Cationic Sterically Stabilized Diblock Copolymer Nanoparticles Exhibit Exceptional Tolerance toward Added Salt.

For certain commercial applications such as enhanced oil recovery, sterically stabilized colloidal dispersions that exhibit high tolerance toward added salt are desirable. Herein, we report a series of new cationic diblock copolymer nanoparticles that display excellent colloidal stability in concentrated aqueous salt solutions. More specifically, poly(2-(acryloyloxy)ethyltrimethylammonium chloride) (PATAC) has been chain-extended by reversible addition-fragmentation chain transfer aqueous dispersion polymerization of diacetone acrylamide (DAAM) at 70 °C to produce PATAC100-PDAAMx diblock copolymer spheres at 20% w/w solids via polymerization-induced self-assembly. Transmission electron microscopy and dynamic light scattering (DLS) analysis confirm that the mean sphere diameter can be adjusted by systematic variation of the mean degree of polymerization of the PDAAM block. Remarkably, DLS studies confirm that highly cationic PATAC100-PDAAM1500 spheres retain their colloidal stability in the presence of either 4.0 M KCl or 3.0 M ammonium sulfate for at least 115 days at 20 °C. The mole fraction of PATAC chains within the stabilizer shell was systematically varied by the chain extension of various binary mixtures of non-ionic poly(N,N-dimethylacrylamide) (PDMAC) and cationic PATAC with DAAM to produce ([n] PATAC100 + [1 - n] PDMAC67)-PDAAMz diblock copolymer spheres at 20% w/w. DLS studies confirmed that a relatively high mole fraction of cationic PATAC stabilizer chains (n ≥ 0.75) is required for the dispersions to remain colloidally stable in 4.0 M KCl. Cationic worms and vesicles could also be synthesized using a binary mixture of PATAC and PDMAC precursors, where n = 0.10. However, the vesicles only remained colloidally stable up to 1.0 M KCl, whereas the worms proved to be stable up to 2.0 M KCl. Such block copolymer nanoparticles are expected to be useful model systems for understanding the behavior of aqueous colloidal dispersions in extremely salty media. Finally, zeta potentials determined using electrophoretic light scattering are presented for such nanoparticles dispersed in highly salty media.

Low-Viscosity Route to High-Molecular-Weight Water-Soluble Polymers: Exploiting the Salt Sensitivity of Poly(N-acryloylmorpholine).

We report a new one-pot low-viscosity synthetic route to high molecular weight non-ionic water-soluble polymers based on polymerization-induced self-assembly (PISA). The RAFT aqueous dispersion polymerization of N-acryloylmorpholine (NAM) is conducted at 30 °C using a suitable redox initiator and a poly(2-hydroxyethyl acrylamide) (PHEAC) precursor in the presence of 0.60 M ammonium sulfate. This relatively low level of added electrolyte is sufficient to salt out the PNAM block, while steric stabilization is conferred by the relatively short salt-tolerant PHEAC block. A mean degree of polymerization (DP) of up to 6000 was targeted for the PNAM block, and high NAM conversions (>96%) were obtained in all cases. On dilution with deionized water, the as-synthesized sterically stabilized particles undergo dissociation to afford molecularly dissolved chains, as judged by dynamic light scattering and 1H NMR spectroscopy studies. DMF GPC analysis confirmed a high chain extension efficiency for the PHEAC precursor, but relatively broad molecular weight distributions were observed for the PHEAC-PNAM diblock copolymer chains (Mw/Mn > 1.9). This has been observed for many other PISA formulations when targeting high core-forming block DPs and is tentatively attributed to chain transfer to polymer, which is well known for polyacrylamide-based polymers. In fact, relatively high dispersities are actually desirable if such copolymers are to be used as viscosity modifiers because solution viscosity correlates closely with Mw. Static light scattering studies were also conducted, with a Zimm plot indicating an absolute Mw of approximately 2.5 × 106 g mol-1 when targeting a PNAM DP of 6000. Finally, it is emphasized that targeting such high DPs leads to a sulfur content for this latter formulation of just 23 ppm, which minimizes the cost, color, and malodor associated with the organosulfur RAFT agent.

Nile Blue-based nanosized pH sensors for simultaneous far-red and near-infrared live bioimaging.

Diblock copolymer vesicles are tagged with pH-responsive Nile Blue-based labels and used as a new type of pH-responsive colorimetric/fluorescent biosensor for far-red and near-infrared imaging of live cells. The diblock copolymer vesicles described herein are based on poly(2-(methacryloyloxy)ethyl phosphorylcholine-block-2-(diisopropylamino)ethyl methacrylate) [PMPC-PDPA]: the biomimetic PMPC block is known to facilitate rapid cell uptake for a wide range of cell lines, while the PDPA block constitutes the pH-responsive component that enables facile vesicle self-assembly in aqueous solution. These biocompatible vesicles can be utilized to detect interstitial hypoxic/acidic regions in a tumor model via a pH-dependent colorimetric shift. In addition, they are also useful for selective intracellular staining of lysosomes and early endosomes via subtle changes in fluorescence emission. Such nanoparticles combine efficient cellular uptake with a pH-responsive Nile Blue dye label to produce a highly versatile dual capability probe. This is in marked contrast to small molecule dyes, which are usually poorly uptaken by cells, frequently exhibit cytotoxicity, and are characterized by intracellular distributions invariably dictated by their hydrophilic/hydrophobic balance.

Ultra-High-Molecular-Weight, Narrow-Polydispersity Polyacrylamides Synthesized Using Photoiniferter Polymerization to Generate High-Performance Flocculants.

Ultra-high-molecular-weight, water-soluble polyelectrolytes are commonly employed as flocculants for solid-liquid separation via colloidal destabilization, enabling the rapid and efficient removal of particulate matter from wastewater streams. A drive toward more sustainable and less polluting industrial practices, coupled with the desire to reduce freshwater usage and improve closed-loop systems, demands the development of flocculants with ever-higher dewatering dose performance. Herein, the use of trithiocarbonate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization under either blue LED (λmax = 470 nm) or UV (λmax = 365 nm) irradiation, known as photoiniferter polymerization, was successfully utilized to generate ultra-high-molecular-weight (Mn > 1,000,000 g mol-1) polyelectrolyte copolymer flocculants with narrow molecular weight distributions (Mw/Mn < 1.2). Cationic and anionic polyelectrolyte flocculants were synthesized containing various monomer compositions of acrylamide (AM), dimethylacrylamide (DMA), 3-(acryloyloxyethyll)trimethylammonium chloride (DMAEAq), 3-(acrylamidopropyl)trimethylammonium chloride (APTAC), sodium acrylate (NaAA), and sodium 2-(acrylamido)-2-methylpropylsulfonate (NaATBS) with high monomer conversion using simple experimental apparatus. The narrow molecular weight distribution cationic polyelectrolytes showed improved flocculation efficiency in the clarification of kaolin suspensions of up to 50% in comparison to a broad polydispersity (Mw/Mn > 5.0) commercial benchmark with an equivalent number average molecular weight. The improved performance of the narrow-polydispersity copolymers is attributed to the reduction in the content of the lower-molecular-weight polymer chains, which impart lower flocculation performance.

Sterilizable gels from thermoresponsive block copolymer worms.

Biocompatible hydrogels have many applications, ranging from contact lenses to tissue engineering scaffolds. In most cases, rigorous sterilization is essential. Herein we show that a biocompatible diblock copolymer forms wormlike micelles via polymerization-induced self-assembly in aqueous solution. At a copolymer concentration of 10.0 w/w %, interworm entanglements lead to the formation of a free-standing physical hydrogel at 21 °C. Gel dissolution occurs on cooling to 4 °C due to an unusual worm-to-sphere order-order transition, as confirmed by rheology, electron microscopy, variable temperature (1)H NMR spectroscopy, and scattering studies. Moreover, this thermo-reversible behavior allows the facile preparation of sterile gels, since ultrafiltration of the diblock copolymer nanoparticles in their low-viscosity spherical form at 4 °C efficiently removes micrometer-sized bacteria; regelation occurs at 21 °C as the copolymer chains regain their wormlike morphology. Biocompatibility tests indicate good cell viabilities for these worm gels, which suggest potential biomedical applications.

Synthesis of High Molecular Weight Water-Soluble Polymers as Low-Viscosity Latex Particles by RAFT Aqueous Dispersion Polymerization in Highly Salty Media.

We report the synthesis of sterically-stabilized diblock copolymer particles at 20% w/w solids via reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of N,N'-dimethylacrylamide (DMAC) in highly salty media (2.0 M (NH4)2SO4). This is achieved by selecting a well-known zwitterionic water-soluble polymer, poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC), to act as the salt-tolerant soluble precursor block. A relatively high degree of polymerization (DP) can be targeted for the salt-insoluble PDMAC block, which leads to the formation of a turbid free-flowing dispersion of PDMAC-core particles by a steric stabilization mechanism. 1H NMR spectroscopy studies indicate that relatively high DMAC conversions (>99%) can be achieved within a few hours at 30 °C. Aqueous GPC analysis indicates high blocking efficiencies and unimodal molecular weight distributions, although dispersities increase monotonically as higher degrees of polymerization (DPs) are targeted for the PDMAC block. Particle characterization techniques include dynamic light scattering (DLS) and electrophoretic light scattering (ELS) using a state-of-the-art instrument that enables accurate ζ potential measurements in a concentrated salt solution. 1H NMR spectroscopy studies confirm that dilution of the as-synthesized dispersions using deionized water lowers the background salt concentration and hence causes in situ molecular dissolution of the salt-intolerant PDMAC chains, which leads to a substantial thickening effect and the formation of transparent gels. Thus, this new polymerization-induced self-assembly (PISA) formulation enables high molecular weight water-soluble polymers to be prepared in a highly convenient, low-viscosity form. In principle, such aqueous PISA formulations are highly attractive: there are various commercial applications for high molecular weight water-soluble polymers, while the well-known negative aspects of using a RAFT agent (i.e., its cost, color, and malodor) are minimized when targeting such high DPs.

Mechanistic insights for block copolymer morphologies: how do worms form vesicles?

Amphiphilic diblock copolymers composed of two covalently linked, chemically distinct chains can be considered to be biological mimics of cell membrane-forming lipid molecules, but with typically more than an order of magnitude increase in molecular weight. These macromolecular amphiphiles are known to form a wide range of nanostructures (spheres, worms, vesicles, etc.) in solvents that are selective for one of the blocks. However, such self-assembly is usually limited to dilute copolymer solutions (<1%), which is a significant disadvantage for potential commercial applications such as drug delivery and coatings. In principle, this problem can be circumvented by polymerization-induced block copolymer self-assembly. Here we detail the synthesis and subsequent in situ self-assembly of amphiphilic AB diblock copolymers in a one pot concentrated aqueous dispersion polymerization formulation. We show that spherical micelles, wormlike micelles, and vesicles can be predictably and efficiently obtained (within 2 h of polymerization, >99% monomer conversion) at relatively high solids in purely aqueous solution. Furthermore, careful monitoring of the in situ polymerization by transmission electron microscopy reveals various novel intermediate structures (including branched worms, partially coalesced worms, nascent bilayers, "octopi", "jellyfish", and finally pure vesicles) that provide important mechanistic insights regarding the evolution of the particle morphology during the sphere-to-worm and worm-to-vesicle transitions. This environmentally benign approach (which involves no toxic solvents, is conducted at relatively high solids, and requires no additional processing) is readily amenable to industrial scale-up, since it is based on commercially available starting materials.

Aqueous dispersion polymerization: a new paradigm for in situ block copolymer self-assembly in concentrated solution.

Reversible addition-fragmentation chain transfer polymerization has been utilized to polymerize 2-hydroxypropyl methacrylate (HPMA) using a water-soluble macromolecular chain transfer agent based on poly(2-(methacryloyloxy)ethylphosphorylcholine) (PMPC). A detailed phase diagram has been elucidated for this aqueous dispersion polymerization formulation that reliably predicts the precise block compositions associated with well-defined particle morphologies (i.e., pure phases). Unlike the ad hoc approaches described in the literature, this strategy enables the facile, efficient, and reproducible preparation of diblock copolymer spheres, worms, or vesicles directly in concentrated aqueous solution. Chain extension of the highly hydrated zwitterionic PMPC block with HPMA in water at 70 °C produces a hydrophobic poly(2-hydroxypropyl methacrylate) (PHPMA) block, which drives in situ self-assembly to form well-defined diblock copolymer spheres, worms, or vesicles. The final particle morphology obtained at full monomer conversion is dictated by (i) the target degree of polymerization of the PHPMA block and (ii) the total solids concentration at which the HPMA polymerization is conducted. Moreover, if the targeted diblock copolymer composition corresponds to vesicle phase space at full monomer conversion, the in situ particle morphology evolves from spheres to worms to vesicles during the in situ polymerization of HPMA. In the case of PMPC(25)-PHPMA(400) particles, this systematic approach allows the direct, reproducible, and highly efficient preparation of either block copolymer vesicles at up to 25% solids or well-defined worms at 16-25% solids in aqueous solution.

Unique aqueous self-assembly behavior of a thermoresponsive diblock copolymer.

It is well-recognized that block copolymer self-assembly in solution typically produces spheres, worms or vesicles, with the relative volume fraction of each block dictating the copolymer morphology. Stimulus-responsive diblock copolymers that can undergo either sphere/worm or vesicle/worm transitions are also well-documented. Herein we report a new amphiphilic diblock copolymer that can form spheres, worms, vesicles or lamellae in aqueous solution. Such self-assembly behavior is unprecedented for a single diblock copolymer of fixed composition yet is achieved simply by raising the solution temperature from 1 °C (spheres) to 25 °C (worms) to 50 °C (vesicles) to 70 °C (lamellae). Heating increases the degree of hydration (and hence the effective volume fraction) of the core-forming block, with this parameter being solely responsible for driving the sphere-to-worm, worm-to-vesicle and vesicle-to-lamellae transitions. The first two transitions exhibit excellent reversibility but the vesicle-to-lamellae transition exhibits hysteresis on cooling. This new thermoresponsive diblock copolymer provides a useful model for studying such morphological transitions and is likely to be of significant interest for theoretical studies.

Controlling cellular uptake by surface chemistry, size, and surface topology at the nanoscale.

Cell cytosol and the different subcellular organelles house the most important biochemical processes that control cell functions. Effective delivery of bioactive agents within cells is expected to have an enormous impact on both gene therapy and the future development of new therapeutic and/or diagnostic strategies based on single-cell-bioactive-agent interactions. Herein a biomimetic nanovector is reported that is able to enter cells, escape from the complex endocytic pathway, and efficiently deliver actives within clinically relevant cells without perturbing their metabolic activity. This nanovector is based on the pH-controlled self-assembly of amphiphilic copolymers into nanometer-sized vesicles (or polymersomes). The cellular-uptake kinetics can be regulated by controlling the surface chemistry, the polymersome size, and the polymersome surface topology. The latter is controlled by the extent of polymer-polymer phase separation within the external envelope of the polymersome.

Diffusion studies of nanometer polymersomes across tissue engineered human oral mucosa.

PURPOSE: To measure the diffusion of nanometer polymersomes through tissue engineered human oral mucosa. METHODS: In vitro models of full thickness tissue engineered oral mucosa (TEOM) were used to assess the penetration properties of two chemically different polymersomes comprising two of block copolymers, PMPC-PDPA and PEO-PDPA. These copolymers self-assemble into membrane-enclosed vesicular structures. Polymersomes were conjugated with fluorescent rhodamine in order to track polymersome diffusion. Imaging and quantification of the diffusion properties were assessed by confocal laser scanning microscopy (CLSM). RESULTS: TEOM is morphologically similar to natural oral mucosa. Using CLSM, both formulations were detectable in the TEOM within 6 h and after 48 h both penetrated up to 80 microm into the TEOM. Diffusion of PMPC-PDPA polymersomes was widespread across the epithelium with intra-epithelial uptake, while PEO-PDPA polymersomes also diffused into the epithelium. CONCLUSIONS: CLSM was found to be an effective and versatile method for analysing the level of diffusion of polymersomes into TEOM. The penetration and retention of PMPC-PDPA and PEO-PDPA polymersomes means they may have potential for intra-epithelial drug delivery and/or trans-epithelial delivery of therapeutic agents.

Critical Dependence of Molecular Weight on Thermoresponsive Behavior of Diblock Copolymer Worm Gels in Aqueous Solution.

Reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of 2-hydroxypropyl methacrylate was used to prepare three poly(glycerol monomethacrylate) x -poly(2-hydroxypropyl methacrylate) y (denoted G x -H y  or PGMA-PHPMA) diblock copolymers, namely G37-H80, G54-H140, and G71-H200. A master phase diagram was used to select each copolymer composition to ensure that a pure worm phase was obtained in each case, as confirmed by transmission electron microscopy (TEM) and small-angle x-ray scattering (SAXS) studies. The latter technique indicated a mean worm cross-sectional diameter (or worm width) ranging from 11 to 20 nm as the mean degree of polymerization (DP) of the hydrophobic PHPMA block was increased from 80 to 200. These copolymer worms form soft hydrogels at 20 °C that undergo degelation on cooling. This thermoresponsive behavior was examined using variable temperature DLS, oscillatory rheology, and SAXS. A 10% w/w G37-H80 worm dispersion dissociated to afford an aqueous solution of molecularly dissolved copolymer chains at 2 °C; on returning to ambient temperature, these chains aggregated to form first spheres and then worms, with the original gel strength being recovered. In contrast, the G54-H140 and G71-H200 worms each only formed spheres on cooling to 2 °C, with thermoreversible (de)gelation being observed in the former case. The sphere-to-worm transition for G54-H140 was monitored by variable temperature SAXS: these experiments indicated the gradual formation of longer worms at higher temperature, with a concomitant reduction in the number of spheres, suggesting worm growth via multiple 1D sphere-sphere fusion events. DLS studies indicated that a 0.1% w/w aqueous dispersion of G71-H200 worms underwent an irreversible worm-to-sphere transition on cooling to 2 °C. Furthermore, irreversible degelation over the time scale of the experiment was also observed during rheological studies of a 10% w/w G71-H200 worm dispersion. Shear-induced polarized light imaging (SIPLI) studies revealed qualitatively different thermoreversible behavior for these three copolymer worm dispersions, although worm alignment was observed at a shear rate of 10 s-1 in each case. Subsequently conducting this technique at a lower shear rate of 1 s-1 combined with ultra small-angle x-ray scattering (USAXS) also indicated that worm branching occurred at a certain critical temperature since an upturn in viscosity, distortion in the birefringence, and a characteristic feature in the USAXS pattern were observed. Finally, SIPLI studies indicated that the characteristic relaxation times required for loss of worm alignment after cessation of shear depended markedly on the copolymer molecular weight.

Preparation and Cross-Linking of All-Acrylamide Diblock Copolymer Nano-Objects via Polymerization-Induced Self-Assembly in Aqueous Solution.

Various carboxylic acid-functionalized poly( N , N -dimethylacrylamide) (PDMAC) macromolecular chain transfer agents (macro-CTAs) were chain-extended with diacetone acrylamide (DAAM) by reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization at 70 °C and 20% w/w solids to produce a series of PDMAC-PDAAM diblock copolymer nano-objects via polymerization-induced self-assembly (PISA). TEM studies indicate that a PDMAC macro-CTA with a mean degree of polymerization (DP) of 68 or higher results in the formation of well-defined spherical nanoparticles with mean diameters ranging from 40 to 150 nm. In contrast, either highly anisotropic worms or polydisperse vesicles are formed when relatively short macro-CTAs (DP = 40-58) are used. A phase diagram was constructed to enable accurate targeting of pure copolymer morphologies. Dynamic light scattering (DLS) and aqueous electrophoresis studies indicated that in most cases these PDMAC-PDAAM nano-objects are surprisingly resistant to changes in either solution pH or temperature. However, PDMAC40-PDAAM99 worms do undergo partial dissociation to form a mixture of relatively short worms and spheres on adjusting the solution pH from pH 2-3 to around pH 9 at 20 °C. Moreover, a change in copolymer morphology from worms to a mixture of short worms and vesicles was observed by DLS and TEM on heating this worm dispersion to 50 °C. Postpolymerization cross-linking of concentrated aqueous dispersions of PDMAC-PDAAM spheres, worms, or vesicles was performed at ambient temperature using adipic acid dihydrazide (ADH), which reacts with the hydrophobic ketone-functionalized PDAAM chains. The formation of hydrazone groups was monitored by FT-IR spectroscopy and afforded covalently stabilized nano-objects that remained intact on exposure to methanol, which is a good solvent for both blocks. Rheological studies indicated that the cross-linked worms formed a stronger gel compared to linear precursor worms.

Controlled aqueous polymerization of acrylamides and acrylates and "in situ" depolymerization in the presence of dissolved CO2.

Aqueous copper-mediated radical polymerization of acrylamides and acrylates in carbonated water resulted in high monomer conversions (t < 10 min) before undergoing depolymerization (60 min > t > 10 min). The regenerated monomer was characterized and repolymerized following deoxygenation of the resulting solutions to reyield polymers in high conversions that exhibit low dispersities.

Efficient synthesis of sterically-stabilized nano-objects via RAFT dispersion polymerization of benzyl methacrylate in alcoholic media.

Synthesis of diblock copolymer nano-objects: alcohol is a good idea! RAFT dispersion polymerization of benzyl methacrylate in alcohol using weak polyelectrolyte-based chain transfer agents allows the facile synthesis of sterically stabilized diblock copolymer nano-objects with very high monomer conversions. Such syntheses are usually problematic when conducted in water due to electrostatic repulsion between highly charged stabilizer chains, which impedes in situ self-assembly. Construction of a detailed phase diagram facilitates reproducible syntheses of well-defined diblock copolymer spheres, worms or vesicles, since it allows mixed phase regions to be avoided. Aqueous electrophoresis studies confirm that these nano-objects can acquire substantial surface charge when transferred to aqueous solution due to ionization (or protonation) of the polyacid (or polybase) stabilizer chains.

Controlling polymersome surface topology at the nanoscale by membrane confined polymer/polymer phase separation.

Nature has the exquisite ability to design specific surface patterns and topologies on both the macro- and nanolength scales that relate to precise functions. Following a biomimetic approach, we have engineered fully synthetic nanoparticles that are able to self-organize their surface into controlled domains. We focused on polymeric vesicles or "polymersomes"; enclosed membranes formed via self-assembly of amphiphilic block copolymers in water. Exploiting the intrinsic thermodynamic tendency of dissimilar polymers to undergo phase separation, we mixed different vesicle-forming block copolymers in various proportions in order to obtain a wide range of polymersomes with differing surface domains. Using a combination of confocal laser scanning microscopy studies of micrometer-sized polymersomes, and electron microscopy, atomic force microscopy, and fluorescence spectroscopy on nanometer-sized polymersomes, we find that the domains exhibit similar shapes on both the micro- and nanolength scales, with dimensions that are linearly proportional to the vesicle diameter. Finally, we demonstrate that such control over the surface "patchiness" of these polymersomes determines their cell internalization kinetics for live cells.

Enhanced fluorescence imaging of live cells by effective cytosolic delivery of probes.

BACKGROUND: Microscopic techniques enable real-space imaging of complex biological events and processes. They have become an essential tool to confirm and complement hypotheses made by biomedical scientists and also allow the re-examination of existing models, hence influencing future investigations. Particularly imaging live cells is crucial for an improved understanding of dynamic biological processes, however hitherto live cell imaging has been limited by the necessity to introduce probes within a cell without altering its physiological and structural integrity. We demonstrate herein that this hurdle can be overcome by effective cytosolic delivery. PRINCIPAL FINDINGS: We show the delivery within several types of mammalian cells using nanometre-sized biomimetic polymer vesicles (a.k.a. polymersomes) that offer both highly efficient cellular uptake and endolysomal escape capability without any effect on the cellular metabolic activity. Such biocompatible polymersomes can encapsulate various types of probes including cell membrane probes and nucleic acid probes as well as labelled nucleic acids, antibodies and quantum dots. SIGNIFICANCE: We show the delivery of sufficient quantities of probes to the cytosol, allowing sustained functional imaging of live cells over time periods of days to weeks. Finally the combination of such effective staining with three-dimensional imaging by confocal laser scanning microscopy allows cell imaging in complex three-dimensional environments under both mono-culture and co-culture conditions. Thus cell migration and proliferation can be studied in models that are much closer to the in vivo situation.

Internalization and biodistribution of polymersomes into oral squamous cell carcinoma cells in vitro and in vivo.

The prognosis for oral squamous cell carcinoma (OSCC) is not improving despite advances in surgical treatment. As with many cancers, there is a need to deliver therapeutic agents with greater efficiency into OSCC to improve treatment and patient outcome. The development of polymersomes offers a novel way to deliver therapy directly into tumor cells. Here we examined the internalization and biodistribution of two different fluorescently labeled polymersome formulations; polyethylene oxide (PEO)-poly 2-(diisopropylamino)ethyl methacrylate (PDPA) and poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)-PDPA, into SCC4 OSCC cells in vitro and in vivo. In vitro SCC4 monolayers internalized PMPC-PDPA and PEO-PDPA at similar rates. However, in vivo PMPC-PDPA polymersomes penetrated deeper and were more widely dispersed in SCC4 tumors than PEO-PDPA polymersomes. In the liver and spleen PMPC-PDPA mainly accumulated in tissue macrophages. However, in tumors PMPC-PDPA was found extensively in the nucleus and cytoplasm of tumor cells as well as in tumor-associated macrophages. Use of PMPC-PDPA polymersomes may enhance polymersome-mediated antitumor therapy.

Self-Assembled Block Copolymer Aggregates: From Micelles to Vesicles and their Biological Applications.

The ability of amphiphilic block copolymers to self-assemble in selective solvents has been widely studied in academia and utilized for various commercial products. The self-assembled polymer vesicle is at the forefront of this nanotechnological revolution with seemingly endless possible uses, ranging from biomedical to nanometer-scale enzymatic reactors. This review is focused on the inherent advantages in using polymer vesicles over their small molecule lipid counterparts and the potential applications in biology for both drug delivery and synthetic cellular reactors.

Synthesis of well-defined glycopolymers and some studies of their aqueous solution behaviour.

Well-defined polymers with carbohydrate residues pendant to the main chain (glycopolymers) were prepared by reversible addition fragmentation chain transfer (RAFT) polymerisation. Excellent control over molecular weight and narrow polydispersities (1.1-1.2) were achieved over a range of molecular weights. In addition, efficient synthesis of block copolymers by sequential monomer addition with both hydrophilic and hydrophobic non-carbohydrate blocks was demonstrated. The aqueous solution behaviour of amphiphilic block glycopolymers was investigated, revealing the formation of multivalent carbohydrate-bearing aggregates in solution with the capability for the solubilisation of hydrophobic species (a water-insoluble dye). One such amphiphilic glycopolymer shows by TEM the formation of a worm-like micelle phase. Further investigations of these novel bioactive macromolecular assemblies are underway.