Maleimide functionalized polycaprolactone micelles for glutathione quenching and doxorubicin delivery.

High glutathione production is known to be one of the defense mechanisms by which many cancer cells survive elevated oxidative stress. By explicitly targeting glutathione in these cancer cells and diminishing its levels, oxidative stress can be intensified, ultimately triggering apoptosis or programmed cell death. Herein, we developed a novel approach by creating maleimide-functionalized polycaprolactone polymers, specifically using 2,3-diiodomaleimide functionality to reduce the level of glutathione in cancer cells. Polycaprolactone was chosen to conjugate the 2,3-diiodomaleimide functionality due to its biodegradable and biocompatible properties. The amphiphilic block copolymer was synthesized using PEG as a macroinitiator to make corresponding polymeric micelles. The resulting 2,3-diiodomaleimide-conjugated polycaprolactone micelles effectively quenched glutathione, even at low concentrations (0.01 mg mL-1). Furthermore, we loaded these micelles with the anticancer drug doxorubicin (DOX), which exhibited pH-dependent drug release. We obtained a loading capacity (LC) of 3.5% for the micelles, one of the highest LC reported among functional PCL-based micelles. Moreover, the enhanced LC doesn't affect their release profile. Cytotoxicity experiments demonstrated that empty and DOX-loaded micelles inhibited cancer cell growth, with the DOX-loaded micelles displaying the highest cytotoxicity. The ability of the polymer to quench intracellular GSH was also confirmed. This approach of attaching maleimide to polycaprolactone polymers shows promise in depleting elevated glutathione levels in cancer cells, potentially improving cancer treatment efficacy.

Effect of aromatic substituents on thermoresponsive functional polycaprolactone micellar carriers for doxorubicin delivery.

Amphiphilic functional polycaprolactone (PCL) diblock copolymers are excellent candidates for micellar drug delivery. The functional groups on the backbone significantly affect the properties of PCL. A systematic investigation of the effect of aromatic substituents on the self-assembly of γ-functionalized PCLs and the delivery of doxorubicin (DOX) is presented in this work. Three thermoresponsive amphiphilic diblock copolymers with poly(γ-benzyloxy-ε-caprolactone) (PBnCL), poly(γ-phenyl- ε-caprolactone) (PPhCL), poly(γ-(4-ethoxyphenyl)-ε-caprolactone) (PEtOPhCL), respectively, as hydrophobic block and γ-tri(ethylene glycol) functionalized PCL (PME3CL) as hydrophilic block were prepared through ring-opening polymerization (ROP). The thermoresponsivity, thermodynamic stability, micelle size, morphology, DOX-loading, and release profile were determined. The LCST values of amphiphilic diblock copolymers PME3CL-b-PBnCL, PME3CL-b-PPhCL, and PME3CL-b-PEtOPhCL are 74.2°C, 43.3°C, and 37.3°C, respectively. All three copolymers formed spherical micelles in phosphate-buffered saline (PBS, 1×, pH = 7.4) at low concentrations ranging from 8.7 × 10-4 g/L to 8.9 × 10-4 g/L. PME3CL-b-PBnCL micelles showed the highest DOX loading capacity of 3.01 ± 0.18 (wt%) and the lowest drug release, while PME3CL-b-PEtOPhCL micelles exhibited the lowest DOX loading capacity of 1.95 ± 0.05 (wt%) and the highest drug release. Cytotoxicity and cellular uptake of all three micelles were assessed in vitro using MDA-MB-231 breast cancer cells. All three empty micelles did not show significant toxicity to the cells at concentrations high up to 0.5 mg/mL. All three DOX-loaded micelles were uptaken into the cells, and DOX was internalized into the nucleus of the cells.

Reversible Cross-linked Thermoresponsive Polycaprolactone Micelles for Enhanced Stability and Controlled Release.

Thermoresponsive amphiphilic poly(ε-caprolactone)s (PCL)s are excellent candidates for drug delivery due to their biodegradability, biocompatibility, and controlled release. However, the thermoresponsivity of modified PCL can often lead to premature drug release because their lower critical solution temperature (LCST) is close to physiological temperature conditions. To address this issue, we developed a novel approach that involves functionalizing redox-responsive lipoic acid to the hydrophobic block of PCL. Lipoic acid has disulfide bonds that undergo reversible cross-linking after encapsulating the drug. Herein, we synthesized an ether-linked propargyl-substituted PCL as the hydrophobic block of an amphiphilic copolymer along with unsubstituted PCL. The propargyl group was used to attach lipoic acid through a postpolymerization modification reaction. The hydrophilic block is composed of an ether-linked, thermoresponsive tri(ethylene glycol)-substituted PCL. Anticancer drug doxorubicin (DOX) was encapsulated within the core of the micelles and induced cross-linking in the presence of a reducing agent, dithiothreitol. The developed micelles are thermodynamically stable and demonstrated thermoresponsivity with an LCST value of 37.5 °C but shifted to 40.5 °C after cross-linking. The stability and release of both uncross-linked (LA-PCL) and cross-linked (CLA-PCL) micelles were studied at physiological temperatures. The results indicated that CLA-PCL was stable, and only 35% release was observed after 46 h at 37 °C while LA-PCL released more than 70% drug at the same condition. Furthermore, CLA-PCL was able to release a higher amount of DOX in the presence of glutathione and above the LCST condition (42 °C). Cytotoxicity experiments revealed that CLA-PCL micelles are more toxic toward MDA-MB-231 breast cancer cells at 42 °C than at 37 °C, which supported the thermoresponsive release of the drug. These results indicate that the use of reversible cross-linking is a great approach toward synthesizing stable thermoresponsive micelles with reduced premature drug leakage.

Chalcogenopheno[3,2-b]pyrrole-Containing Donor-Acceptor-Donor Organic Semiconducting Small Molecules for Organic Field-Effect Transistors.

A group of chalcogenopheno[3,2-b]pyrroles, including thieno[3,2-b]pyrrole (TP), furo[3,2-b]pyrrole (FP), and selenopheno[3,2-b]pyrrole (SeP), and thieno[3,2-b]thiophene (TT) electron-donating units were coupled with a thiophene-flanked diketopyrrolo[3,4-c]pyrrole (ThDPP) acceptor to generate four donor-acceptor-donor (D-A-D) semiconducting small molecules (ThDPP-TT, ThDPP-FP, ThDPP-TP, and ThDPP-SeP). This study systematically investigated the differences between chalcogenopheno[3,2-b]pyrroles and TT. From the characterizations, chalcogenopheno[3,2-b]pyrrole-containing molecules showed lower band gaps and binding-energy cold crystallization behavior. The enthalpies of cold crystallization were correlated with the weight of the chalcogen in ThDPP-FP, ThDPP-TP, and ThDPP-SeP, which were evaluated as intermolecular chalcogen-bond interactions between chalcogen and pyrrole nitrogen in chalcogenopheno[3,2-b]pyrroles. A stronger chalcogen bond interaction resulted in stronger self-aggregation in thin films with thermal treatment, which resulted in a polycrystalline structure in chalcogenopheno[3,2-b]pyrrole-containing molecules. For the application in an organic field-effect transistor, all four molecules showed good performance with the highest hole mobilities as 6.33 × 10-3 cm2 V-1 s-1 for ThDPP-TT, 2.08 × 10-2 cm2 V-1 s-1 for ThDPP-FP, 1.87 × 10-2 cm2 V-1 s-1 for ThDPP-TP, and 6.32 × 10-3 cm2 V-1 s-1 for ThDPP-SeP, and the change of mobility is well correlated to the root-mean-square roughness of the thin films. Overall, all the chalcogenopheno[3,2-b]pyrrole-containing molecules showed lower band gaps, polymorphism, and better charge transport properties compared to TT-containing molecules, which motivates replacing TT with chalcogenopheno[3,2-b]pyrroles in conjugated polymers, non-fullerene small molecular acceptors, and narrow-band-gap donors.

Regioselective Direct C-H Bond Heteroarylation of Thiazoles Enabled by an Iminopyridine-Based α-Diimine Nickel(II) Complex Evaluated by DFT Studies.

Direct C-H bond arylation is a highly effective method for synthesizing arylated heteroaromatics. This method reduces the number of synthetic steps and minimizes the formation of impurities. We report an air- and moisture-stable iminopyridine-based α-diimine nickel(II) complex for direct C5-H bond arylation of thiazole derivatives. Under a low catalyst loading and performing the reactions at lower temperatures (80 °C) under aerobic conditions, we produced mono- and diarylated thiazole units. Competition experiments and density functional theory calculations revealed that the mechanism of C-H activation in 4-methylthiazole involves an electrophilic aromatic substitution.

Recent Advances in Polycaprolactones for Anticancer Drug Delivery.

Poly(ε-Caprolactone)s are biodegradable and biocompatible polyesters that have gained considerable attention for drug delivery applications due to their slow degradation and ease of functionalization. One of the significant advantages of polycaprolactone is its ability to attach various functionalities to its backbone, which is commonly accomplished through ring-opening polymerization (ROP) of functionalized caprolactone monomer. In this review, we aim to summarize some of the most recent advances in polycaprolactones and their potential application in drug delivery. We will discuss different types of polycaprolactone-based drug delivery systems and their behavior in response to different stimuli, their ability to target specific locations, morphology, as well as their drug loading and release capabilities.

Improved Self-Assembly of P3HT with Pyrene-Functionalized Methacrylates.

A block copolymer with discotic liquid crystalline behavior was synthesized using Grignard metathesis polymerization (GRIM) and initiators for continuous activator regeneration atom transfer radical polymerization (ICAR-ATRP). A novel discotic liquid crystalline mesogen, 6-(pyren-1-yloxy)hexyl methacrylate (PyMA), comprises a block that is attached to regioregular poly(3-hexylthiophene) (rr-P3HT) generated by GRIM and subjected to end-group modification. Due to the continuous regeneration of Cu+ in the reaction mixture in ICAR-ATRP compared to conventional methods, the synthesis was successfully performed with less catalyst. The purity and yield of the final product are increased by eliminating rigorous post-synthesis purification. Stacked pyrene units have contributed to the enhanced long-range π-π interactions and aligning of the P3HT block as observed in thin-film X-ray diffraction (XRD). Furthermore, field-effect mobilities in the order of 10-2 cm2 V-1 s-1 in bottom-gate, top-contact organic field-effect transistors (OFETs) suggest an enhancement in charge transport due to the discotic electron-rich pyrene units that help mitigate the insulating effect of the methacrylate backbone. The formation of uniform microdomains of P3HT-b-poly(PyMA) observed with tapping mode atomic force microscopy (TMAFM) on the channel regions of OFETs indicates the unique packing of the block copolymer in comparison to pristine P3HT. Thermotropic properties of the novel discotic mesogen in the presence and absence of P3HT were observed with both the poly(3-hexylthiophene)-b-poly(6-(pyren-1-yloxy)hexyl methacrylate) (P3HT-b-poly(PyMA)) block copolymer and poly(6-(pyren-1-yloxy)hexyl methacrylate) (poly(PyMA)) homopolymer using polarized optical microscopy (POM) and differential scanning calorimetry (DSC).

Ligand Steric Effects of α-Diimine Nickel(II) and Palladium(II) Complexes in the Suzuki-Miyaura Cross-Coupling Reaction.

Nickel catalysts represent a low cost and environmentally friendly alternative to palladium-based catalytic systems for Suzuki-Miyaura cross-coupling (SMC) reactions. However, nickel catalysts have suffered from poor air, moisture, and thermal stabilities, especially at high catalyst loading, requiring controlled reaction conditions. In this report, we examine a family of mono- and dinuclear Ni(II) and Pd(II) complexes with a diverse and versatile α-diimine ligand environment for SMC reactions. To evaluate the ligand steric effects, including the bite angle in the reaction outcomes, the structural variation of the complexes was achieved by incorporating iminopyridine- and acenaphthene-based ligands. Moreover, the impact of substrate bulkiness was investigated by reacting various aryl bromides with phenylboronic acid, 2-naphthylboronic acid, and 9-phenanthracenylboronic acid. Yields were the best with the dinuclear complex, being nearly quantitative (93-99%), followed by the mononuclear complexes, giving yields of 78-98%. Consequently, α-diimine-based ligands have the potential to deliver Ni-based systems as sustainable catalysts in SMC.

Peroxide-Templated Assembly of a Trimetal Neodymium Complex Single-Molecule Magnet.

In this work, we present a trimetal neodymium complex with two notable qualities. First, the assembly of the complex is templated by peroxide derived from atmospheric oxygen. Second, the bulk material behaves as a superparamagnet, implying that the individual complexes are molecular magnets. Peroxide-templated assembly is possible because of the confluence of the high oxophilicity of neodymium along with the use of an azeotropic distillation synthesis method, which excludes water but admits oxygen. SQUID magnetometry measurements show an extremely high magnetic susceptibility as well as a lack of remanence.

Pyrrole-Containing Semiconducting Materials: Synthesis and Applications in Organic Photovoltaics and Organic Field-Effect Transistors.

Organic semiconducting materials derived from π-electron-rich pyrroles have garnered attention in recent years for the development of organic semiconductors. Although pyrrole is the most electron-rich five-membered heteroaromatic ring, it has found few applications in organic photovoltaics and organic field-effect transistors due to synthetic challenges and instability. However, computational modeling assisted screening processes have indicated that relatively stable materials containing pyrrolic units can be synthesized without compromising their inherent electron-donating properties. In this work, we provide a complete, up-to-date review of pyrrole-containing semiconducting materials used for organic photovoltaics and organic field-effect transistors and highlight recent advances in the synthesis of these materials.

Enhancement of Loading Efficiency by Coloading of Doxorubicin and Quercetin in Thermoresponsive Polymeric Micelles.

Chemotherapy faces challenges, including poor aqueous solubility of the drugs, and cardiotoxicity. Micellar drug delivery systems (DDS) are used to encapsulate anticancer drugs for better therapeutic effects, however, with poor loading content. Herein, we synthesized a micellar DDS using γ-benzyloxy substituted poly(ε-caprolactone) as the hydrophobic block and coloaded anticancer doxorubicin (Dox) and antioxidant quercetin (Que). γ-Substituted oligo(ethylene) glycol (OEG) poly(ε-caprolactone)s were used as hydrophilic blocks to make the polymers thermoresponsive. Variation of the OEG chain allowed the tunability of the lower critical solution temperature. Moreover, drug loading and release were studied. Thermodynamic stability, size, and morphology were determined by fluorescence measurements, dynamic light scattering, and transmission electron microscopy. Combination loading demonstrated improved loading of Dox and Que. Biological studies were performed using HepG2 human liver cancer and H9c2 rat heart cells. The use of biodegradable, biocompatible, and thermoresponsive polymers along with the coloading approach is a good strategy in developing DDSs.

Thieno[3,2-b]pyrrole and Benzo[c][1,2,5]thiadiazole Donor-Acceptor Semiconductors for Organic Field-Effect Transistors.

Two p-type donor-acceptor (D-A) semiconducting small molecules were synthesized to investigate the effect of the backbone curvature on the organic field-effect transistor performance. The backbone curvature of the donor-acceptor small molecules was modified by changing the spacer group from bithiophene to thienothiophene. Bithiophene to thienothiophene spacer groups were placed between 4H-thieno[3,2-b]pyrrole (donor) and benzo[c][1,2,5]thiadiazole (acceptor) to generate TP-BT4T-TP and TP-BT2TT-TP donor-acceptor molecules. A good charge carrier mobility of 2.59 × 10-2 cm2 V-1 s-1 was measured for the curved molecule (TP-BT4T-TP), while the linear molecule analog (TP-BT2TT-TP) only gave a low mobility of 5.41 × 10-5 cm2 V-1 s-1 after annealing at 120 °C in bottom-contact bottom-gate devices. Out-of-plane grazing-incidence X-ray diffraction analysis revealed more drastic thermally induced crystallinity for TP-BT4T-TP as compared to TP-BT2TT-TP, explaining the difference observed in the performance of devices fabricated from each molecule.

Oxidative Degradation of Polypropylene Mesh in E. coli Environment.

Medical implants of polypropylene (PP) are commonly used in many surgical procedures to support tissues. Previous studies on polypropylene meshes removed from patients demonstrated biodegradation relative to the amount of time after implantation. Among the many possible factors, bacterial colonization is believed to be one of the causes for the biodegradation of PP. To gain insights on this hypothesis, PP mesh samples were tested in Luria-Bertani broth (LB) media containing Escherichia coli (E. coli) to observe possible degradation in a controlled single-organism environment. Mesh samples were immersed in either an LB media with E. coli or a control solution, and the biodegradation was measured at 1-, 2-, and 3-month intervals. The samples were then harvested from both LB media with E. coli and the control media for analysis, and results were then compared with pristine polypropylene mesh. The experimental results demonstrate qualitative and quantitative bioerosion, increased oxygen content, and enhanced hydrophilicity over the surface of the mesh structure, thus confirming the oxidative degradation in vitro.

Halide-free neodymium phosphate based catalyst for highly cis-1,4 selective polymerization of dienes.

Neodymium-based Ziegler-Natta type catalytic systems are known to produce polydienes with high cis-1,4 content. It is generally believed that in Ziegler-Natta catalytic systems, a halide or pseudohalide, whether in the catalyst itself or a separate source, is required for the success of the polymerization. In this work, we have synthesized an unusual halide-free neodymium diethyl phosphate catalyst for diene polymerization. This neodymium complex combined with triisobutylaluminum (TIBA), formed a binary catalytic system and was used to polymerize ß-myrcene. The catalytic system displays high stereospecificity and produces poly(ß-myrcene) with 96% cis-1,4 content and a relatively narrow molecular weight distribution (M w/M n = 1.80). Also, kinetic studies indicated the catalytic system gives a pseudo-living polymerization. The block copolymer poly(ß-myrcene)-b-poly(isoprene) was successfully synthesized by sequential monomer addition, further demonstrating the pseudo-living nature of polymerization with the neodymium diethyl phosphate catalyst.

Thieno[3,2- b]pyrrole-benzothiadiazole Banana-Shaped Small Molecules for Organic Field-Effect Transistors.

We report two banana-shaped organic semiconducting small molecules containing the relatively unexplored thieno[3,2- b]pyrrole with thiophene and furan flanked benzothiadiazole. Theoretical insights gained by DFT calculations, supported by single crystal structures show that furan flanked benzothiadiazole-thieno[3,2- b]pyrrole small molecule has a higher curvature compared to the thiophene flanked small molecule due to the shorter carbon-oxygen bond in furan. Despite similar optical and electrochemical properties, thiophene flanked small molecule shows average hole mobility up to 8 × 10-2 cm2 V-1 s-1, however furan flanked small molecule performs poorly in thin film transistor devices (µh ≈ 5 × 10-6 cm2 V-1 s-1). The drastic difference in hole mobilities was due to the annealing-induced crystallinity which was demonstrated by the out-of-plane grazing incidence X-ray diffraction and surface morphology studies by tapping mode atomic force microscopy analysis.

Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy.

The short chain fatty acid, 4-phenylbutyric acid (PBA), is used for the treatment of urea cycle disorders and sickle cell disease as an endoplasmic reticulum stress inhibitor. PBA is also known as a histone deacetylase inhibitor (HDACi). We report here the effect of combination therapy on HeLa cancer cells using PBA as the HDACi together with the anticancer drug, doxorubicin (DOX). We synthesized γ-4-phenylbutyrate-ε-caprolactone monomer which was polymerized to form poly(γ-4-phenylbutyrate-ε-caprolactone) (PPBCL) homopolymer using NdCl3·3TEP/TIBA (TEP = triethyl phosphate, TIBA = triisobutylaluminum) catalytic system. DOX-loaded nanoparticles were prepared from the PPBCL homopolymer using poly(ethylene glycol) as a surfactant. An encapsulation efficiency as high as 88% was obtained for these nanoparticles. The DOX-loaded nanoparticles showed a cumulative release of >95% of DOX at pH 5 and 37 °C within 12 h, and PBA release was monitored by 1H NMR spectroscopy. The efficiency of the combination therapy can notably be seen in the cytotoxicity study carried out on HeLa cells, where only ∼20% of cell viability was observed after treatment with the DOX-loaded nanoparticles. This drastic cytotoxic effect on HeLa cells is the result of the dual action of DOX and PBA on the DNA strands and the HDAC enzymes, respectively. Overall, this study shows the potential of combination treatment with HDACi and DOX anticancer drug as compared to the treatment with an anticancer drug alone.

Combination Loading of Doxorubicin and Resveratrol in Polymeric Micelles for Increased Loading Efficiency and Efficacy.

Combined loading of doxorubicin (DOX) and resveratrol (RSV) in polymeric micelles enabled an increased loading of DOX into a micellar drug delivery system. Herein, we report the coloading of DOX and RSV in amphiphilic diblock copolymer micelles of poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) and poly(ethylene glycol)-b-poly(γ-benzyl-ε-caprolactone) (PEG-b-PBCL) for which an increase in the loading efficiency and increased in vitro cytotoxicity was observed. The increased loading was attributed to the favorable interactions of DOX and RSV as well as to the interaction with benzyl substituents of PEG-b-PBCL diblock copolymer micelles. Combination loaded micelles made of PEG-b-PBCL diblock copolymer showed a dramatic improvement in DOX loading in comparison to DOX-only loaded PEG-b-PBCL with an increase in encapsulation efficiency of DOX from 31.0 to 87.7%. Combination loaded micelles also showed increased cytotoxicity to HeLa cells as compared to that of DOX-only loaded micelles. Optimization of the combination loading, size and morphology, drug release, and cellular studies is also reported here. Combination loading was shown to improve the loading capacity and efficiency of both systems and shows promise to improve loading of DOX in polymer micelle systems regardless of the polymer used.

Incorporation of Thieno[3,2-b]pyrrole into Diketopyrrolopyrrole-Based Copolymers for Efficient Organic Field Effect Transistors.

Recent advancements in organic field effect transistors have switched chemists' focus from synthesizing libraries of organic semiconductors to a more targeted approach where chemical alterations are performed on known semiconductors to further improve electronic properties. Among successful semiconducting polymer candidates, copolymers based on diketopyrrolopyrrole-and thieno[3,2-b]thiophene [P(DPP-TT)] have been subjected to modifications on the diketopyrrolopyrrole unit by using flanking groups and side chain engineering. Thieno[3,2-b]thiophene moiety, however, has seen minimal modifications due to the limited number of modifying sites. Isoelectronic thieno[3,2-b]pyrrole could serve as an alternative since it is easily tunable via N-alkylation reactions. Therefore, for the first time, we report the replacement of the thieno[3,2-b]thiophene unit of P(DPP-TT) with thieno[3,2-b]pyrrole unit and its performance in p-channel field effect transistors. The copolymer exhibits linear characteristics to achieve a relatively high average hole mobility of 0.12 cm2 V-1 s-1 in bottom-gate/top-contact field effect transistors with threshold voltages as low as 0 V. These preliminary results highlight the potential of this thieno[3,2-b]pyrrole monomer for utilization in organic field effect transistors.

HDAC Inhibitor Conjugated Polymeric Prodrug Micelles for Doxorubicin Delivery.

Amphiphilic diblock copolymers bearing histone deacetylase inhibitors (HDACi) (4-phenyl butyric acid and valproic acid) were synthesized by the ring-opening polymerization of γ-4-phenylbutyrate-ε-caprolactone (PBACL), γ-valproate-ε-caprolactone (VPACL), and ε-caprolactone (CL) from a poly(ethylene glycol) macroinitiator (PEG). These amphiphilic diblock copolymers self-assembled into stable pro-drug micelles and demonstrated excellent biocompatibility. High loading of doxorubicin (DOX) up to 5.1 wt% was achieved. Optimized micelles enabled sustained drug release in a concentration-dependent manner over time to expand the therapeutic window of cytotoxic small molecule drugs.

Systematic variation of thiophene substituents in photochromic spiropyrans.

Spiropyrans are notable among different classes of photochromic compounds due to their large structural and electronic transformation upon isomerization. In order to parlay the electronic differences associated with the two isomeric forms into a materials based switch, the spiropyran ultimately requires a covalent attachment through a conjugated pathway. In this work a synthetic method was developed to incorporate spiropyran (SP) into thiophene based materials. A series of compounds with a systematic variation of substituents were synthesized (SP-T, SP-T-Br, SP-T-T, SP-T-T-T and SP-T-T-T-T-SP) and their photochromism in both polar (methanol) and non-polar (toluene) solvents were studied. These compounds showed a systematic variation of photochromic properties.