Star-shaped Poly Research Articles

Synergistic Effect of Multi-Arm Architecture and Molecular Weight on Crystallization and Degradation Behavior of Star-Shaped Poly(Lactic Acid)

Synergistic Effect of Multi-Arm Architecture and Molecular Weight on Crystallization and Degradation Behavior of Star-Shaped Poly(Lactic Acid)

Synthesis of miktoarm star-shaped polymers with polyoxazoline arms and macrocyclic calix[8]arene branching center

A novel approach to the synthesis of miktoarm star-shaped poly(2-alkyl-2-oxazolines) with calix[8]arene core was developed using a combination of the “core first” (grafting from) and “grafting onto” methods. The star-shaped polymers of A8B8 type with grafted poly(2-ethyl-2-oxazoline) and poly(2-isopropyl-2-oxazoline) arms were obtained using calix[8]arene based multifunctional branching center with sulfonyl chloride initiating moieties and as well as acyl hydrazide termination ones. The polymer structure has been confirmed by 1H NMR spectroscopy and UV spectroscopy. The molar mass characteristics of the samples were determined by size-exclusion chromatographic and light scattering. It was experimentally confirmed that all synthesized polymers had the target arm number, namely 8 or 16. The obtained miktoarm stars were characterized by narrow molar mass distributions, and the polymerization degree of the arms was 15. The synthesized stars had a high intramolecular density, which increased with the arm number. It is shown that the thermoresponsiveness of the studied stars depends on the number and structure of arms and on intramolecular density, while molecular mass is not a decisive factor determining their LCST behavior.For miktoarm stars, phase separation temperatures do not depend on the grafting configuration of poly(2-ethyl-2-oxazoline) and poly(2-isopropyl-2-oxazoline) on the upper or lower rim of calix[8]arene.

Degradable 4D-printed hydration-driven actuators from a single family of amphiphilic star-shaped copolymers

Actuators are largely used in biomedical applications in the presence of sensitive live cells or biomolecules, which makes actuators triggered by water uptake highly appealing. Dual-material printing and hydration driven expansion is a method of choice to produce such actuators, but mostly rely of non-degradable polymers or on the combination of polymers of different nature that may lead to interface incompatibilities. To overcome this challenge, we report here on two photocrosslinkable resins based on a single family of degradable hydrophilic or hydrophobic star-shaped poly(ethylene glycol)-poly(lactide) copolymers. The two materials are first printed individually and characterized to ensure that their properties enable the printing of dual material objects by stereolithographic digital-light processing. Dual-materials actuators are then printed by sequential switching of the hydrophobic and hydrophilic resin baths. Objects of simple and complex shapes are easily obtained and exhibit rapid actuation (<60 s) upon hydration. The swelling-induced shape changes are accurately reproduced by numerical modeling of the printed geometries using the obtained material swelling properties. This set of results offers new perspectives to develop 4D-printed temporary medical devices.

Cucurbit[8]uril Mediated Supramolecular and Photocrosslinked Interpenetrating Network Hydrogel Matrices for 3D-Bioprinting.

Printing of biologically functional constructs is significant for applications in tissue engineering and regenerative medicine. Designing bioinks remains remarkably challenging due to the multifaceted requirements in terms of the physical, chemical, and biochemical properties of the three-dimensional matrix, such as cytocompatibility, printability, and shape fidelity. In order to promote matrix and materials stiffness, while not sacrificing stress relaxation mechanisms which support cell spreading, migration, and differentiation, this work reports an interpenetrating network (IPN) bioink design. The approach makes use of a chemically defined network, combining physical and chemical crosslinking units with a tunable composition and network density, as well as spatiotemporal control over post-assembly material stiffening. To this end, star-shaped poly(ethylene glycol)s functionalized with Phe-Gly-Gly tripeptide or photoactive stilbazolium are synthesized, and used to prepare three-dimensional networks with cucurbit[8]uril (CB[8]) through supramolecular host-guest complexation. The hydrogel obtained shows fast relaxation and thus supports the proliferation and differentiation of cells. Upon irradiation, the mechanical properties of the hydrogel can be rapidly adapted via selective photochemical dimerization of stilbazolium within CB[8], leading to IPNs with increased form stability while retaining the dynamic nature of the hydrogels. This modular approach opens new design opportunities for extrudable and cell-friendly dynamic biomaterials for applications in 3D-bioprinting.

Disulfide-Cross-Linked Tetra-PEG Gels.

The preparation of polymer gels via cross-linking of four-arm star-shaped poly(ethylene glycol) (Tetra-PEG) precursors is an attractive strategy to prepare networks with relatively well-defined topologies. Typically, Tetra-PEG gels are obtained by cross-linking heterocomplementary reactive Tetra-PEG precursors. This study, in contrast, explores the cross-linking of self-reactive, thiol-end functional Tetra-PEG macromers to form disulfide-cross-linked gels. The structure of the disulfide-cross-linked Tetra-PEG gels was studied with multiple-quantum NMR (MQ-NMR) spectroscopy and small-angle neutron scattering (SANS) experiments. In line with earlier simulation studies, these experiments showed a strong dependence of the relative fractions of the different network connectivities on the concentration of the thiol-end functional Tetra-PEG macromer that was used for the synthesis of the networks. Disulfide-cross-linked Tetra-PEG gels prepared at macromer concentrations below the overlap concentration (c = 0.66c*) primarily feature defect connectivity motifs, such as primary loops and dangling ends. For networks prepared at macromer concentrations above the overlap concentration, the fraction of single-link connectivities was found to be similar to that in amide-cross-linked Tetra-PEG gels obtained by heterocomplementary cross-linking of N-hydroxysuccinimide ester and amine functional Tetra-PEG macromers. Since disulfide bonds are susceptible to reductive cleavage, these disulfide-cross-linked gels are of interest, e.g., as reduction-sensitive hydrogels for a variety of biomedical applications.

Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy.

In the face of severe side effects of systemic chemotherapy used in cervical cancer, topical selective drug carriers with long-lasting effects are being sought. Hydrogels are suitable platforms, but their use is problematic in the case of delivery of hydrophobic drugs with anticancer activity. Herein, hydrogels constructed of unimolecular micelles displaying enhanced solubilization of aromatic lipophilic bioactive compounds are presented. Star-shaped poly(benzyl glycidyl ether)-block-poly(glycidyl glycerol ether) with an aryl-enriched core show high encapsulation capacity of poor water-soluble nifuratel and clotrimazole. Nifuratel attained selectivity against cervical cancer cells, whereas clotrimazole preserved its original selectivity. The combination of unimolecular micelles loaded with both drugs provided synergism; however, they were still selective against cervical cancer cells. The cross-linking of drug-loaded unimolecular micelles via dynamic boronic esters provided injectable and self-healable hydrogel drug carriers also displaying synergistic anticancer activity, suitable for intravaginal administration and assuring the effective coverage of the afflicted tissue area and efficient tissue permeability with hydrophobic bioactive compounds. Here, we show that the combination of star-shaped polyether amphiphiles and boronic ester cross-linking chemistry provides a new strategy for obtaining hydrogel platforms suitable for efficient hydrophobic drug delivery.

Complexation of poly(methacrylic acid) star polyelectrolytes with lysozyme

Protein-polyelectrolyte complexes are of great interest due to their applications in both biological and industrial systems. This study focuses on investigating the electrostatic complexation between (hen egg white) lysozyme (LYZ), a well-studied enzyme, and two star-shaped poly(methacrylic acid) (PMAA) polymers with different arm molar masses, namely S-PMAA5K and S-PMAA10K. Depending on the mixing ratio of the two components (protein/star polyelectrolyte) either stable solutions were formed or macroscopic phase separation, i.e. coacervation, was observed. Dynamic and electrophoretic light scattering results reveal that the overall physicochemical properties of the complexes and the strength of the interaction depends on the ratio of the two components as well as on the molar mass of the polymer, with the S-PMAA10K series exhibiting stronger interactions compared to S-PMAA5K. Additional information regarding the molar mass of the star polyelectrolytes and the corresponding complexes with lysozyme were acquired by analytical ultracentrifugation. The morphology of the complexes was further elucidated through atomic force and cryo-transmission electron microscopy showing globular raspberry-like objects. Moreover, fluorescence and infrared spectroscopic techniques were employed to explore potential conformational changes of the protein upon complexation, with both techniques indicating that the protein does not undergo significant structural changes. Furthermore, UV–Vis spectroscopy was utilized to quantify the amount of protein present in the supernatant of the coacervated complex solutions, thus allowing the quantification of the unbound protein remaining in the solution after complex formation.

Synthesis of star-shaped poly(lactide)s, poly(valerolactone)s and poly(caprolactone)s via ROP catalyzed by N-donor tin(ii) cations and comparison of their wetting properties with linear analogues.

In this study, we report the use of N-coordinated tin(ii) cations [L1→Sn(H2O)][OTf]2·THF (1) and [L1→SnCl][SnCl3] (2) (L1 = 1,2-(C5H4N-2-CH = N)2CH2CH2) as efficient ROP catalysts, which, in combination with benzyl alcohol, afford well-defined linear poly(ε-caprolactone) (PCL) and poly(δ-valerolactones) (PVL) via an activated monomer mechanism (AMM). Thanks to the versatility of complexes 1 and 2 as catalysts, star-shaped PCL, PVL and PLA were also prepared using three-, four-, five- and six-functional alcohols. The number of arms was determined by SEC-MALS-Visco analysis. Spin-coated thin layers of linear and selected six-armed polymers were further studied in terms of their wettability to water. Attention was focused on the influence of the composition and structure of the polymers. Finally, to increase the hydrophobic properties of the studied polymers, stannaboroxines L2(Ph)Sn[(OB-(C6H4-4-CF3))2O] and L2(Ph)Sn[(OB-(C6H4-3,5-CF3)2)2O] (L2 = C6H3-2,6-(Me2NCH2)2) were applied.

Self-assembled PHEA-based block copolymers for the synthesis of gold nanoparticles

Copolymer based on poly(2-hydroxyethyl acrylate) comprising cholesteryl and cholic acid and their participation in forming AuNPs.

Modeling Acute Myeloid Leukemia Using StarPEG-Heparin Hydrogels.

Biomimetic semi-synthetic hydrogels formed from a combination of star-shaped poly(ethylene glycol) (starPEG) and the glycosaminoglycan, heparin, allows for the three-dimensional (3D) culture of various cells and tissues. In this chapter, we describe methods for the use of starPEG-heparin hydrogels to cultivate primary and immortalized human acute myeloid leukemia (AML) cells. The resulting 3D culture models allow for the study of AML development and response to chemotherapeutic agents.

Molecular structure design and epoxy functional modification of star-shaped poly(lactic acid) by a melt polycondensation strategy

PET and SB were used as core molecules for melt polycondensation with LA. The 6PLAs was solution-grafted with AGE, which is flexible and difficult to self-polymerize, resulting in the preparation of 6PLAs-g-AGE with an epoxy value of 0.293 mol/100 g.

PH-responsive star-shaped poly (ε-carprolactone)-co-poly maleic anhydride micelles for synergistic breast cancer combination chemotherapy

Polymeric micelles produced from amphiphilic copolymers, are considered promising drug delivery platforms. Because of their ability to co-deliver hydrophilic (Dox) and hydrophobic (natural sesquiterpene coumarin, Conf) drugs through their shell and core, these nanosized micelles can benefit adjuvant therapy by modulating MDR proteins and increasing cellular uptake. In this study, a novel star-shaped biodegradable pH-sensitive pentaerythritol-grafted anhydride maleic copolymerized with Poly(ε-caprolactone) (PEE-g-PMA-co-PCL) was synthesized and developed as micellar nano-carriers for combination therapy of MDA-MB-231 breast cancer cell line. The physicochemical, characteristics of the synthesized copolymers and micelles were validated using Nuclear Magnetic Resonance Spectroscopy (NMR), Fourier Transform Infrared Spectroscopy (FTIR), CHNS elemental analysis, Dynamic Light Scattering (DLS), Zeta potential, Scanning Electron Microscopy (SEM), and Differential Scanning Calorimetry (DSC). The engineered micelles exhibited nearly 100% encapsulation efficiency for both Dox and Conf. Micelles possess a CMC value of 0.1 μg/mL, an average size of 40.3 nm with uniform distribution; ζ-potential of −11.5 mV in blank form and + 6.82 mV in co-drug-loaded form. Furthermore, micelles' in vitro biodegradation and drug release profiles followed an intensive pH-dependent pattern that benefited targeted delivery. The results of MTT, cellular uptake, cell cycle, and apoptosis by Annexin V assay on MDA-MB-231 cell line cells treated by co-drug loaded micelles (E2D) demonstrated higher cytotoxicity, more cellular uptake, superior inhibitory yield on DNA duplication, and greater apoptosis with a lower necrosis rate compared to monotherapy (ED and EC) and free drugs (Conf, Dox and 2D) which confirmed the synergistic effect of this combination therapy system (CI < 1) in a reduced Dox dosage. In addition, western blot and RT-PCR showed that co-drug-loaded micelles triggered an apoptotic response via the mitochondrial pathway. In conclusion, the novel developed multi-functional pH-sensitive micelles here could open a new perspective for the development of nanomedicine for combination chemo-adjuvant therapy against malignant cancer.

Thermoresponsive DNA hydrogels through hydrophilic pre-polymer cross-linker and self-assembly

Denatured DNA molecules were used as building blocks to fabricate thermoresponsive hydrogels by cross-linking DNA strands with an isocyanate (NCO) end-capped star-shaped poly(EO-stat-PO) cross-linker. The NCO groups reacted with the amine groups of DNA’s bases through urea links while base pairing between the matching strands of DNA led to the self-assembly of DNA into a three-dimensional hydrogel network. Analysis of the ultrastructure by scanning force microscopy (SFM) revealed the temperature-mediated transition from the rod-to-coil structure as a result of the destabilization of double-stranded DNA (dsDNA) to form a single-stranded DNA (ssDNA), which eventually resulted in a DNA network due to base pairing, along with hairpin loops due to mismatches between nucleotides. Dynamic oscillatory and large deformation creep tests, as well as stress relaxation tests, revealed the formation of robust cross-linked gels: A ten-fold rise in the elastic modulus was observed for the covalent DNA gel compared to the physical gel at the identical DNA concentration. The thermoresponsiveness of the hydrogels was confirmed by a heating–cooling cycle while the non-porous internal morphology of the hydrogel was demonstrated through scanning electron microscopic analysis. Overall, this is the first study showing the fabrication of covalent DNA hydrogels using an NCO-end-capped hydrophilic prepolymer. Such gels have a high potential to be exploited in many fields to benefit from the structural properties of DNA molecules.

Asymmetric Block Extension of Star-Shaped [PEG-SH]4 - toward Poly(dehydroalanine)-Functionalized PEG Hydrogels for Catch and Release of Charged Guest Molecules.

With the incorporation of polyampholytic segments into soft matter, hydrogels can serve as a reservoir for a variety of charged molecules which can be caught and released upon changes in pH value. Asymmetric block extension of one arm for star-shaped poly(ethylene glycol) [PEG26 -SH]4 using short segments of polyampholytic poly(dehydroalanine) (PDha) is herein demonstrated while maintaining the functional thiol end groups for network formation. For subsequent hydrogel synthesis with up to 10wt.% PDha a straightforward and biocompatible photoinitiated thiol-ene click reaction is exploited. The investigation of the swelling properties of the hydrogel revealed responsive behavior toward ionic strength and variations in pH value. Moreover, the reversible adsorption of the model dyes methylene blue (MB) and acid orange 7 (AO7) is investigated by UV-vis measurements and the procedure can be successfully transferred to the adsorption of the adhesion peptide RGDS resulting in an uptake of 1.5 wt% RGDS with regard to the dry weight of the hydrogel.

Star-Shaped Thermoplastic Elastomers Prepared via RAFT Polymerization.

Styrene-based thermoplastic elastomers (TPEs) demonstrate excellent overall performance and account for the largest industrial output. The traditional methods of preparation styrene-based thermoplastic elastomers mainly focused on anionic polymerization, and strict equipment conditions were required. In recent years, controlled/living radical polymerization (CRP) has developed rapidly, enabling the synthesis of polymers with various complex topologies while controlling their molecular weight. Herein, a series of core crosslinked star-shaped poly(styrene-b-isoprene-b-styrene)s (SISs) was synthesized for the first time via reversible addition-fragmentation chain transfer (RAFT) polymerization. Meanwhile, linear triblock SISs with a similar molecular weight were synthesized as a control. We achieved not only the controlled/living radical polymerization of isoprene but also investigated the factors influencing the star-forming process. By testing the mechanical and thermal properties and characterizing the microscopic fractional phase structure, we found that both the linear and star-shaped SISs possessed good tensile properties and a certain phase separation structure, demonstrating the characteristics of thermoplastic elastomers.

Crystallization of Star-Shaped Poly(l-lactide)s with Arm Chains Aligned in the Same Direction in Two-Dimensional Crystals in a Langmuir Monolayer

Polylactide (PLA) crystallizes to form extended-chain crystals in a Langmuir monolayer because crystallization is accelerated on the water surface. This is a unique situation where chain packing can be analyzed by simply measuring the lamellar thickness. Herein, star-shaped poly(l-lactide)s (PLLAs) with 2-12 arms were synthesized through the polymerization of l-lactide with various polyols as initiators, and their crystallization behavior in a monolayer was studied via atomic force microscopy. The PLLAs comprising 2-4 arms crystallized with all arms aligned in the same direction and being folded at the central polyol unit. Meanwhile, the PLLAs comprising 6 and 12 arms crystallized with both halves of the arms extended from the center to the opposite directions, most likely due to the steric hindrance of the crowded arms. Considering that the PLLAs crystallized from a once-formed condensed amorphous state during compression, they have a strong tendency to crystallize with the arms aligned in the same direction. The crystallization rate of star-shaped PLAs is known to reduce compared with that of a linear PLA even if the number of arms is as few as 2. This should be closely related to the unique crystallization behavior of the star-shaped PLLAs with the arms aligned in the same direction.

Sustained Release of Human Adipose Tissue Stem Cell Secretome from Star-Shaped Poly(ethylene glycol) Glycosaminoglycan Hydrogels Promotes Motor Improvements after Complete Transection in Spinal Cord Injury Rat Model.

Adipose tissue-derived stem cells (ASCs) have been shown to assist regenerative processes after spinal cord injury (SCI) through their secretome, which promotes several regenerative mechanisms, such as inducing axonal growth, reducing inflammation, promoting cell survival, and vascular remodeling, thus ultimately leading to functional recovery. However, while systemic delivery (e.g., i.v. [intravenous]) may cause off-target effects in different organs, the local administration has low efficiency due to fast clearance by body fluids. Herein, a delivery system for human ASCs secretome based on a hydrogel formed of star-shaped poly(ethylene glycol) (starPEG) and the glycosaminoglycan heparin (Hep) that is suitable to continuously release pro-regenerative signaling mediators such as interleukin (IL)-4, IL-6, brain-derived neurotrophic factor, glial-cell neurotrophic factor, and beta-nerve growth factor over 10 days, is reported. The released secretome is shown to induce differentiation of human neural progenitor cells and neurite outgrowth in organotypic spinal cord slices. In a complete transection SCI rat model, the secretome-loaded hydrogel significantly improves motor function by reducing the percentage of ameboid microglia and systemically elevates levels of anti-inflammatory cytokines. Delivery of ASC-derived secretome from starPEG-Hep hydrogels may therefore offer unprecedented options for regenerative therapy of SCI.

Exploring the Potential of PEG-Heparin Hydrogels to Support Long-Term Ex Vivo Culture of Patient-Derived Breast Explant Tissues.

Breast cancer is a complex, highly heterogenous, and dynamic disease and the leading cause of cancer-related death in women worldwide. Evaluation of the heterogeneity of breast cancer and its various subtypes is crucial to identify novel treatment strategies that can overcome the limitations of currently available options. Explant cultures of human mammary tissue have been known to provide important insights for the study of breast cancer structure and phenotype as they include the context of the surrounding microenvironment, allowing for the comprehensive exploration of patient heterogeneity. However, the major limitation of currently available techniques remains the short-term viability of the tissue owing to loss of structural integrity. Here, an ex vivo culture model using star-shaped poly(ethylene glycol) and maleimide-functionalized heparin (PEG-HM) hydrogels to provide structural support to the explant cultures is presented. The mechanical support allows the culture of the human mammary tissue for up to 3 weeks and prevent disintegration of the cellular structures including the epithelium and surrounding stromal tissue. Further, maintenance of epithelial phenotype and hormonal receptors is observed for up to 2 weeks of culture which makes them relevant for testing therapeutic interventions. Through this study, the importance of donor-to-donor variability and intra-patient tissue heterogeneity is reiterated.

Star-shaped poly(l-lysine) with polyester bis-MPA dendritic core as potential degradable nano vectors for gene delivery

Efficient initiation from ammonium trifluoroacetate salts (TFA) dendritic end-groups yields well-defined poly(l-lysine) star polypeptides with 8, 16 and 32 arms. Hydrolytic core degradation and plasmid DNA complexation is demonstrated.

A Tumor Microenvironment Model of Pancreatic Cancer to Elucidate Responses toward Immunotherapy.

Pancreatic cancer is a devastating malignancy with minimal treatment options. Standard-of-care therapy, including surgery and chemotherapy, is unsatisfactory, and therapies harnessing the immune system have been unsuccessful in clinical trials. Resistance to therapy and disease progression are mediated by the tumor microenvironment, which contains excessive amounts of extracellular matrix and stromal cells, acting as a barrier to drug delivery. There is a lack of preclinical pancreatic cancer models that reconstruct the extracellular, cellular, and biomechanical elements of tumor tissues to assess responses toward immunotherapy. To address this limitation and explore the effects of immunotherapy in combination with chemotherapy, a multicellular 3D cancer model using a star-shaped poly(ethylene glycol)-heparin hydrogel matrix is developed. Human pancreatic cancer cells, cancer-associated fibroblasts, and myeloid cells are grown encapsulated in hydrogels to mimic key components of tumor tissues, and cell responses toward treatment are assessed. Combining the CD11b agonist ADH-503 with anti-PD-1 immunotherapy and chemotherapy leads to a significant reduction in tumor cell viability, proliferation, metabolic activity, immunomodulation, and secretion of immunosuppressive and tumor growth-promoting cytokines.