Preparation and Performance of Hydroxypropyl Methylcellulose Esters of Substituted Succinates for <i>in Vitro</i> Supersaturation of a Crystalline Hydrophobic Drug

We prepared hydroxypropyl methylcellulose (HPMC) esters of substituted succinates and examined their performance for improving the aqueous solubility of crystalline hydrophobic drugs in spray-dried dispersions (SDDs). From one HPMC, we synthesized five HPMC esters using various monosubstituted succinic anhydrides. These HPMC esters along with a commercial HPMC acetate succinate (HPMCAS) were spray-dried from solutions with phenytoin. The SDDs with different matrices at 10 wt % loading had very similar bulk properties with a minimal amount of detectable crystalline phenytoin as revealed by scanning electron microscopy (SEM), powder X-ray diffraction (powder XRD), and differential scanning calorimetry (DSC). In solution, while the SDD with HPMCAS was very effective at achieving high levels of phenytoin supersaturation initially, it was not competent at maintaining such supersaturation due to the rapid crystallization of the dissolved phenytoin. Alternatively, SDDs with several synthesized HPMC esters of substituted succinates not only achieved rather high initial supersaturation but also maintained high concentrations for extended time (i.e., 1.5 h and longer). Such maintenance was largely ascribed to the inhibition of phenytoin nucleation. Structure–property relationships were established, and the most successful systems contained a high degree of substitution and a combination of a thioether with neighboring weak electron-withdrawing groups in the substituted succinic anhydrides. The effective maintenance of supersaturated solutions was only found in SDDs with rather low drug loadings, which indicates the significance of sufficiently high concentrations of polymer additives in the dissolution media

Oxidatively Stable Polyolefin Thermoplastics and Elastomers for Biomedical Applications

Statistical copolymers were prepared by the Ring Opening Metathesis coPolymerization (ROMP) of (<i>Z</i>)-5,5-dimethylcyclooct-1-ene and <i>cis</i>-cyclooctene. Subsequent hydrogenation yielded poly­(ethylene-<i>co</i>-isobutylene) (PEIB) materials. The feed ratio of the comonomers controls the degree of branching and resulting thermal and mechanical properties of the PEIB samples. Oxidative degradation studies, conducted under accelerated in vitro conditions were used to assess and predict their long-term biostability. Relative to commercial poly­(ether urethanes) and a structurally similar polyolefin, poly­(ethylene-<i>co</i>-1-butylene), the PEIB samples showed much better oxidative resistance. The facile synthesis, improved stability, and excellent mechanical performance of these PEIB materials bode well for their use in biomedical applications that require long-term biostability

Carboxy-Telechelic Polyolefins in Cross-Linked Elastomers

We demonstrate that ring-opening metathesis copolymerization of 3-hexyl-<i>cis</i>-cyclooctene and <i>cis</i>-cyclooctene in the presence of maleic acid as a chain transfer agent leads to precise control over the molar mass, branching and crystallinity of the resulting carboxy-telechelic polyalkenamers. Subsequent hydrogenation using a silica-supported platinum catalyst had a negligible effect on the carboxy functionality and led to telechelic polyolefins with high thermal resistance, low glass transition temperatures (<−57 °C), little to no crystallinity, and viscosities similar to those of liquid silicon rubber prior to cross-linking. These properties are ideal for easily processable reactive polyolefin prepolymers that can be readily cured to form elastomers. We demonstrate that a fast and controlled curing process can be achieved in the presence of polyfunctional aziridines. The properties of the thermoset elastomer products were evaluated by tensile, differential scanning calorimetry, and dynamic mechanical analyses

Nanoporous Poly(lactide) by Olefin Metathesis Degradation

We describe an approach to ordered nanoporous poly­(lactide) that relies on self-assembly of poly­(butadiene)–poly­(lactide) (PB–PLA) diblock copolymers followed by selective degradation of PB using olefin metathesis. The block copolymers were obtained by a combination of anionic and ring-opening transesterification polymerizations. The molar mass of each block was tailored to target materials with either a lamellar or cylindrical microphase-separated morphology. Orientation of these nanoscale domains was induced in thin films and monolithic samples through solvent annealing and mechanical deformation, respectively. Selective degradation of PB was achieved by immersing the samples in a solution of Grubbs first-generation catalyst in cyclohexane, a nonsolvent for PLA. Successful elimination of PB was confirmed by size-exclusion chromatography and ¹H NMR spectroscopy. Direct imaging of the resulting nanoporous PLA was obtained by scanning electron microscopy

Functionalized Nanoporous Polyethylene Derived from Miscible Block Polymer Blends

Functionalized nanoporous polyethylene (PE) was prepared through controlled introduction of thermo-responsive poly­[2-(2-methoxyethoxy)­ethyl methacrylate] (PMe­(OE)₂MA), or poly­{2-[2-(2-methoxyethoxy)­ethoxy]­ethyl methacrylate} (PMe­(OE)₃MA) onto the pore walls. The compatibility of polylactide (PLA) and PMe­(OE)_<i>x</i>MA (<i>x</i> = 2, 3) was investigated by blending the corresponding homopolymers. The blends showed only one glass transition when the molar masses of both components were relatively low, whereas two glass transitions were observed in case of higher molar mass samples. PMe­(OE)_<i>x</i>MA-<i>b</i>-PE-<i>b</i>-PMe­(OE)_<i>x</i>MA (<i>x</i> = 2, 3) block polymers were synthesized by a combination of ring-opening metathesis polymerization, atom transfer radical polymerization, and hydrogenation. Those block polymer blends formed a disordered bicontinuous structure consisting of a mixed PLA/PMe­(OE)_<i>x</i>MA domain and a semicrystalline PE domain. The PLA component was selectively removed from those blends by mild base treatment. The resulting nanoporous polyethylene showed an improved water uptake as a result of the hydrophilic PMe­(OE)_<i>x</i>MA on the pore walls

Aliphatic Polyester Block Polymer Design

Aliphatic polyester block polymers constitute a highly useful and amazingly versatile class of self-assembled materials. Analogous to styrenic block polymers in both design and function, the property profiles of these degradable materials can be precisely tailored by altering the chemical structure of the components. Driven by this ideal, we have examined the impact of <i>n</i>-alkyl substituents on the polymerization thermodynamics and kinetics of substituted δ-valerolactone monomers and developed guiding design principles based on critical structure–property relationships in the resulting aliphatic polyesters. Under bulk room temperature conditions the polymerization rate depends strongly on substituent position and exhibits a more modest dependence on alkyl length (from −CH₃ to −(CH₂)₈CH₃). The enthalpy and entropy of polymerization are significantly influenced by substituent position, but both are largely insensitive to <i>n</i>-alkyl length. However, the physical properties of the resulting aliphatic polyesters depend much more on substituent length than on substituent position. Notably, we demonstrate that polymer entanglement molar mass and solubility parameter can be systematically tuned by changing the substituent length. We discuss how these key structure property relationships can be used to inform the design of advanced sustainable materials for future technologies important in the arena of environmentally friendly materials

Tuning Mesoporosity in Cross-Linked Nanostructured Thermosets via Polymerization-Induced Microphase Separation

Using the synthetic approach of polymerization-induced microphase separation (PIMS), we prepared cocontinuous and cross-linked nanostructured monoliths from bulk polymerizations of styrene and divinylbenzene (DVB) in the presence of polylactide macro-chain-transfer agents (PLA-CTAs). The resulting monolithic precursors were converted to cross-linked mesoporous materials following hydrolytic degradation of the PLA domain, the morphology and porosity of which were characterized through a combination of small-angle X-ray scattering, scanning electron microscopy, and nitrogen sorption experiments. This report highlights the concept, functionality, and limitations of PIMS for the generation of mesoporous materials through variation of reaction parameters found to strongly influence the porous properties of the matrix: the cross-linker-to-monomer ratio, reaction temperature, molar mass and mass fraction of PLA-CTA, and the reactivity of the DVB isomer. Increases in the cross-linker-to-monomer ratio (≥40 mol % DVB) induced formation of smaller mesopores within the matrix in addition to the principal pore mode largely defined by the molar mass and mass fraction of the PLA-CTA. Higher reaction temperatures and the increased relative reactivity of the <i>p</i>-DVB isomer are shown to influence the matrix integrity, ultimately achieving surface areas as high as 796 m² g^–1 using 8 kg mol^–1 PLA-CTA. In combination, these parameters suggest methods to circumvent limitations of pore collapse associated with concomitant reductions in the molar mass of PLA-CTA

“Uncontrolled” Preparation of Disperse Poly(lactide)-<i>block</i>-poly(styrene)-<i>block</i>-poly(lactide) for Nanopatterning Applications

We report the facile synthesis of well-defined ABA poly­(lactide)-<i>block</i>-poly­(styrene)-<i>block</i>-poly­(lactide) (LSL) triblock copolymers having a disperse poly­(styrene) midblock (<i>Đ</i> = 1.27–2.24). The direct synthesis of telechelic α,ω-hydroxy­poly­(styrene) (HO-PS-OH) midblocks was achieved using a commercially available difunctional free radical diazo initiator 2,2′-azobis­[2-methyl-<i>N</i>-(2-hydroxy­ethyl)­propionamide]. Poly­(lactide) (PLA) end blocks were subsequently grown from HO-PS-OH macroinitiators via ring-opening transesterification polymerization of (±)-lactide using the most common and prevalent catalyst system available, tin­(II) 2-ethylhexanoate. Fourteen LSL triblock copolymers with total molar masses <i>M</i>_n,total = 24–181 kg/mol and PLA volume fractions <i>f</i>_PLA = 0.15–0.68 were synthesized and thoroughly characterized. The self-assembly of symmetric triblocks was analyzed in the bulk using small-angle X-ray scattering and in thin films using grazing incidence small-angle X-ray scattering and atomic force microscopy. We demonstrate both the bulk and thin film self-assembly of LSL disperse triblocks gave well-organized nanostructures with uniform domain sizes suitable for nanopatterning applications

Nanoporous Thermosets with Percolating Pores from Block Polymers Chemically Fixed above the Order–Disorder Transition

A lamellar diblock polymer combining a cross-linkable segment with a chemically etchable segment was cross-linked above its order–disorder temperature (<i>T</i>_ODT) to kinetically trap the morphology associated with the fluctuating disordered state. After removal of the etchable block, evaluation of the resulting porous thermoset allows for an unprecedented experimental characterization of the trapped disordered phase. Through a combination of small-angle X-ray scattering, nitrogen sorption, scanning electron microscopy, and electron tomography experiments we demonstrate that the nanoporous structure exhibits a narrow pore size distribution and a high surface to volume ratio and is bicontinuous over a large sample area. Together with the processability of the polymeric starting material, the proposed system combines attractive attributes for many advanced applications. In particular, it was used to design new composite membranes for the ultrafiltration of water

Bioresorbable Polymersomes for Targeted Delivery of Cisplatin

Nontoxic bioresorbable polymersomes have been developed that efficiently and site-selectively tether targeting peptides under mild conditions with no toxic catalysts. The binding and release properties of these polymersomes have been evaluated when targeting DLD-1 human colon cancer cells overexpressing the α₅β₁ integrin. The delivery efficacy to these cells is markedly improved over commonly used RGD targeting peptides by use of an α₅β₁-specific targeting peptide, PR_b. Release profiles in buffered solution from pH 7.4 to 4.5 were evaluated and compared to release after binding to cells, and enzymatic degradation was identified as a major cause of rapid payload release in the cell. Intracellular trafficking and release were imaged <i>via</i> confocal microscopy in live cells and colocalization with organelles was evaluated quantitatively over time. Finally, the anticancer drug cisplatin was encapsulated in the PR_b functionalized polymersomes and the presence of PR_b greatly improved delivery efficacy, with increased cisplatin-induced losses to targeted DLD-1 colon cancer cell viability. When delivered to CACO-2 model human epithelial cells expressing low levels of α₅β₁ integrin, low toxicity was maintained, suggesting that targeting was specific to α₅β₁ overexpressing cells. These results demonstrate that PR_b-functionalized bioresorbable polymersomes may be an attractive route to minimizing the dose-limiting side effects associated with existing approaches to cisplatin chemotherapy