Aptamer-targeted hyperbranched polymers: Towards greater specificity for tumours in vivo

Hyperbranched polymers conjugated to a peptide-aptamer were prepared using a combination of RAFT polymerisation and click chemistry for targeting tumour cells in vivo. The polymers showed enhanced cell-uptake in vitro (compared to unconjugated polymer)while excellent specificity for solid tumours was observed in vivo using a mouse model of melanoma.

Site-Specific Functionalization of Hyperbranched Polymers Using ``Click'' Chemistry

Different strategies for functionalization of the core region and periphery of core-shell type hyperbranched polymers (HBP) using the ``click'' reaction have been explored. For achieving periphera functionalization, an AB(2) + A-R-1 + A-R-2 type copolymerization approach was used, where A-R-1 is heptaethylene glycol monomethyl ether (HPEG-M) and A-R-2 is tetraethylene glycol monopropargyl ether (TEG-P). A very small mole fraction of the propargyl containing monomer, TEG-P, was used to ensure that the water-solubility of the hyperbranched polymer is minimally affected. Similarly, to incorporate propargyl groups in the core region, a new propargyl group bearing B-2-typ monomer was designed and utilized in an AB(2) + A(2) + B-2 + A-R-1 type copolymerization, such that the total mole fraction of B-2 + A(2) is small and their mole-ratio is 1: 1. Further, using a combination of both the above approaches, namely AB(2) + A(2) + B-2 + A-R-1 + A-R-2, hyperbranched structures that incorporate propargyl groups both at theperiphery and within the core were synthesized. Since the AB(2) monomer carries a hexamethylene spacer (C-6) and the periphery is PEGylated all the derivatized polymers form core-shell type structures in aqueous solutions. Attempts were made to ascertain and probe the location of the propargyl groups in these HBP's, by ``clicking'' azidomethylpyrene, onto them. However, the fluorescence spectra of aqueous solutions of the pyrene derivatized polymers were unable to discriminate between the various locations, possibly because the relatively hydrophobic pyrene units insert themselves into the core region to minimize exposure to water.

AB2 + A Type Copolymerization Approach for the Preparation of Thermosensitive PEGylated Hyperbranched Polymers

Hyperbranched polyethers having poly(ethylene glycol) (PEG) segments at their molecular periphery were prepared by a simple procedure wherein an AB2 type monomer was melt-polycondensed with an A-type monomer, namely, heptaethylene glycol monomethyl ether. The presence of a large number of PEG units at the termini rendered a lower critical solution temperature (LCST) to these copolymers, above which they precipitated out of an aqueous solution. In an effort to understand the effect of various molecular structural parameters on their LCST, the length of the hydrophobic spacer segment within the hyperbranched core and the extent of PEGylation were varied. Additionally, linear analogues that incorporates pendant PEG segments were also prepared and comparison of their LCST with that of the hyperbranched analogue clearly revealed that hyperbranched topology leads to a substantial increase in the LCST, highlighting the importance of the peripheral placement of the PEG units.

Control of Molecular Weight and Polydispersity of Hyperbranched Polymers Using a Reactive B(3) Core: A Single-Step Route to Orthogonally Functionalizable Hyperbranched Polymers

Molecular weight and polydispersity are two structural features of hyperbranched polymers that are difficult to control because of the statistical nature of the step-growth polycondensation of AB(2) type monomers; the statistical growth also causes the polydispersity index to increase with percent conversion (or molecular weight). We demonstrate that using controlled amounts of a specifically designed B(3) core, containing B-type functionality that are more reactive than those present in the AB(2) monomer, both the molecular weight and the polydispersity can be readily controlled; the PDI was shown to improve with increasing mole-fraction of the B(3) core while the polymer molecular weight showed an expected decrease. Incorporation of a ``clickable'' propargyl group in the B(3) core unit permitted the generation of a core-functionalizable hyperbranched polymer. Importantly, this clickable core, in combination with a recently developed AB(2) monomer, wherein the B-type groups are allyl ethers and A is an hydroxyl group, led to the generation of a hyperbranched polymer carrying orthogonally functionalizable core and peripheral groups, via a single-step melt polycondensation. Selective functionalization of the core and periphery using two different types of chromophores was achieved, and the occurrence of fluorescence resonance energy transfer (FRET) between the donor and acceptor chromophores was demonstrated.

Control of Molecular Weight and Polydispersity of Hyperbranched Polymers Using a Reactive B(3) Core: A Single-Step Route to Orthogonally Functionalizable Hyperbranched Polymers

Molecular weight and polydispersity are two structural features of hyperbranched polymers that are difficult to control because of the statistical nature of the step-growth polycondensation of AB(2) type monomers; the statistical growth also causes the polydispersity index to increase with percent conversion (or molecular weight). We demonstrate that using controlled amounts of a specifically designed B(3) core, containing B-type functionality that are more reactive than those present in the AB(2) monomer, both the molecular weight and the polydispersity can be readily controlled; the PDI was shown to improve with increasing mole-fraction of the B(3) core while the polymer molecular weight showed an expected decrease. Incorporation of a ``clickable'' propargyl group in the B(3) core unit permitted the generation of a core-functionalizable hyperbranched polymer. Importantly, this clickable core, in combination with a recently developed AB(2) monomer, wherein the B-type groups are allyl ethers and A is an hydroxyl group, led to the generation of a hyperbranched polymer carrying orthogonally functionalizable core and peripheral groups, via a single-step melt polycondensation. Selective functionalization of the core and periphery using two different types of chromophores was achieved, and the occurrence of fluorescence resonance energy transfer (FRET) between the donor and acceptor chromophores was demonstrated.

Janus Hybramers: Self-Adapting Amphiphilic Hyperbranched Polymers

Janus structures have attracted a great deal of interest because of their fascinating properties and potential for applications. In this study, we demonstrate that hyperbranched polymers, bearing randomly placed docosyl (C22 alkyl segment) and PEG segments on their periphery, can readily reconfigure so as to segregate the alkyl and PEG segments, thereby generating Janus-type structures that we have termed Janus hybramers. DSC studies clearly reveal an endothermic transition that corresponds to the melting of the docosyl domains, while Langmuir isotherms demonstrate that these polymers form stable monolayers that appear to undergo a slight densification beyond a critical surface pressure; this suggested possible crystallization of the docosyl segments at the air-water interface. AFM studies of the transferred monolayers reveal various interesting aggregate morphologies at different surface pressures suggestive of island formation at the air-water interface; at the same time they also provided an estimate of the monolayer thickness. These Janus HBPs also form vesicles as evident from TEM and AFM studies; the AFM height of the deposited vesicles, as expected, was roughly 4 times that of the monolayer. SAXS studies revealed the formation of lamellar structures; the interlamellar spacing was largest when the relative mole fractions of docosyl and PEG segments were similar, but the spacing decreased when the mole fraction of either of these peripheral segments is substantially smaller; this suggested the possible presence of interdigitation within the domains of the minor component.

Self-Adapting Peripherally Heterofunctionalized Hyperbranched Polymers: Formation of Janus and Tripodal Structures

A peripherally clickable hyperbranched polyester carrying numerous propargyl terminal groups was prepared by a simple melt transesterification polycondensation of a suitably designed AB(2) monomer; this clickable hyperscaffold was then transformed into a variety of different derivatives by using the Cu-catalyzed azide-yne click reaction. Functionalization of the periphery with equimolar quantities of mutually immiscible segments, such as hydrocarbon, fluorocarbon, and PEG, yielded frustrated molecular systems that readapt and form structures wherein the immiscible segments appear to self-segregate to generate either Janus structures (when two immiscible segments are present) or tripodal structures (when three immiscible segments are present). Evidence for such self-segregation was obtained from a variety of studies, such as differential scanning calorimetry, Langmuir isotherms, AFM imaging, and small-angle X-ray scattering measurements. Crystallization of one or more of the peripheral segments reinforced this self-segregation; the weight-fraction-normalized enthalpies of melting associated with the different domains revealed a competition between the segments to optimize their crystalline organization. When one or more of the segments are amorphous, the remaining segments crystallize more effectively and consequently exhibit a higher melting enthalpy. AFM images of monolayers, transferred from the Langmuir trough, revealed that the thickness matches the expected values; furthermore, contact angle measurements clearly demonstrated that the monolayer films are fairly hydrophobic, and in the case of the tripodal hybramers, the presence of domains of hydrocarbon and fluorocarbon appears to impart nanoscale chemical heterogeneity that is reflected in the strong hysteresis in the advancing and receding contact angles.

Synthesis of novel star-like hyperbranched polymers with poly(amido amine) core and poly(L-lysine) shell

Hyperbranched poly(amido amine)s containing vinyl and hydroxyl groups were successfully synthesized via Michael addition polymerization of triacrylamide (TT) and 3-amino-1,2-propanediol (APD) with equal molar ratio in feed. H-1, C-13 and HSQC NMR techniques were used to clarify the structure of hyperbranched polymers and polymerization mechanism.

Synthesis of Hyperbranched Polymers with Pendent Norbornene Functionalities via RAFT Polymerization of a Novel Asymmetrical Divinyl Monomer

Hyperbranched polymers with numerous pendent norbornene functionalities have been synthesized via the radical polymerization of a novel asymmetrical divinyl monomer hearing a higher reactivity methacrylate group and it lower reactivity norbornene group. Mediated by a rapid reversible addition-fragmentation chain transfer (RAFT) equilibrium, the concentration of polymeric chain radicals is decreased, and thus the gelation did not occur until higher monomer conversions (ca. 90%). An increase in reaction temperature call also significantly promote the formation of the hyperbranched structure owing to the decreased stability of the intermediate radicals derived from the norbornene group, which was confirmed by a model copolymerization system of two single vinyl monomers with similar structures to the vinyl groups in the asymmetrical divinyl monomer. Furthermore, Tri-SEC and conventional Sin-SEC as well as H-1 NMR.

Synthesis and applications of hyperbranched polymers

The development of hyperbranched polymers is a rapidly expanding field in the area of macromolecular science. This short review highlights some of the notable examples in the synthesis of hyperbranched polymers and some of the key advances that have been made in the application of these hyperbranched materials in the areas of material property modifications and in high value technologies. (C) 2004 Elsevier Ltd. All rights reserved.

Synthesis of novel hyperbranched polymers featuring oxazoline linear units and their application in fast-drying solvent-borne coating formulations

Novel acid-terminated hyperbranched polymers (HBPs) containing adipic acid and oxazoline monomers derived from oleic and linoleic acid have been synthesized via a bulk polymerization procedure. Branching was achieved as a consequence of an acid-catalyzed opening of the oxazoline ring to produce a trifunctional monomer in situ which delivered branching levels of >45% as determined by 1H and 13C NMR spectroscopy. The HBPs were soluble in common solvents, such as CHCl3, acetone, tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide and were further functionalized by addition of citronellol to afford white-spirit soluble materials that could be used in coating formulations. During end group modification, a reduction in branching levels of the HBPs (down to 12–24%) was observed, predominantly on account of oxazoline ring reformation and trans-esterification processes under the reaction conditions used. In comparison to commercial alkyd resin paint coatings, formulations of the citronellol-functionalized hyperbranched materials blended with a commercial alkyd resin exhibited dramatic decreases of the blend viscosity when the HBP content was increased. The curing characteristics of the HBP/alkyd blend formulations were studied by dynamic mechanical analysis which revealed that the new coatings cured more quickly and produced tougher materials than otherwise identical coatings prepared from only the commercial alkyd resins.

Hyperbranched polymers containing oxazoline monomers andsuccinic anhydride: applications in fast drying, low solvent coating formulations

tMelt-polycondensation of succinic acid anhydride with oxazoline-based diol monomers gave hyper-branched polymers with carboxylicacids terminal groups.1H NMR and quantitative13C NMRspectroscopy coupled with DEPT-13513C NMR experiment showed high degrees of branching (over 60%).Esterification of the acid end groups by addition of citronellol at 160◦C produced novel white spirit solubleresins which were characterized by Fourier transform-infrared (FTIR) spectroscopy, gel permeation chro-matography (GPC), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Blendsof the new hyperbranched materials with commercial alkyd resins resulted in a dramatic, concentrationdependent drop in viscosity. Solvent-borne coatings were formulated containing the hyperbranchedpolymers. Dynamic mechanical analysis studies revealed that the air drying rates of the new coatingsystems were enhanced compared with identical formulations containing only commercial alkyd resins.

Efficiency comparison of hyperbranched polymers as toughening agents for a one-part epoxy resin

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