar, Adrian J Thrasher, Christof von Kalle, Manfred Schmidt, Gerard Wagemaker. (2011) Insertion Sites in Engrafted Cells Cluster Within a Limited Repertoire of Genomic Areas After Gammaretroviral Vector Gene Therapy. Molecular Therapy 19, 2031-2039
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Stefan Stein, Marion G Ott, Stephan Schultze-Strasser, Anna Jauch, Barbara Burwinkel, Andrea Kinner, Manfred Schmidt, Alwin Krämer, Joachim Schwäble, Hanno Glimm, Ulrike Koehl, Carolin Preiss, Claudia Ball, Hans Martin, Gudrun Göhring, Kerstin Schwarzwaelder, Wolf-Karsten Hofmann, Kadin Karakaya, Sandrine Tchatchou, Rongxi Yang, Petra Reinecke, Klaus Kühlcke, Brigitte Schlegelberger, Adrian J Thrasher, Dieter Hoelzer, Reinhard Seger, Christof von Kalle, Manuel Grez. (2010) Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nature Medicine 16, 198-204
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Steven J. Howe, Marc R. Mansour, Kerstin Schwarzwaelder, Cynthia Bartholomae, Michael Hubank, Helena Kempski, Martijn H. Brugman, Karin Pike-Overzet, Stephen J. Chatters, Dick de Ridder, Kimberly C. Gilmour, Stuart Adams, Susannah I. Thornhill, Kathryn L. Parsley, Frank J.T. Staal, Rosemary E. Gale, David C. Linch, Jinhua Bayford, Lucie Brown, Michelle Quaye, Christine Kinnon, Philip Ancliff, David K. Webb, Manfred Schmidt, Christof von Kalle, H. Bobby Gaspar, Adrian J. Thrasher. (2008) Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. Journal of Clinical Investigation 118, 3143-3150
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The influence of surface modification on the cytotoxicity of PAMAM dendrimers was examined using Caco-2 cells. Dendrimers were modified by conjugating either lauroyl chains or polyethylene glycol (PEG) 2000 onto the surface of cationic PAMAM dendrimers (G2, G3, G4). The cytotoxicity of unmodified dendrimers towards Caco-2 cells was appreciably higher for cationic (whole generation) compared with anionic (half generation) dendrimers and for both types increased with increasing size (generation) and concentration. A marked decrease in the cytotoxicity of cationic PAMAM dendrimers was noted when the surface was modified, with the addition of six lauroyl or four PEG chains being particularly effective in decreasing cytotoxicity. This decrease in cytotoxicity is thought to be due to a reduction/shielding of the positive charge on the dendrimer surface by the attached chains. The cytotoxicity of dendrimer-based delivery systems is likely to be very different from the parent dendrimer.
Dendrimers are versatile, derivatisable, well-defined, compartmentalised chemical polymers with sizes and physicochemical properties resembling those of biomolecules e.g. proteins. The present critical review (citing 158 references) briefly describes dendrimer design, nomenclature and divergent/convergent dendrimer synthesis. The characteristic physicochemical features of dendrimers are highlighted, showing the effect of solvent pH and polarity on their spatial structure. The use of dendrimers in biological systems are reviewed, with emphasis on the biocompatibility of dendrimers, such as in vitro and in vivo cytotoxicity, as well as biopermeability, biostability and immunogenicity. The review deals with numerous applications of dendrimers as tools for efficient multivalent presentation of biological ligands in biospecific recognition, inhibition and targeting. Dendrimers may be used as drugs for antibacterial and antiviral treatment and have found use as antitumor agents. The review highlights the use of dendrimers as drug or gene delivery devices in e.g. anticancer therapy, and the design of different host-guest binding motifs directed towards medical applications is described. Other specific examples are the use of dendrimers as 'glycocarriers' for the controlled multimeric presentation of biologically relevant carbohydrate moieties which are useful for targeting modified tissue in malignant diseases for diagnostic and therapeutic purposes. Finally, the use of specific types of dendrimers as scaffolds for presenting vaccine antigens, especially peptides, for use in vaccines is presented.
A series of water-soluble polycationic dendrimers with a phosphoramidothioate backbone (P-dendrimers) was studied in human cell culture. Preliminary studies have shown that P-dendrimers of series 1 and 2, possessing N,N-diethyl-ethylenediamine hydrochloride functions at the surface, show rather moderate cytotoxicity toward HeLa, HEK 293, and HUVEC cells in a standard MTT assay in serum-containing medium, generally lower than lipofectin. The experiments of cellular uptake have shown the necessity for the presence of serum for transfection with P-dendrimers of series 1 and 2. These compounds efficiently delivered fluorescein-labeled oligodeoxyribonucleotide into HeLa cells in serum-containing medium, but they failed to do so in HUVEC cell culture. The dendrimers were found to be successful mediators of transfection of the HeLa cells with a DNA plasmid containing the functional gene of enhanced green fluorescent protein (EGFP).
Nine spermines are better than one: Compound G2 exhibits high-affinity, salt-independent DNA binding as a consequence of the spermine array on its surface. Comparison with smaller dendrons and model compounds indicates a clear multivalency effect on binding.
and references therein. b) Dendrimers and other Dendritic Polymers
- Chem
- Int
Chem. Int. Ed. 1999, 38, 884 – 905, and references therein. b) Dendrimers and other Dendritic Polymers (Eds.: J. M. FrØchet, D. A.
1.59, (s, 2 H; NH 2 ), 1.35 (m, 2 H
- H Nmr
H NMR (CDCl 3 ): d = 2.62 (t, 2 H; CH 2 N), 1.59, (s, 2 H;
NH 2 ), 1.35 (m, 2 H; SiCH 2 CH 2 CH 2 N), 0.87 (t, 9 H; CH 2 CH 3 ),
0.46 ppm (m, 8 H; CH 2 Si and CH 2 CH 3 );
13 C NMR (CDCl 3 ): d = 45.6
CH 2 ) 3 NH 2 : Et 3 SiH was added to neat allylamine in the presence of Speier catalyst
- C H T U N G T R E N N U N G 3 Si-A C H T U N G T R E N N U N G Synthesis Of Et 3 Sia
Synthesis of Et 3 SiA C H T U N G T R E N N U N G (CH 2 ) 3 NH 2 : Et 3 SiH was added to neat allylamine
in the presence of Speier catalyst. Selected data for Et 3 Si-
A C H T U N G T R E N N U N G (CH 2 ) 3 NH 2 :
1
58 ppm (G 2 -Si); elemental analysis calcd (%) for C 112 H 226 N 16 O 8 Si 13 : C 57
- Si
Si), 0.93 (G 1 -Si), 17.58 ppm (G 2 -Si); elemental analysis calcd (%) for
C 112 H 226 N 16 O 8 Si 13 : C 57.67, H 11.58, N 9.61; found: C 57.20, H 11.40, N
9.52; MALDI-TOF-MS: m/z 2332.8 [M+H] + (calcd 2332.8).