Triblock Copolymer Gels Research Articles

Local, Sustained, and Targeted Co-Delivery of MEK Inhibitor and Doxorubicin Inhibits Tumor Progression in E-Cadherin-Positive Breast Cancer.

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the α5β1 integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy.

Nanostructure Scaling in Semi‐Dilute Triblock Copolymer Gels

AbstractThere is a considerable body of work that describes the scaling of diblock copolymer micelle dimensions in dilute and semi‐dilute solution based upon block degrees of polymerization and copolymer concentration. However, there is a lack of analogous information for semi‐dilute ABA triblock copolymer gels, which consist of ABA triblock copolymer dissolved in midblock‐selective (B‐selective) solvent. The present study uses small angle X‐ray scattering to extract micelle dimensions for numerous triblock copolymer gels that vary in copolymer identity (and hence block lengths) and copolymer concentration, as well as gels that contain various ratios of two unique triblock copolymers. Analysis of micelle structural data subsequently translates to universal scaling expressions for the micelle core radius – rA ≈ NA0.53NB−0.14ϕABA0.16 where NA and NB are the endblock and midblock degrees of polymerization, respectively, and ϕABA is the volume fraction of triblock copolymer in the gel – and for the intermicelle spacing – lAA ≈ NA0.09NB0.29ϕABA−0.35. Each scaling expression describes the full collection of experimental data very well. Additionally, these scaling expressions are partially in line with expectations from semi‐dilute diblock copolymer solution theory.

Implications of styrenic triblock copolymer gel mechanics on midblock bridging fraction

Triblock copolymer gels have garnered considerable scientific interest over the past few decades and are used in a variety of applications including consumer cushioning, pressure-sensitive adhesives, and ballistics gels. While many of their applications rely upon understanding mechanical properties, mechanical studies of block copolymer gels are relatively disjointed with each focusing on specific copolymers, which inherently have a fixed molecular weight and composition. The present study examines the quasistatic mechanical response of styrenic triblock copolymer gels composed of seven unique triblock copolymers at various concentrations. Resultant stress-extension data is fitted with the slip-tube network (STN) theory that describes gel mechanics based upon crosslinked network (Gc) and chain entanglement (Ge) modulus contributions. Collectively, modulus contributions imply that midblock bridging is independent of copolymer identity (i.e., molecular weight and block fraction) and dependent on triblock copolymer concentration via Fb ∝ φABA0.91±0.39 over the concentration range examined (φABA = 0.05–0.39). Gels composed of a complementary diblock-triblock copolymer pair were subsequently analyzed to explore the influence of interlocking loop-loop and loop-bridge pairs within the effective midblock bridging population. These results point to the presence of a physically significant quantity of interlocked loops, but quantitative analysis was inconclusive.

Design, Physicochemical Characterization, and In Vitro Permeation of Innovative Resatorvid Topical Formulations for Targeted Skin Drug Delivery.

Nonmelanoma skin cancers (NMSCs) are the most common malignancies worldwide and affect more than 5 million people in the United States every year. NMSC is directly linked to the excessive exposure of the skin to solar ultraviolet (UV) rays. The toll-like receptor 4 (TLR4) antagonist, resatorvid (TAK-242), is a novel prototype chemo preventive agent that suppresses the production of inflammation mediators induced by UV exposure. This study aimed to design and develop TAK-242 into topical formulations using FDA-approved excipients, including DermaBaseTM, PENcreamTM, polyethylene glycol (PEG)-400, propylene glycol (PG), carbomer gel, hyaluronic acid (HA) gel, and Pluronic® F-127 poloxamer triblock copolymer gel for the prevention of skin cancer. The physicochemical properties of raw TAK-242, which influence the compatibility and solubility in the selected base materials, were confirmed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Raman spectroscopy, and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopic analysis. The permeation behavior of TAK-242 from the prepared formulations was determined using Strat-M® transdermal diffusion membranes, and 3D cultured primary human-derived epidermal keratinocytes (EpiDermTM). Despite TAK-242′s high molecular weight and hydrophobicity, it can permeate through reconstructed human epidermis from all formulations. The findings, reported for the first time in this study, emphasize the capabilities of the topical application of TAK-242 via these multiple innovative topical drug delivery formulation platforms.

Dynamics of small molecules within the F127 PEO-PPO-PEO triblock copolymer gel and sol phases studied at the molecular scale.

Triplet excited states of guest molecules with different hydrophobicities were used to probe the association and dissociation dynamics of these guests with F127 micelles in the gel and sol phases. The dynamics probed was on a longer length scale than amenable with fluorescence techniques, but at a shorter length scale than probed in translational diffusion studies. The mobility of the guests at the molecular scale showed that subtle changes in the guest's structure affect the guest's release time from the micelles, where the structural features of the guest are more important than the phase, gel vs. sol, of the system.

Capturing the Transient Microstructure of a Physically Assembled Gel Subjected to Temperature and Large Deformation

The microstructure of physically assembled gels depends on mechanical loading and environmental stimuli such as temperature. Here, we report the real-time change in the structure of physically assembled triblock copolymer gels that consist of 10 wt% and 20 wt% of poly(styrene)-poly(isoprene)-poly(styrene) [PS-PI-PS] triblock copolymer in mineral oil (i) during the gelation process with decreasing temperature, (ii) subjected to large oscillatory deformation, and (iii) during the stress-relaxation process after the application of a step-strain. The presence of loosely bounded PS-aggregates at temperatures higher than the rheometrically determined gelation temperature (Tgel) captures the progressive gelation process spanning over a broad temperature range. However, the microstructure fully develops at temperatures suciently lower than Tgel, and the storage modulus (G0 ) also reaches a plateau at those temperatures. The microstructure orients in the stretching direction with the applied strain. In an oscillation strain cycle, such oriented structure has been observed at low-strain. But, at large-strain, the oriented structure splits, and only a fraction of midblock participates in load-bearing. This has been attributed to the endblock pullout from the aggregates, likely caused by the strain localization in the samples. Both microstructure recovery and time-dependent moduli during the stress-relaxation process after the application of a step-strain can be captured using a stretched-exponential model. However, the microstructure recovery time has been found to be two orders of magnitude slower than the stress-relaxation time at room temperature, indicating a complex nature of relaxation process involving midblock relaxation, endblock pullout and reassociation process. Due to their viscoelastic nature, these gels' mechanical responses are sensitive to strain, temperature, and rate of deformation. Therefore, insights into the microstructural information as a function of these parameters will assist these gels' real-life applications and design new gels with improved properties

Small extracellular vesicles in combination with sleep-related circRNA3503: A targeted therapeutic agent with injectable thermosensitive hydrogel to prevent osteoarthritis

Osteoarthritis (OA), characterized by chondrocyte apoptosis and disturbance of the balance between catabolism and anabolism of the extracellular matrix (ECM), is the most common age-related degenerative joint disease worldwide. As sleep has been found to be beneficial for cartilage repair, and circular RNAs (circRNAs) have been demonstrated to be involved in the pathogenesis of OA, we performed RNA sequencing (RNA-seq), and found circRNA3503 was significantly increased after melatonin (MT)-induced cell sleep. Upregulation of circRNA3503 expression completely rescued the effects of interleukin-1β (IL-1β), which was used to simulate OA, on apoptosis, ECM degradation- and synthesis-related genes. Mechanistically, circRNA3503 acted as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p. Moreover, as we previously showed that small extracellular vesicles (sEVs) derived from synovium mesenchymal stem cells (SMSCs) can not only successfully deliver nucleic acids to chondrocytes, but also effectively promote chondrocyte proliferation and migration, we assessed the feasibility of sEVs in combination with sleep-related circRNA3503 as an OA therapy. We successfully produced and isolated circRNA3503-loaded sEVs (circRNA3503-OE-sEVs) from SMSCs. Then, poly(D,l-lactide)-b-poly(ethylene glycol)-b-poly(D,l-lactide) (PDLLA-PEG-PDLLA, PLEL) triblock copolymer gels were used as carriers of sEVs. Through in vivo and in vitro experiments, PLEL@circRNA3503-OE-sEVs were shown to be a highly-effective therapeutic strategy to prevent OA progression. Through multiple pathways, circRNA3503-OE-sEVs alleviated inflammation-induced apoptosis and the imbalance between ECM synthesis and ECM degradation by acting as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p. In addition, circRNA3503-OE-sEVs promoted chondrocyte renewal to alleviate the progressive loss of chondrocytes. Our results highlight the potential of PLEL@circRNA3503-OE-sEVs for preventing OA progression.

Concentration-Dependent Mechanical Behavior of Physically Assembled Triblock Copolymer Gels

Physically assembled gels have promising applications in many fields because of their tunable mechanical properties. Here, we report the mechanical properties as a function of polymer volume fracti...

Mechanical Properties and Failure Behavior of Physically Assembled Triblock Copolymer Gels with Varying Midblock Length

ABSTRACTMechanical properties including the failure behavior of physically assembled gels or physical gels are governed by their network structure. To investigate such behavior, we consider a physical gel system consisting of poly(styrene)‐poly(isoprene)‐poly(styrene)[PS‐PI‐PS] in mineral oil. In these gels, the endblock (PS) molecular weights are not significantly different, whereas, the midblock (PI) molecular weight has been varied such that we can access gels with and without midblock entanglement. Small angle X‐ray scattering data reveals that the gels are composed of collapsed PS aggregates connected by PI chains. The gelation temperature has been found to be a function of the endblock concentration. Tensile tests display stretch‐rate dependent modulus at high strain for the gels with midblock entanglement. Creep failure behavior has also been found to be influenced by the entanglement. Fracture experiments with predefined cracks show that the energy release rate scales linearly with the crack‐tip velocity for all gels considered here. In addition, increase of midblock chain length resulted in higher viscous dissipation leading to a higher energy release rate. The results provide an insight into how midblock entanglement can possibly affect the mechanical properties of physically assembled triblock copolymer gels in a midblock selective solvent. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys.2019,57, 1014–1026

Effect of Polymer Volume Fraction on Fracture Initiation in Soft Gels at Small Length Scales.

The influence of polymer volume fraction, ϕv on fracture initiation via puncture is studied in self-assembled triblock copolymer gels. Spherically tipped indenters of radii varying over a wide range were used to characterize puncture at length scales on the same order of magnitude as the elasto-capillary length (∼μm) and significantly below the elasto-fracture length (∼mm) for ϕv = 0.12-0.53. Critical energy release rate, Gc for ϕv = 0.12-0.30 was found to be in agreement with the predicted scaling from the classical Lake-Thomas model modified for gel fracture via the failure mechanism of chain pull-out and plastic yielding of micelles (Gc ∼ ϕv2.2). Interestingly, we demonstrate that fracture initiation energy, o, from puncture scales as o ∼ ϕv, thus, indicating the role played by different fundamental mechanisms governing fracture initiation in soft gels. Additionally, gels with ϕv = 0.53 show deviation from experimental scalings for Gc and o, likely due to a change in micellar morphology leading to anomalous fracture behavior.

Effect of far-field compliance on local failure dynamics of soft solids

The resistive forces and failure of a soft gel upon large strain indentation with small, spherically-tipped indenters (or puncture mechanics) has been studied previously by Fakhouri et al., (2015). The above work is extended to include the effect of far-field compliance on the critical crack initiation event via puncture in soft acrylic triblock copolymer gels. It is found that critical puncture force, Pc, reduces with increasing far-field compliance, Cs, due to the change in local probe velocity, vg. A power-law relation between Pc and Cs is established and is shown to be valid across a range of global probe velocity, vc, varied over three orders of magnitude. Small-strain mechanical response of the gels characterized via oscillatory shear rheology and large strain response measured from puncture mechanics show rate-independent behavior. Our experiments and analysis provide insight into local rate-dependent failure processes in elastic triblock copolymer gels.

Nanostructured DPA-MPC-DPA triblock copolymer gel for controlled drug release of ketoprofen and spironolactone.

Uncontrolled rapid release of drugs can reduce their therapeutic efficacy and cause undesirable toxicity; however, controlled release from reservoir materials helps overcome this issue. The aims of this study were to determine the release profiles of ketoprofen and spironolactone from a pH-responsive self-assembling DPA-MPC-DPA triblock copolymer gel and elucidate underlying physiochemical properties. Drug release profiles from DPA50 -MPC250 -DPA50 gel (pH 7.5), over 32 h (37 °C), were determined using UV-Vis spectroscopy. Nanoparticle size was measured by dynamic light scattering (DLS) and critical micelle concentration (CMC) by pyrene fluorescence. Polymer gel viscosity was examined via rheology, nanoparticle morphology investigated using scanning transmission electron microscopy (STEM) and the gel matrix observed using cryo-scanning electron microscopy (Cryo-SEM). DPA50 -MPC250 -DPA50 copolymer (15% w/v) formed a free-standing gel (pH 7.5) that controlled drug release relative to free drugs. The copolymer possessed a low CMC, nanoparticle size increased with copolymer concentration, and DLS data were consistent with STEM. The gel displayed thermostable viscosity at physiological temperatures, and the gel matrix was a nanostructured aggregation of smaller nanoparticles. The DPA50 -MPC250 -DPA50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone.

Temperature-dependent self-assembly and rheological behavior of a thermoreversible pmma-PnBA-PMMA triblock copolymer gel

Self-assembly and mechanical properties of triblock copolymers in a mid-block selective solvent are of interest in many applications. Herein, we report physical assembly of an ABA triblock copolymer, [PMMA–PnBA–PMMA] in two different mid-block selective solvents, n-butanol and 2-ethyl-1-hexanol. Gel formation resulting from end-block associations and the corresponding changes in mechanical properties have been investigated over a temperature range of −80 °C to 60 °C, from near the solvent melting points to above the gelation temperature. Shear-rheometry, thermal analysis, and small-angle neutron scattering data reveal formation and transition of structure in these systems from a liquid state to a gel state to a percolated cluster network with decrease in temperature. The aggregated PMMA end-blocks display a glass transition temperature. Our results provide new understanding into the structural changes of a self-assembled triblock copolymer gel over a large length scale and wide temperature range. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2017, 55, 877–887

Nonlinear elasticity and cavitation of a triblock copolymer gel.

Polymer gels are subjected to large-strain deformation during their applications. The gel deformation at large-strain is non-linear and can often lead to failure of the material. Here, we report the large-strain deformation behavior of a physically cross-linked, swollen triblock copolymer gel, which displays unique strain-stiffening response at large-strain. Investigations were performed using large amplitude oscillatory shear (LAOS) and custom developed cavitation rheology techniques. The Gent constitutive equation, which considers finite extensibility of midblock, was fitted with the LAOS data, thereby, linking the estimated parameters from LAOS analysis to the structure of the gel. The pressure responses obtained from the cavitation experiments were modeled using neo-Hookean and Gent constitutive equations. Our results capture the failure behavior of a gel with finite chain extensibility, initiated from a defect within the gel.

Effect of graphene on the self-assembly and rheological behavior of a triblock copolymer gel

Self-assembly and the mechanical properties of graphene containing physical gels are reported in this work.

Fracture-Healing Kinetics of Thermoreversible Physical Gels Quantified by Shear Rheophysical Experiments.

The fracture-healing behavior of model physically associating triblock copolymer gels was investigated with experiments coupling shear rheometry and particle tracking flow visualization. Fractured gels were allowed to rest for specific time durations, and the extent of strength recovered during the resting time was quantified as a function of temperature (20-28 °C) and gel concentration (5-6 vol %). Measured times for full strength recovery were an order of magnitude greater than characteristic relaxation times of the system. The Arrhenius activation energy for post-fracture strength recovery was found to be greater than the activation energy associated with stress relaxation, most likely due to the entropic barrier related to the healing mechanism of dangling chain reassociation with network junctions.

The effect of polymer chain length on the mechanical properties of triblock copolymer gels

An ABA triblock copolymer in a midblock selective solvent is studied as a function of the chain length, using a novel dissipative particle dynamics (DPD) model which includes a modified segmental repulsive potential (mSRP) that restricts chain crossing. Deformation under uniaxial tension using the DPD method, with and without the mSRP, was used to extract the cross-link and entanglement portions of the modulus. The results exhibit the expected theoretical scaling with chain length for lower strain rates. Structural properties, such as bridge fraction and the extent of entanglements in the polymer matrix, were also quantified.

Computational study of the morphology and mechanical properties of dilute ABC triblock copolymers

Dissipative particle dynamics was used to predict the morphology and mechanical properties of unentangled linear ABC triblock copolymer gels, where the midblock is solvophilic. By varying the A, B, and C fraction in the triblock, we observe a variety of multicomponent micelles in addition to singular A and C micelles. These multicomponent micelles include sphere-on-sphere micelles, multi-sphere-on-sphere, worm-like micelles, and branched micelles. Simulation cells were also subjected to deformation under uni-axial tension, and correlated to the extent of macrophase separation. Values of elastic modulus were also extracted from the calculated stress using the theory of linear elasticity. Extracted values of the modulus are shown to scale inversely with the midblock length which agrees with other theoretical predictions.

Mechanical Properties of Designed Multicompartment Gels Formed by ABC Graft Copolymers

In the present work, we designed a multicompartment gel by taking advantage of the ABC graft copolymer with a solvophilic A backbone and solvophobic B and C grafts. The mechanical properties of such designed gels were investigated by a combination of dissipative particle dynamics simulation and a nonequilibrium deformation technique. The extensional moduli of multicompartment gels were found to be dependent on polymer concentration and architectural parameters of the graft copolymers (the sequence of graft arms and the position of the graft points). The graft copolymer solutions undergo a sol-gel transition as the polymer concentration increases. This leads to an abrupt increase in the extensional modulus. The studies also revealed that the multicompartment gels of graft copolymers exhibit higher extensional moduli than those of nonmulticompartment gels of graft copolymers and triblock copolymer gels. The position of graft points plays another important role in determining the extensional moduli of the multicompartment gels. The effects of graft positions on the gel modulus were found to be associated with the bridging fraction of graft copolymer chains. The results gained through the present work may provide useful guidance for designing high-performance gels.

Entangled triblock copolymer gel: Morphological and mechanical properties

The morphological and mechanical properties of entangled ABA triblock copolymer gels, where solvent were selective to the midblock, were studied as a function of polymer concentration using a novel dissipative particle dynamics model which includes a modified segmental repulsive potential that restricts chain crossing. Morphological properties, such as micelle size, distance between micelles, and the bridge fraction, were calculated as a function of concentration. Although the micelle size was shown to have a strong dependence on concentration, the bridge fraction and distance between micelles were shown to plateau at moderate concentrations. Deformation under uni-axial tension was also performed to extract the cross-link and entanglement contribution to the elastic modulus. Scaling results qualitatively agree with other theoretical predications.