The preparation of heterocycles by [2+2+2] cyclization and inverse electron demand Dels-Alder reactions of arynes with 1,2,4-triazines

Transition metal mediated [2 + 2 + 2] cyclizations have been well researched over the past several years. As a well-developed methodology, [2 + 2 + 2] chemistry has been employed as a major pathway to various carbo- and heterocyclic synthetic targets. Numerous transition metals have been applied as catalysts for these cyclizations. Previous work in our group developed cobalt(I) catalyzed inter- and intramolecular [2 + 2 + 2] cyclizations of two alkynes and a nitrile, leading to the preparation of tetrahydro-naphthyridines. Pyridazines could be generated if the cyclization could be accomplished with two nitriles and an alkyne, which would be a novel way to synthesize 1,2-diazines through the formation of the N-N bond. To this end, metal-catalyzed intramolecular [2 + 2 + 2] cyclizations between an alkyne and two nitriles were investigated. The intramolecular nature of the reaction provided the entropic advantage to successfully assist the formation of the critical N-N bond. Optimal conditions were achieved with cobalt(I) catalysts under microwave irradiation in chlorobenzene, producing the desired pyridazines in moderate to good yields. This success led to the preparation of a series of annulated pyridazines. The use of two tethering nitrogens in the preparation of the cyclization precursors incorporated points for further diversification, the next step in the development of this chemistry. This ring closure through N,N-bond formation allowed the construction of annulated pyridazine scaffolds that were utilized further in a small molecule library synthesis. Using this methodology, sixteen new annulated pyridazines were prepared. Inverse electron demand Diels-Alder (IEDDA) reactions of arynes and 1,2,4-triazines were also investigated for the generation of isoquinoline core structures. The results showed that only triazines with electron withdrawing groups participated in the IEDDA reactions with benzyne as a partner after screening of several different arynes, which limited the scope of the reaction. Liebeskind–Srogl reactions of 3-methylthiotriazines and boronic acids were investigated during the diversification of triazines, and microwave irradiation with palladium and copper catalysts were found to be the optimal conditions for the coupling. The chemistry allowed for further triazine diversification

Biodegradable polymer micro- and nanoparticles as protein delivery systems : influence of microparticle morphology and improvement of protein loading capacity of nanoparticles

In this work, microparticles and nanoparticles were investigated as protein delivery system. Chapter 1 firstly describes development and current status of degradable polymer microspheres as protein delivery systems.In Chapter 2 with the aim to establish the relationship of particles morphology, drug distribution and release profiles based on different polymer properties, relatively hydrophobic and hydrophilic PLGAs with different end functional groups were selected to prepare microspheres using W/O/W method with different porosity, pore size and drug loading. The results showed that morphology of particles play a different role in the release process depending on the property of polymer. For relative hydrophilic polymer, as RG503H, morphology influenced the burst release to the less extent relative to hydrophobic polymer RG502. Vice verse, at the slow release stage, morphology showed much less pronounced influence for hydrophobic polymer RG502. In Chapter 3 with the purpose to achieve high protein loading and to improve the release profiles, we supposed that protein can be effectively absorbed onto charged nanoparticles and can be released in the controlled manner. PLGA and PSS polymer blend were used to mimic negatively charged polymer and to prepare charged nanoparticles with variable surface charge density through adjusting the ratio of PSS to PLGA. Increased PSS led to the increment of size and high charge density of nanoparticles. Adsorption isotherm showed higher affinity of protein to the nanoparticles with increased PSS. Loading capacity of lysozyme closely related to charge density of nanoparticles. Adsorption process of protein and loading capacity investigations suggest that the electrostatic forces dominate the interaction between proteins and nanoparticles. Bioactivity determination showed protein remains intact during whole process and the release profiles were dependent on protein loading. This study proves our hypothesis that it is a feasible and mild method using charged nanoparticles to effectively load oppositely charged protein with full bioactivity. In Chapter 4 due to the fast release and location of protein on the surface of nanoparticles prepared in chapter 3, a layer-by-layer nanostructure was assumed to fulfill these requirements. Using chitosan and its derivatives as coating materials with potential functional application like mucoadhesivity, penetration enhancement, layer-by-layer nanocarriers through deposition of polymer on the surface of protein loaded nanoparticles were investigated. Increased size and inversion of zeta-potential of particles, as well as TEM observations evidenced the coating of chitosan on the surface. Due to the stronger electrostatic interaction between chitosan and nanoparticles, dissociation of lysozyme was observed. Dissociation of lysozyme was dependent on polymer composite, irrespective of initial protein loading. Moreover, with this polymer coating more stable particles were detected in PBS, without initial release within 24 hours. This study showed the feasibility of designing a layer-by-layer protein nanocarrier with polymer coating on the surface of protein loaded nanoparticles to further improve the stability and release profiles of protein. In Chapter 5 based on the promising results of chapter 3, same strategies including nanoparticles preparation and protein loading method were employed using negatively charged polymer SB-PVA-PLGA and P(VS-VA)-PLGA. Stable nanoparticles suspension with narrow size distribution, and high reproducibility was obtained with polymer SB-PVA-PLGA. Based on equal sulfonic substitution, longer PLGA chain length of P(VS-VA)-PLGA demonstrated better nanoparticles properties as narrow size and single peak zeta-potential distribution than shorter PLGA chain length polymer. Increased sulfonic substitution degree of P(VS-VA)-PLGA decreased the size linearly, however, no significant difference in zeta-potential was observed. SB-PVA-PLGA showed higher loading capacity as 77 µg/mg relative to this new class polymer P(VS-VA)-PLGA. Additionally, higher sulfonic substitution degree resulted in higher loading capacity. Whereas, lower loading capacity of lysozyme was observed for polymer with longer PLGA chain length, indicating that the balance of charge density and hydrophilic property is necessary for this protein adsorption process

Tablets of paliperidone using compression-coated technology for controlled ascending release

The aim of this work was to prepare ascending release compression-coated (CC) tablets with paliperidone (PAL) using a simple manufacturing technique and short manufacturing process. The release behavior and mechanisms in vitro of the final tablets was investigated and evaluated. The PAL CC tablets were comprised of a core layer of high viscosity hydroxypropyl cellulose (HPC-H) and a coating layer of high viscosity hydroxypropyl methylcellulose (HPMC-K100M). Several factors such as materials and core tablet compositions were studied for their influence in the formulation procedure. The drug release mechanism was studied using gravimetric analysis. The data could be fitted to the Peppas model. The ascending drug release results were expressed in terms of the slope of the release curve at different time points. Results showed that the formulation could achieve a good ascending drug release when the weight ratio of PAL was 5:1 (core:layer). The fraction of HPC and HPMC was 33 %, and the combination of Eudragit RL-PO was 10%. The ascending release mechanism was due to solvent penetration into the PAL CC tablets, and subsequent drug dissolution from the gelatinous HPC and HPMC matrix erosion. The release mechanism was therefore a combination of diffusion and erosion. This work demonstrated that the compression-coated tablets could achieve controlled ascending release over 24 h for the oral administration systems. Keywords: Paliperidone, Compression-coated tablet, Ascending release, Controlled releas

Exosome-based small RNA delivery: Progress and prospects

RNA interfering (RNAi), mediated by small interfering RNAs and microRNAs, is currently one of the most promising tools of gene therapy. Small RNAs are capable of inducing specific post-transcriptional gene silencing, providing a potentially effective platform for the treatment of a wide array of diseases. However, similar to other nucleic acid-based drugs, the major hurdle of RNAi therapy is lack of efficient and non-immunogenic delivery vehicles. Currently, viruses, synthetic polymers, and lipid-based carriers are among the most widely studied vehicles for small RNA delivery. However, many drawbacks are reported to be associated with these delivery vehicles. There is a pressing need to replace them with more efficient and better-tolerated approaches. Exosomes secreted from the endocytic compartment of live cells, are a subtype of endogenous extracellular vesicles that transfer genetic and biochemical information among different cells, thus playing an important role in cell-cell communication. Recently, accumulating attention has been focused on harnessing exosomes as nanaocarriers for small RNAs delivery. Due to their natural role in shuttling endogenous nucleic acid in our body, exosomes may exhibit higher delivery efficiency, lower immunogenicity, and better compatibility than existing foreign RNA carriers. Importantly, exosomes own intrinsic homing capacity that can guide small RNAs across natural membranous barriers. Moreover, such a capacity can be further improved by adding appropriate targeting moieties. In this manuscript, we briefly review the progress and challenges of RNAi therapy, and discuss the potential of exosomes' applications in small RNA delivery with focus on the most recent advances in exosome-based small RNA delivery for disease therapy

Low viscosity and highly flexible stereolithographic 3D printing resins for flexible sensors

Flexible sensors show the wide range of applications in electronic products. However, challenges remain in developing sensors with internal complex construction, excellent flexibility, elasticity and strength. In this paper, a prepolymer (PU-PDMS-OH-HEMA) contain polyurethane (PU) segments and polysiloxane (PDMS) segments was synthesized, and the photosensitive resins with low viscosity for 3D printing were prepared by mixing prepolymers with diluents and photoinitiators. The resultant cured photosensitive resins showed the improved mechanical properties. The PDMS-OH-30 sample exhibit the excellent mechanical properties, with tensile strength and elongation at break of 10.03 MPa and 1046.15 %, respectively, and the resin viscosity of 62 cP. Conductive ionic liquids were added to the above photosensitive resins to prepare flexible sensors, which show the electrical sensitivity and stability. The findings in the work propose a contribution to the development of highly flexible 3D printing resins for fabricating flexible sensors