No description available.

No description available.

No description available.

No description available.

<p>Collagen crosslinking with a polypropyleneimine octaamine dendrimers, via carbodiimide chemistry, was further exploited to demonstrate the ability of this technology for various tissue engineering strategies, including tissue engineered corneal equivalents (TECE) and blood-contacting biomaterials. In addition, modification with extracellular matrix components and other biomimetic molecules may enhance tissue-host interactions for greater <em>in vivo </em>compatibility.</p> <p>First, the efficacy of the dendrimer crosslinking technology was further validated with commercially available collagen-based materials, from bovine or human sources (Chapter 4: Paper 1), as determined via transmittance, water uptake, differential scanning calorimetry, collagenase stability and <em>in vitro </em>cell compatibility. Despite gel formation, the matrix integrity was compromised with collagen-based materials manufactured under acidic conditions and purified via freeze-drying.</p> <p>To continue the theme of dendrimer crosslinked collagen gels as TECE materials, growth factor incorporation was investigated with epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), as a method for improving device epithelialization and subsequent host integration. However, given the short half lives of these growth factors, an effective growth factor delivery system is necessary to protect growth factor bioactivity. As heparan sulphate proteoglycans sequester and release heparin-binding growth factors <em>in vivo</em>, the use of heparinized dendrimer crosslinked collagen (CHG) gels for HB-EGF delivery would provide prolonged, controlled delivery, while maintaining growth factor effectiveness (Chapter 5: Paper 2). HB-EGF release was prolonged and capable of inducing human cornea epithelial cell (HCEC) proliferation. Thus, HB-EGF delivery from CHG gels could aid in TECE device retention through enhanced device-host integration via epithelialization.</p> <p>Alternatively, tethering EGF or HB-EGF to dendrimer crosslinked collagen (CG) gels could also supply growth factor stimulation in a manner that maintains bioactivity, while stimulating growth factor receptors continually with minute concentrations (Chapter 6: Paper 3). Growth factor uptake and bioactivity was assessed with radiolabeled growth factor and through <em>in vitro </em>epithelial cell culture, respectively. Surface-modification of CG gels with growth factors demonstrated greater bioactivity, compared to growth factor bulk-modification of CG gels.</p> <p>Finally, dendrimer crosslinked collagen gels, with pre-activated heparin (PH gels) were investigated as a tissue engineered blood-contacting biomaterial (Chapter 7: Paper 4), as we hypothesized that biomaterial induced coagulation is not only influenced by an anticoagulant surface, but also by the underlying material and that improved blood-biomaterial interactions may be achieved by utilizing a natural polymer that emulates biomimetic properties. Pre-activation of heparin was utilized to increase heparin gel content, while antithrombotic properties were evaluated via antithrombin and fibrinogen adsorption and plasma recalcification times. PH gels had increased heparinization, but extensive crosslinking compromised antithrombin-heparin interactions, compared to CHG gels. CHG gels demonstrated improved antithrombotic properties and further evaluation of these gels for blood-contacting applications is warranted.</p> / Doctor of Philosophy (PhD)

<p>The synthesis of new macromolecular diagnostic imaging agents has been a growing field in polymeric chemistry research. Dendrimers provide a viable scaffold for such applications due to their unique, defined macromolecular architecture. The precise structural control afforded via the step-wise synthesis of dendrimers yields exceptional and precise macromolecules that can be functionalized to include necessary imaging moieties with the same degree of precision.</p> <p>We have herein contributed to this growing field by attempting the synthesis of a series of PEGylated poly(2,2-bis[hydroxymethyl]propanoic acid) PMPA dendrons using thiol-ene "click" chemistry. The series consisted of three dendritic architectures peripherally functionalized with poly(ethylene glycol) (PEG) chains of varying length (n= 3, 8, 16), with the goal of determining the effect of PEG chain length on blood circulation times. Synthesis of these conjugates began first with functionalization of the dendron periphery to incorporate alkene functionalities using anhydride-mediated esterification chemistry.</p> <p>The core of the alkene PMPA dendrons was then modified to introduce a metal chelating bis-pyridyl functionality, which has been observed to chelate the radionuclide technetium-99m (^99mTc) with high binding affinity. ^99mTc is the most widely used diagnostic radioisotope in diagnostic medicine due to its ideal isotopic properties, widespread availability, low cost, and its ability to be traced, in real time, <em>in vivo</em> using Single Photon Emission Computed Tomography (SPECT).</p> <p>PEGylation at the periphery was performed by thiol-ene “click” chemistry using thiol-terminated PEG chains. Metallation of the core of each PEGylated dendron was then attempted according to literature procedures for ^99mTc radiolabeling with the bis-pyridyl chelate.</p> / Master of Science (MSc)

(Metallo-)Dendrimers in Catalysis, Nanoparticle Stabilization and Biological Application Technische Universität Chemnitz, Fakultät für Naturwissenschaften Dissertation 2011, 165 Seiten Die vorliegende Dissertationsschrift befasst sich mit der Darstellung, Charakterisierung und Anwendung neuartiger (Metallo-)Dendrimere. Den Schwerpunkt der Arbeit bildet dabei die terminale Funktionalisierung (Poly)amidoamin-basierender Dendrimere kleiner Generationen. Durch Standardpeptid-Knüpfungsreaktionen von 1,1´-(Diphenylphosphino)ferrocen-carbonsäure an dendritische (Poly)amidoamine ist eine Serie entsprechend funktionalisierter Metallodendrimere zugänglich. Die metallorganischen, Dendrimer-immobilisierten Engruppen können durch Zugabe von [Pd(3-C3H5)Cl]2 in heterobimetallische Übergangsmetallkomplexe umgewandelt werden und finden Einsatz als katalytisch aktive Systeme in C,C-Kreuzkupplungsreaktionen nach Heck. Ein weiterer Gegenstand der Arbeit ist die terminale Modifikation von (dendritischen) Ami-nen mit (Sp)-2-(Diphenylphosphino)ferrocen-1-carbonsäure. Nach erfolgter Umsetzung mit [Pd(3-C3H5)Cl]2 werden die erhaltenen planar-chiralen Verbindungen als Katalysatoren in asymmetrischen allylischen Substitutionsreaktionen eingesetzt. Ferner ist die Darstellung (Oligo)ethylenglykolether-terminierter (Poly)amidoamin-Dendrimere beschrieben. Diese werden als Stabilisatoren zur in-situ Generierung von Gold- sowie Magnetit-Nanopartikeln eingesetzt. Der Einfluss der dendritischen Template auf die Kolloidgrößen und Morphologien sowie die Eigenschaften der gebildeten Hybridmaterialien werden aufgezeigt. Darüber hinaus befasst sich die Arbeit mit der Verwendung biokompatibler (Oligo)ethylenglykolether-Dendrimere als Wirkstoffträger für Zytostatika bei der Krebsthera-pie. Die im Rahmen von in vitro Untersuchungen erhaltenen Ergebnisse werden präsentiert.

Elastic properties of carbon nanotubes (CNT), boron nitride nanotubes (BNNT), double stranded DNA (dsDNA), paranemic-juxtapose crossover (PX-JX) DNA and dendrimer bound DNA are discussed in this thesis. Structural phase transitions of nucleic acids induced by external force, carbon nanotubes and graphene substrate are also studied extensively. Electrostatic interactions have a strong effect on the elastic properties of BNNTs due to large partial atomic charges on boron and nitrogen atoms. We have computed Young’s modulus (Y ) and shear modulus (G) of BNNT and CNT as a function of the nanotube radius and partial atomic charges on boron and nitrogen atoms using molecular mechanics calculation. Our calculation shows that Young’s modulus of BNNTs increases with increase in magnitude of the partial atomic charges on B and N atoms and can be larger than the Young’s modulus of CNTs of same radius. Shear modulus, on the other hand depends weakly on the magnitude of partial atomic charges and is always less than the shear modulus of the CNT. The values obtained for Young’s modulus and shear modulus are in excellent agreement with the available experimental results. We also study the elasticity of dsDNA using equilibrium fluctuation methods as well as nonequilibrium stretching simulations. The results obtained from both methods quantitatively agree with each other. The end-to-end length distribution P(ρ) and angle distribution P(θ) of the dsDNA has a Gaussian form which gives stretch modulus (γ1) to be 708 pN and persistence length (Lp) to be 42 nm, respectively. When dsDNA is stretched along its helix axis, it undergoes a large conformational change and elongates about 1.7 times its initial contour length at a critical force. Applying a force perpendicular to the DNA helix axis, dsDNA gets unzipped and separated into two single-stranded DNA (ssDNA). DNA unzipping is a fundamental process in DNA replication. As the force at one end of the DNA is increased the DNA starts melting above a critical force depending on the pulling direction. The critical force fm , at which dsDNA melts completely decreases as the temperature of the system is increased. The melting force in the case of unzipping is smaller compared to the melting force when the dsDNA is pulled along the helical axis. In the case of melting through unzipping, the double-strand separation has jumps which correspond to the different energy minima arising due to sequence of different base-pairs. Similar force-extension curve has also been observed when crossover DNA molecules are stretched along the helix axis. In the presence of mono-valent Na+ counterions, we find that the stretch modulus (γ1 ) of the paranemic crossover (PX) and its topoisomer juxtapose (JX) DNA structure is significantly higher (30 %) compared to normal B-DNA of the same sequence and length. When the DNA motif is surrounded by a solvent of divalent Mg2+ counterions, we find an enhanced rigidity compared to in Na+ environment due to the electrostatic screening effects arising from the divalent nature of Mg2+ counterions. This is the first direct determination of the mechanical strength of these crossover motifs which can be useful for the design of suitable DNA motifs for DNA based nanostructures and nanomechanical devices with improved structural rigidity. Negatively charged DNA can be compacted by positively charged dendrimer and the degree of compaction is a delicate balance between the strength of the electrostatic interaction and the elasticity of DNA. When the dsDNA is compacted by dendrimer, the stretch modulus, γ1 and persistence length, Lp decreases dramatically due to backbone charge neutralization of dsDNA by dendrimer. We also study the effect of CNT and graphene substrate on the elastic as well as adsorption properties of small interfering RNA (siRNA) and dsDNA. Our results show that siRNA strongly binds to CNT and graphene surface via unzipping its base-pairs and the propensity of unzipping increases with the increase in the diameter of the CNTs and is maximum on graphene. The unzipping and subsequent wrapping events are initiated and driven by van der Waals interactions between the aromatic rings of siRNA nucleobases and the CNT/graphene surface. However, dsDNA of the same sequence undergoes much less unzipping and wrapping on the CNT/graphene due to smaller interaction energy of thymidine of dsDNA with the CNT/graphene compared to that of uridine of siRNA. Unzipping probability distributions fitted to single exponential function give unzipping time (τ) of the order of few nanoseconds which decrease exponentially with temperature. From the temperature variation of unzipping time we estimate the free energy barrier to unzipping. We have also investigated the binding of siRNA to CNT by translocating siRNA inside CNT and find that siRNA spontaneously translocates inside CNT of various diameters and chiralities. Free en- ergy profiles show that siRNA gains free energy while translocating inside CNT and the barrier for siRNA exit from CNT ranges from 40 to 110 kcal/mol depending on CNT chirality and salt concentration. The translocation time τ decreases with the increase of CNT diameter having a critical diameter of 24 A for the translocation. After the optimal binding of siRNA to CNT/graphene, the complex is very stable which can serve as siRNA delivery agent for biomedical applications. Since siRNA has to undergo unwinding process in the presence of RNA-induced silencing complex, our proposed delivery mechanism by single wall CNT possesses potential advantages in achieving RNA interference (RNAi).

In the frame of this thesis different calix[4]resorcin- and calix[4]pyrogallolarene derivatives were used as platform for the synthesis of novel star polymers and dendritic structures. The objectives of this work can be portrayed under the following points: First: Synthesis and modification of calix[4]resorcin- and calix[4]pyrogallolarenes with a varying number and varying type of functional sites and their precise characterization by modern NMR techniques and single crystal X-ray diffraction. Second: Synthesis of well-defined star polymers and dendrimers with different number of arms and accordingly dendrons, based on calix[4]resorcin- and calix[4]pyrogallolarenes, via convenient polymerization and generation growth reactions and analysis of the obtained products by different methods (MALDI-TOF-MS, SEC-RI and SEC-MALLS, NMR).

Cationic polymers have shown potential as gene delivery vectors due to their ability to condense DNA and protect it from cellular and restriction nucleases. Dendrimers are hyperbranched macromolecules with precisely defined molecular weights and highly symmetric branches stemming from a central core. The nanosize, tunable surface chemistries and ease of surface functionalization has made dendrimers an attractive alternative to conventional linear polymers for DNA delivery applications. The commercially available, cationic dendrimer poly(amidoamine) or PAMAM is the most widely studied dendrimer for use as a gene delivery vector. The aim of this dissertation is to provide an increased understanding of the packaging and forces within PAMAM–DNA complexes. In Chapter 4, we will discuss the effect of molecular chain architecture on DNA-DNA intermolecular forces by examining DNA condensed by low generation (G0 & G1) PAMAM and comparing them to comparably charged linear arginine peptides. Using osmotic stress coupled with X-ray scattering, we are able to determine the structure and forces within dendrimer-DNA complexes, or dendriplexes. We show that PAMAM–DNA assemblies display significantly different physical behavior than linear cation–DNA assemblies. In Chapter 5, we examine the role of pH on condensation in these same low generation PAMAM-DNA complexes. PAMAM dendrimers have both terminal primary amines and internal tertiary amines with different pKas of approximately 9 and 6, respectively. We show changes in the pH at condensation greatly influence the resulting packaging as well as the resulting phase behavior for PAMAM dendriplexes. In Chapter 6, we examine the packaging of DNA by G4 PAMAM as a function of the percent zwitterionic modification. Many cationic polymers, including PAMAM, have shown high transfection efficiency in cell culture and potential for in vitro and in vivo applications, but its development is hindered by cytotoxicity in many cell lines and tissues. We hypothesize that zwitterionic PAMAM (zPAMAM) represent a new means to tune polymer-DNA interactions through PAMAM surface charge potentially enhancing intracellular unpackaging while reducing cellular toxicity. These zPAMAM complexes are currently under investigation for their potential as safer and more efficient materials for DNA delivery.