MtDNA instability is associated with a wide spectrum of clinical presentations, from dominant or recessive progressive external ophthalmoplegia (PEO) to juvenile-onset spino-cerebellar ataxia and epilepsy (SCAE) or infantile Alpers-Huttenlocher syndrome. We present here the clinical and molecular features of a patient with a clinical presentation characterized initially by PEO with mtDNA multiple deletions lately evolving into a severe neurological syndrome, which included sensory and cerebellar ataxia, peripheral neuropathy, parkinsonism, and depression. This complex phenotype is the result of mutations in two distinct proteins, ANT1 and PolgammaA, which cause additive, deleterious effects on mtDNA maintenance and integrity.

BSA adsorption onto bimodal PEO brushes at a solid surface was measured using optical reflectometry. Bimodal brushes consist of long (N=770) and short (N=48) PEO chains and were prepared on PS surfaces, applying mixtures of PS(29)-PEO(48) and PS(37)-PEO(770) block copolymers and using the Langmuir-Blodgett technique. Pi-A isotherms of (mixtures of) the block copolymers were measured to establish the brush regime. The isotherms of PS(29)-PEO(48) show hysteresis between compression and expansion cycles, indicating aggregation of the PS(29)-PEO(48) upon compression. Mixtures of PS(29)-PEO(48) and PS(37)-PEO(770) demonstrate a similar hysteresis effect, which eventually vanishes when the ratio of PS(37)-PEO(770) to PS(29)-PEO(48) is increased. The adsorption of BSA was determined at brushes for which the grafting density of the long PEO chains was varied, while the total grafting density was kept constant. BSA adsorption onto monomodal PEO(48) and PEO(770) brushes was determined for comparison. The BSA adsorption behavior of the bimodal brushes is similar to the adsorption of BSA at PEO(770) monomodal brushes. The maximum of BSA adsorption at low grafting density of PEO(770) can be explained by ternary adsorption, implying an attraction between BSA and PEO. The contribution of primary adsorption to the total adsorbed amount is negligible.

Collagen-containing poloxamine hydrogels were produced with the aim of overcoming the low stiffness displayed by collagen gels that are not otherwise chemically crosslinked. Matrices were obtained by functionalization of a four-arm PEO-PPO block copolymer (poloxamine, Tetronic) with methcrylate groups and subsequent free radical polymerization of water solutions of the modified polymer in the presence of collagen. The resulting matrices had a sharp increase in stiffness, when compared to pure collagen gels. For example, whereas collagen had a storage modulus (G') around 70 Pa and a loss modulus (G'') of 10 Pa, a crosslinked collagen/poloxamine system containing 8.3% crosslinked poloxamine had G' and G'' values of 7400 and 1000 Pa, respectively. HepG2 cells were seeded within the gels before the crosslinking and the viability levels estimated by AlamarBlue assay were between 65% and 91% for systems containing 0.04-0.09 wt% photoinitiator. HepG2 and endothelial cells also adhered to and spread on the surface of the collagen-containing specimens, suggesting their potential utility in tissue engineering.

High molecular weight polyethylene oxides (PEOs) have recently been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) in controlled release matrix tablets. In this study, we compared the performance of PEO and HPMC polymers when employed in the Geomatrix technology, a versatile, well-known method to achieve extended release of drugs at a constant rate. Four core formulations were prepared, containing a soluble drug (diltiazem) and, alternatively, PEO or HPMC of two different viscosity grades. These formulations have the same composition except for the polymer employed. Similarly, four barrier formulations were also prepared, which only differ in the kind of polymer employed. Three-layer Geomatrix systems were then prepared using these core and barrier formulations. The release profiles of the different three-layer systems obtained were compared, to verify if PEO could efficiently replace HPMC in this type of dosage form. The results show that slower release rates can be obtained from the plain matrices containing HPMC compared to PEO, moreover HPMC, used in the barrier formulations, is generally more efficient in controlling drug release rate in three-layer Geomatrix systems.

Crystallization processes are in general sensitive to detailed conditions, but our present understanding of underlying mechanisms is insufficient. A crystallizable chain within a diblock copolymer assembly is expected to couple curvature to crystallization and thereby impact rigidity as well as preferred morphology, but the effects on dispersed phases have remained unclear. The hydrophobic polymer polycaprolactone (PCL) is semi-crystalline in bulk (T(m) = 60°C) and is shown here to generate flexible worm micelles or rigid vesicles in water from several dozen polyethyleneoxide-based diblocks (PEO-PCL). Despite the fact that `worms' have a mean curvature between that of vesicles and spherical micelles, `worms' are seen only within a narrow, process-dependent wedge of morphological phase space that is deep within the vesicle phase. Fluorescence imaging shows worms are predominantly in one of two states - either entirely flexible with dynamic thermal undulations or fully rigid; only a few worms appear rigid at room temperature (T (< T(m)), indicating suppression of crystallization by both curvature and PCL hydration. Worm rigidification, which depends on molecular weight, is also prevented by copolymerization of caprolactone with just 10% racemic lactide that otherwise has little impact on bulk crystallinity. In contrast to worms, vesicles of PEO-PCL are always rigid and typically leaky. Defects between crystallite domains induce dislocation-roughening with focal leakiness although select PEO-PCL - which classical surfactant arguments would predict make worms - yield vesicles that retain encapsulant and appear smooth, suggesting a gel or glassy state. Hydration in dispersion thus tends to selectively soften high curvature microphases.

High ionic conductivity solid polymer electrolyte (SPE) has long been desired for the next generation high energy and safe rechargeable lithium batteries. Among all of the SPEs, composite polymer electrolyte (CPE) with ceramic fillers has garnered great interest due to the enhancement of ionic conductivity. However, the high degree of polymer crystallinity, agglomeration of ceramic fillers, and weak polymer-ceramic interaction limit the further improvement of ionic conductivity. Different from the existing methods of blending preformed ceramic particles with polymers, here we introduce an in situ synthesis of ceramic filler particles in polymer electrolyte. Much stronger chemical/mechanical interactions between monodispersed 12 nm diameter SiO2 nanospheres and poly(ethylene oxide) (PEO) chains were produced by in situ hydrolysis, which significantly suppresses the crystallization of PEO and thus facilitates polymer segmental motion for ionic conduction. In addition, an improved degree of LiClO4 dissociation can also be achieved. All of these lead to good ionic conductivity (1.2 × 10(-3) S cm(-1) at 60 °C, 4.4 × 10(-5) S cm(-1) at 30 °C). At the same time, largely extended electrochemical stability window up to 5.5 V can be observed. We further demonstrated all-solid-state lithium batteries showing excellent rate capability as well as good cycling performance.

Degradable copolymers were synthesized by ring opening polymerization of lactide in the presence of poly(ethylene glycol) (PEG), using CaH2 as a biocompatible initiator. The resulting PLA/PEO/PLA triblock copolymers were dissolved in a biocompatible solvent, namely tetraglycol. Physically crosslinked hydrogels were then prepared by introducing small amounts of water into the thus obtained solutions. Hydrolytic degradation of the highly swollen hydrogels was realized in 0.13 M pH=7.4 phosphate buffer, while the enzymatic degradation was carried out in 0.05 M pH=8.6 Tris buffer containing a PLA-degrading enzyme, proteinase K. In both cases, degradation was initially very fast with dramatic weight loss. The LA/EO ratio of the remaining material increased rapidly, in agreement with the release of PEO-rich segments. In a second phase, the degradation rate slowed down. The presence of proteinase K strongly accelerated the degradation rate of the hydrogels, indicating that the enzyme was able to penetrate inside and attack the PLA domains which constituted nanometric nodes in the gel network.

This study investigated the effects of polymer molecular weight, drug solubility, addition of a water-soluble excipient, and drug loading on zero-order release kinetics and elucidated the release mechanism of a drug from directly compressed tablets. Directly compressed tablets consisting of polyethylene oxides (PEO) (MW = 0.9, 2.0 and 4.0 x 10(6)) and drugs (solubility ranging from 290 to 25,000 mg/l) were formulated with or without a water-soluble excipient (lactose). For PEO tablets (MW = 0.9 x 10(6)), drug release is primarily swelling/erosion controlled for drugs for which solubility is below 1%, resulting in zero-order release kinetics. For PEO tablets (MW = 4.0 x 10(6)), drug release is controlled at a zero-order rate by the dissolution rate of the drug at high loading (39%). At low loading (20%), drug diffusion through the swollen gel layer becomes the governing release mechanism. For a highly water-soluble drug (e.g., diclofenac Na), drug diffusion is the controlling mechanism regardless of the molecular weight of the PEOs. Zero-order release kinetics can be achieved with PEO tablets (MW = 0.9 x 10(6)) for drugs for which solubility is below 1%. PEO tablets (MW = 2.0 x 10(6)) provided zero-order release for poorly water-soluble drugs (below 0.2%) at 39% drug loading. It is possible to attain zero-order release kinetics with PEO tablets (MW = 4.0 x 10(6)) using a drug which has a solubility of less than 0.1%.

The strain-dependent electrical resistance characteristics of multi-walled carbon nanotube (MWCNT)/polymer composite films were investigated. In this research, polyethylene oxide (PEO) is used as the polymer matrix. Two representative volume fractions of MWCNT/PEO composite films were selected: 0.56 vol% (near the percolation threshold) and 1.44 vol% (away from the percolation threshold) of MWCNT. An experimental setup which can measure electrical resistance and strain simultaneously and continuously has been developed. Unique and repeatable relationships in resistance versus strain were obtained for multiple specimens with different volume fractions of MWCNT. The overall pattern of electrical resistance change versus strain for the specimens tested consists of linear and nonlinear regions. A resistance change model to describe the combination of linear and nonlinear modes of electrical resistance change as a function of strain is suggested. The unique characteristics in electrical resistance change for different volume fractions imply that MWCNT/PEO composite films can be used as tunable strain sensors and for application into embedded sensor systems in structures.

The temperature sensitive properties of Pluronic F-127 (MW approximately 12600, PEO(98)-PPO(67)-PEO(98)), a block co-polymer or poloxamer, was used to control liposome-cell adhesion. When associated with liposomes, the PEO moiety of the block co-polymer is expected to inhibit liposome-cell adhesion. Liposomes were made using egg phosphatidylcholine and different mole% of Pluronic F-127. Size measurement of the liposomes at different temperatures, in the presence and absence of Pluronic F-127, shows significant reduction in the size of multilamellar vesicles, at higher temperatures, by the Pluronic molecules. Negative stain electron microscopy study showed the presence of individual molecules and micelles of Pluronic, respectively at temperatures below and above the critical micellar temperature (CMT). Measurement of the surface associated Pluronics indicated that they associated with liposomes when the sample was heated above the Pluronic CMT, and dissociated from liposomes when cooled below the CMT. Attachment of the Pluronic containing liposomes to CHO cells was inhibited at temperatures above the CMT, but not at temperatures below CMT, indicating that temperature-sensitive control of liposome-cell adhesion is achieved.

The core-forming blocks of amphiphilic diblock copolymers based on methoxypoly(ethylene oxide)-block-poly(L-aspartate), PEO-b-p(L-Asp), were derivatized to incorporate stearate side chains. The effects of stearate esterification were assessed in terms of micelle stability and amphotericin B (AmB) encapsulation/release. The level of stearate esterification modulates the relative self-aggregation state of encapsulated AmB as evidenced by absorption spectroscopy. When AmB is physically loaded into polymeric micelles, the onset of hemolytic activity toward bovine erythrocytes is delayed relative to that of the free drug. Furthermore, the extent of esterification (0, 46, or 91%) appears to have profound influence on the time-dependent hemolytic profile of AmB toward bovine erythrocytes. Particularly in the case of highly substituted stearate ester micelles, incomplete and gradual build-up of hemolysis was observed over a period of 24 h. On the basis of the corresponding absorption spectra, we speculate that encapsulated AmB may interact strongly with stearate side chains, resulting in sustained release. In a neutropenic murine model of disseminated candidiasis, kidney colony-forming unit determination revealed dose-dependent efficacy for the polymeric micelle/AmB formulation, which was not significantly different from that of Fungizone at doses of 0.2, 0.3, and 0.6 mg/kg (p = 0.7). Thus, AmB administered via a polymeric micelle formulation retained potent in vivo activity.

Progressive external ophthalmoplegia (PEO) with secondary accumulation of multiple deletions of mitochondrial DNA (mtDNA) clinically resembles disorders due to primary mutations of mtDNA but follows a Mendelian inheritance pattern. The disorder belongs to an interesting group of diseases in which both the nuclear and the mitochondrial genome are involved in the pathology. Both autosomal dominant (adPEO) and recessive (arPEO) variants of this disorder occur. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients may have multiple mtDNA deletions and/or depletion of mtDNA. Recent reports of mutations in Thymidine Phosphorylase in MNGIE, and of mutations in adenine nucleotide translocator (ANT1), Twinkle and mitochondrial DNA polymerase gamma (POLG) in adPEO, have lead to new insights in the pathogenesis of these disorders of mtDNA maintenance. We also identified POLG mutations in two families with arPEO, which underlines the crucial role of the mtDNA replication machinery for mtDNA maintenance.

Nanocarriers that combine multiple properties in an all-in-one system hold great promise for drug delivery. The absence of technology to assemble highly functionalized devices has, however, hindered progress in nanomedicine. To address this deficiency, we have chemically synthesized poly(ethylene oxide)-β-poly(ε-caprolactone) (PEO-b-PCL) block polymers modified at the apolar PCL terminus with thioctic acid and at the polar PEO terminus with an acylhydrazide, amine, or azide moiety. The resulting block polymers were employed to prepare nanoparticles that have a gold core, an apolar polyester layer for drug loading, a polar PEO corona to provide biocompatibility, and three different types of surface reactive groups for surface functionalization. The acylhydrazide, amine, or azide moieties of the resulting nanoparticles could be reacted with high efficiencies with modules having a ketone, isocyanate, or active ester and alkyne function, respectively. To demonstrate proof of principle of the potential of multisurface functionalization, we prepared nanoparticles that have various combinations of an oligo-arginine peptide to facilitate cellular uptake, a histidine-rich peptide to escape from lysosomes, and an Alexa Fluor 488 tag for imaging purposes. It has been shown that uptake and subcellular localization of the nanoparticles can be controlled by multisurface modification. It is to be expected that the modular synthetic methodology provides unique opportunities to establish optimal configurations of nanocarriers for disease-specific drug delivery.

Flexible scaffolds are of great interest in engineering functional and mechano-active soft tissues as such scaffolds might allow mechanical stimuli to transfer effectively from the scaffolds to cells during tissue development. Towards this end, we have developed a family of flexible poly(ether carbonate urethane)ureas (PECUUs) with a triblock copolymer poly(trimethylene carbonate)-poly(ethylene oxide)-poly(trimethylene carbonate) (PTMC-PEO-PTMC) or pentablock copolymers PTMC-PEO-PPO-PEO-PTMC (PPO, polypropylene oxide) as soft segments, linked by 1,4-diisocyanatobutane and putrescine. All of the PECUUs had low glass transition temperatures (<-46 degrees C). The PTMC-PEO-PTMC-containing PECUUs had low tensile strength and breaking strain. Replacing PEO with the similar length PEO-PPO-PEO resulted in highly flexible and soft PECUUs possessing breaking strains of 362-711%, tensile strengths of 8-18MPa and moduli of 5.5-7.4MPa at room temperature in air. Under aqueous conditions at 37 degrees C, these polymers remained flexible while their moduli were decreased to 3.4-4.0MPa. PECUUs based on PTMC-PEO-PPO-PEO-PTMC were thermosensitive as the water content at 37 degrees C was lower than that at 4 degrees C. PECUU using PTMC-PEO-PTMC as a soft segment showed 30% weight loss over 6weeks in PBS at 37 degrees C, while that using PTMC-PEO-PPO-PEO-PTMC as a soft segment had weight loss <6%. Degradation products were found to lack cytotoxicity. The mechanical stresses and moduli of PECUUs based on PTMC-PEO-PPO-PEO-PTMC were unchanged during the degradation. To enhance cell adhesion, PECUUs were surface modified with Arg-Gly-Asp-Ser (RGDS). Smooth muscle cell adhesion was 114% of tissue culture polystyrene for unmodified PECUU and >180% for RGDS-modified PECUUs, with cell viability on both surfaces increasing during culture. These low moduli polyurethanes may find applications in engineering cardiovascular or other soft tissues.

A new class of high molecular weight polysulfated PEO dendrimer-like glycopolymer has been synthesized by a combination of arm-first and core-first methodologies followed by trichloroacetimidate glycosidation as a facile bioconjugation strategy. An L-selectin antagonist was identified that exhibits 103-fold greater activity than other multivalent sLex glycopolymers and 20-50 times greater potency than other linear heparinoids. A significant reduction in inflammatory cell recruitment was observed in vivo.

Solid surfaces are modified by grafting poly(ethylene oxide), PEO, to influence their interaction with indwelling particles, in particular molecules of bovine serum albumin and human plasma proteins. As a rule, the grafted PEO layers suppress protein adsorption. The suppression is most effective when the PEO layer is in a molecular brush conformation having a reciprocal grafting density (area per grafted PEO chain) less than the dimensions of the protein molecules. Nevertheless, the protein molecules may penetrate the PEO brush to some extent. For a given grafting density, the penetration is facilitated by increasing thickness of the brush. Tenuous brushes of reciprocal grafting densities exceeding the protein molecular dimensions enhance protein adsorption. The results point to a weak attractive interaction between PEO and protein. The protein repellency of a densely PEO-brushed surface is ascribed to a high activation energy for the protein molecules to enter the brush. Varying the temperature between 22 and 38 degrees C does not significantly affect the range of grafting density over which the brush changes from protein-attractive to protein-repellent.

The effects of PEO-PPO-PEO triblock copolymers, mainly Poloxamer 188, on phospholipid membrane integrity under osmotic gradients were explored using giant unilamellar vesicles (GUVs). Fluorescence leakage assays showed two opposing effects of P188 on the structural integrity of GUVs depending on the duration of their incubation time. A two-state transition mechanism of interaction between the triblock copolymers and the phospholipid membrane is proposed: an adsorption (I) and an insertion (II) state. While the triblock copolymer in state I acts to moderately retard the leakage, their insertion in state II perturbs the lipid packing, thus increasing the membrane permeability. Our results suggest that the biomedical application of PEO-PPO-PEO triblock copolymers, either as cell membrane resealing agents or as accelerators for drug delivery, is directed by the delicate balance between these two states.

Butyrylcholinesterase (BChE) is an efficient bioscavenger of highly toxic organophosphorus poisons and nerve agents. However, BChE administered into the periphery does not provide significant protection of the central nervous system (CNS) due to rejection by the blood-brain barrier. In this study, we evaluated the feasibility of delivering BChE to the CNS by packing it into a block ionomer complex of nanoscale size with a cationic poly(l-lysine)-graft-poly(ethylene oxide) (PLL-g-PEO) copolymer. The multimolecular structure of BChE/PLL-g-PEO complexes was further reinforced by formation of cross-links between the polymer chains. The resulting cross-linked complexes were stable against dilution without significant loss of BChE enzymatic activity. In some cases the BChE was labeled with fluorescent IRDye 800CW before it was incorporated into nanoparticles. BChE/PLL-g-PEO complexes were injected into mice intramuscularly and intravenously. In vivo imaging showed incorporation of the fluorescently labeled BChE in brain. Activity assays showed that BChE remained active in the brain at 72-h post-injection. It was concluded that nanocomplexes can deliver the 340 kDa BChE tetramer to the brain.

A series of PLA/PEO/PLA triblock copolymers was prepared by ring opening polymerization of rac-lactide in the presence of various di-hydroxyl poly (ethylene glycol)s, using CaH2 as a biocompatible initiator. Hydrogels were prepared by a phase separation method consisting of introducing small amounts of water over solutions of the copolymers in a biocompatible organic solvent, namely tetraglycol [poly(ethylene glycol monotetrahydrofurfuryl ether)]. The resulting hydrogels appeared much more hydrophilic than the rather tough hydrogels formed by swelling of dry tablets or films processed from the same copolymers. The phase separation-derived hydrogels were soft enough to be injected through a trochar. Two proteins, namely bovine serum albumine (BSA) and fibrinogen, were physically entrapped in these hydrogels by mixing with the polymer solutions before gel formation. This procedure appeared to be protein-respecting according to circular dichroism analysis on the released BSA. Dramatically different release profiles were obtained for the two proteins. In the case of BSA, the release depended on the quantity of protein incorporated in the hydrogel and presented a parabolic-type profile, in agreement with the behaviors of diffusion-controlled monolitic drug delivery devices. In contrast, almost linear release profiles were observed in the case of fibrinogen, the hydrogels behaving like a reservoir drug delivery system. These findings are tentatively interpreted in terms of gel-protein compatibility in the case of BSA and gel-protein incompatibility in the case of fibrinogen.

A strong beta-sheet forming peptide was conjugated to PEO and utilized to guide the structure formation process toward well-defined, tape-like structures with millimeters in length, about 2 mum width, and approximately 50 nm height. The aggregation tendency of the peptide was temporarily suppressed for ease of synthesis by the integration of multiple switch-peptide defect segments into the peptide backbone. A subsequent rearrangement in the defects re-establishes the native peptide backbone and triggers the assembly by switching the aggregation properties on.

Poly(ethylene oxide) (PEO) is a key material in solid polymer electrolytes, biomaterials, drug delivery devices, and sensors. Through the use of hydrogen bonds, layer-by-layer (LBL) assemblies allow for the incorporation of PEO in a controllable tunable thin film, but little is known about the bulk properties of LBL thin films because they are often tightly bound to the substrate of assembly. The construction technique involves alternately exposing a substrate to a hydrogen-bond-donating polymer (poly(acrylic acid)) and a hydrogen-bond-accepting polymer (PEO) in solution, producing mechanically stable interdigitated layers of PEO and poly(acrylic acid) (PAA). Here, we introduce a new method of LBL film isolation using low-energy surfaces that facilitate the removal of substantial mass and area of the film, allowing, for the first time, the thermal and mechanical characterization that was previously difficult or impossible to perform. To further understand the morphology of the nanoscale blend, the glass transition is measured as a function of assembly pH via differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). The resulting trends give clues as to how the morphology and composition of a hydrogen-bonded composite film evolve as a function of pH. We also demonstrate that LBL films of PEO and PAA behave as flexible elastomeric blends at ambient conditions and allow for nanoscale control of thickness and film composition. Furthermore, we show that the crystallization of PEO is fully suppressed in these composite assemblies, a fact that proves advantageous for applications such as ultrathin hydrogels, membranes, and solid-state polymer electrolytes.

New reverse thermo-responsive polymers systems combining reverse thermal gelation behavior and a gradual increase in the mechanical properties, were created by crosslinking ethoxysilane-capped poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblocks in aqueous solutions at physiological conditions. Pluronic F127 (PEO(99)-PPO(67)-PEO(99)) was functionalized with (3-isocyanatopropyl) triethoxysilane (IPTS) by reacting its terminal hydroxyl groups with the isocyanate. The silane-capped PEO-PPO-PEO triblock was characterized by (1)H-NMR, GPC, FT-IR and DSC and the rheological behavior of its aqueous solutions were studied. The silane-containing triblock retained the reverse thermo-responsive characteristics displayed by the original Pluronic. Over time, the ethoxysilane groups hydrolysed and created silanol moieties that subsequently condensated, crosslinking the material and generating hydrogels that exhibited gradually increasing mechanical properties. It was found that the higher the pH, the faster the process and the higher the viscosity levels attained. Finally, the ability of these gels to perform as matrices for drug delivery was exemplified by releasing metronidazole and methylene blue. Findings showed that while a 30% F127 gel at 37 degrees C delivered all the drug within less than 3 days, F127di-IPTS gels completed the process at a much slower rate (up to 15 days).

Poloxamer 407 was adsorbed onto the surface of model colloidal drug carriers, polystyrene nanoparticles of 40, 70 and 137 nm in diameter, and the effect of the degree of surface coverage and the conformation of the poly(ethylene oxide) (PEO) chains on biological fate was studied. The relationship between the physicochemical and the biological properties of the nanoparticle systems was also investigated. The adsorbed layer of poloxamer 407 was characterised in terms of percentage surface coverage, thickness of the adsorbed layer and average surface area per PEO chain. Computer modelling of the adsorbed layer was performed (applying the self-consistent field technique), to obtain the structural information of the PEO chains in the layer. The in vitro interaction of the nanoparticles with different degrees of poloxamer 407 surface coverage with serum components and the in vivo biodistribution in the rat model were assessed. The results demonstrated that an increase in the surface coverage with poloxamer 407 resulted in an increased volume fraction of the PEO in the adsorbed layer, further extension of the PEO chains from the surface and closer packing of the chains at the surface. With regard to the interaction with the serum components, an increased surface coverage resulted in a reduction of the amount of serum proteins adsorbed, and, importantly, affected the type of proteins adsorbed. High molecular weight proteins were not adsorbed onto the nanoparticles with a surface coverage above approx. 25%. Following the intravenous administration to rats, even the nanoparticles with the lowest degree of surface coverage (approx. 5%) showed improved circulation profiles relative to the uncoated nanoparticles. The effect was more pronounced for the 40 nm nanoparticles. A further increase in the surface coverage to approx. 25% resulted in a significant increase in circulation time, as compared to uncoated and 5% coated systems, for all sizes of nanoparticles. Importantly, it was found that a long in vivo blood circulation time could be achieved for nanoparticles with a relatively low degree of surface coverage with PEO chains.

Novel reverse thermo-responsive (RTG) polymeric systems displaying superior rheological properties were generated by polymerization of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) segments. Two basic synthetic pathways were followed: (1) The bulk polymerization of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock (Pluronic(RTM) F127) (MW=12,600, 70wt% PEO) with hexamethylene diisocyanate (HDI) and (2) The covalent binding of poly(ethylene glycol) and poly(propylene glycol) chains, using phosgene as the connecting molecule. While in the former, the basic amphiphilic F127 repeating unit is known for its own RTG behavior, the latter polymers consist of segments unable of exhibiting reverse thermal gelation of their own. These new materials achieved viscosities at least 15 times higher than F127, at 37 degrees C. Dynamic light scattering measurements revealed that the microstructures formed by these novel polymers were markedly larger than those generated by PEO-PPO-PEO triblocks. While the size of Pluronic F127 micelles ranged from 15 to 20nm, the higher molecular weight amphiphiles generated much larger nanostructures (20-400nm). Finally, the ability of reverse thermo-sensitive gels to perform as drug delivery systems was exemplified by releasing an anti-restenosis model drug (RG-13577). A 30% P[F127](4) gel delivered the drug over 40 days, whereas a F127 gel having the same concentration released the drug over a 7 days period.