Copolymer Carrier Research Articles

A dissipative particle dynamics simulation of controlled loading and responsive release of theranostic agents from reversible crosslinked triblock copolymer vesicles.

To control the transport stability and release efficiency of loaded theranostic drugs in triblock copolymer carriers, the reversible crosslinking ability is of great significance. A molecular level exploration of such a function is needed to extend existing stabilizing and responsive dissociation mechanisms of carriers. Here, dissipative particle dynamics simulations were used to first demonstrate the formation of triblock copolymer vesicular carriers. Chemical crosslinking was used to strengthen the structural stability of the vesicle shell to avoid drug leakage. Reversible decrosslinking along with dissociation of the vesicle and release of loaded drugs were then explored. The structural, energetic and dynamical properties of the system were discussed at the molecular level. The regulation mechanism of drug release patterns was revealed by systematically exploring the effect of intra and intermolecular repulsive interactions. The results indicate that the chemical crosslinking of copolymers enhanced the compactness of the vesicle shell with a strengthened microstructure, increased binding energy, and limited chain migration, thus achieving more stable delivery of drugs. In terms of drug release, we clarified how the pairwise interactions of beads in the solution system affect the responsive dissociation of the vesicle and associated release patterns (speed and amount) of drugs. More efficient delivery and smart release of theranostic drugs are achieved using such reversible crosslinked triblock copolymer vesicles.

Chemosensitization of tumors via simultaneous delivery of STAT3 inhibitor and doxorubicin through HPMA copolymer-based nanotherapeutics with pH-sensitive activation

We synthesized three novel STAT3 inhibitors (S3iD1-S3iD3) possessing oxoheptanoic residue enabling linkage to HPMA copolymer carrier via a pH-sensitive hydrazone bond. HPMA copolymer conjugates bearing doxorubicin (Dox) and our STAT3 inhibitors were synthesized to evaluate the anticancer effect of Dox and STAT3 inhibitor co-delivery into tumors. S3iD1–3 and their copolymer-bound counterparts (P-S3iD1-P-S3iD3) showed considerable in vitro cytostatic activities in five mouse and human cancer cell lines with IC50 ~0.6–7.9 μM and 0.7–10.9 μM, respectively. S3iD2 and S3iD3 were confirmed to inhibit the STAT3 signaling pathway. The combination of HPMA copolymer-bound Dox (P-Dox) and P-S3iD3 at the dosage showing negligible toxicity demonstrated significant antitumor activity in B16F10 melanoma-bearing mice and completely cured 2 out of 15 mice. P-Dox alone had a significantly lower therapeutic activity with no completely cured mice. Thus, polymer conjugates bearing STAT3 inhibitors may be used for the chemosensitization of chemorefractory tumors.

Co-Polymer Carrier with Dual Advantages of Cartilage-Penetrating and Targeting Improves Delivery and Efficacy of MicroRNA Treatment of Osteoarthritis.

Osteoarthritis (OA) is a debilitating joint disease affecting nearly 400 million people with no efficient etiological therapies. OA is primarily identified by cartilage destruction, and gradual degeneration of the whole joint would happen when the OA progresses. Hence, cartilage has been identified as the primary therapeutic target of OA. Unfortunately, numerous barriers block the delivery of therapeutic agents into cartilage, including avascular traits and high hardness of the extracellular matrix. Herein, a cartilage-targeting peptide (CAP) modified polyvinylamine (PVAm)- poly (lactic-co-glycolic acid) (PLGA) copolymer (CAP-PVAm-PLGA) is designed, which can form spherical nanoparticles with the r-miR-140 (CPP-NPs). CPP-NPs possessed enhanced mechanical properties due to the introduction of PLGA to vehicles. Meanwhile, CAP endowed the cartilage targeting which facilitated CPP-NPs localization in cartilage. With such dual advantages, CPP-NPs exhibited outstanding penetrability and accumulation in cartilage even subchondral bone, and can penetrate to a depth of 1000µm into human cartilage. The degeneration area of cartilage is reduced by 65% and synovial inflammation score by 80% in OA mice, and the microarchitecture of subchondral bone is also ameliorated. These studies established a promising platform for therapeutic RNA delivery in OA therapy that overcame the cartilage barriers.

Identification and validation of potential genotoxic impurities, 1,3-dichloro-2-propanol, and 2,3-dichloro-1-propanol, at subtle levels in a bile acid sequestrant, colesevelam hydrochloride, using hyphenated GC-MS technique.

Potential genotoxic impurities (PGI) and N-nitrosamine impurities in active pharmaceutical ingredients (APIs) and their determination at low levels are substantial challenges for cholesterol-lowering agents in recent years. Herein we developed a robust, reliable, rapid, accurate and validated technique of gas chromatography equipped with a mass spectrometer (GC-MS) for quantifying subtle levels of 1,3-dichloro-2-propanol (PGI-I) and 2,3-dichloro-1-propanol (PGI-II) in colesevelam hydrochloride drug substance (bile acid sequestrant). The separation of colesevelam hydrochloride, PGI-I and PGI-II was executed with chromatographic technique using a capillary column, DB-624 measuring with 30 m × 0.32 mm × 1.8μm specification of 6% cyanopropylphenyl-94% dimethylpolysiloxane copolymer and helium carrier gas. This developed technique gave a good intensity peak without any interference and extra masses at the retention times of 11.17 min for PGI-I and 11.59 min for PGI-II, which was adequate, with mass spectra (m/z) of 79 and 62, respectively. The method's sensitivity and linearity are demonstrated by its detection and quantification limits at subtle levels with correlation coefficients of 0.9965 for PGI-I and 0.9910 for PGI-II. The determination is mainly focused on improving sensitivity with the limits of detection and quantitation far below the specifications, which can support tighter limits. This results in a cost-effective and easily adoptable methodology having precise and accurate results in colesevelam hydrochloride APIat subtle levels.

A combined arsenic trioxide/tetrandrine nanoparticle formulation with improved inhibitory effect against promyelocytic leukemia

Co-loading nanoparticles encapsulated in a copolymer carrier is a very effective strategy for anti-tumor treatment. A combination of arsenic trioxide (ATO) and tetrandrine (TET) synergistically inhibits tumor angiogenesis and lung metastasis. Moreover, TET reduces the cardiotoxicity of ATO. However, the bioavailability of this combination is limited due to poor solubility. In this study, co-loading nanoparticle formulations were developed by co-loading poly(lactic-co-glycolic acid) (PLGA) nanoparticles with ATO and TET (ATO/TET@PLGA) and by co-loading methoxypoly(ethylene glycol)-poly(lactide) (mPEG-PLGA) nanoparticles with ATO and TET (ATO/TET@mPEG-PLGA). The sonication emulsion-solvent volatilization method was employed. The combination ratio of ATO and TET was determined by results of the MTT assay, which showed that when the TET: ATO ratio was 3/4, the best synergistic anti-tumor effect was achieved. Transmission electron microscopy and particle size analysis of the nanoparticles showed that the particle size was below 100 nm mPEG-PLGA was an excellent carrier for constructing ATO/TET co-loading nanoparticles based on characterization, release study, and pharmacokinetics results. The average encapsulation efficiencies of ATO and TET were 89.78% and 82.80%, respectively. In vivo distribution experiments showed that the drugs had an improved targeting effect in the liver and bone when formulated as nanoparticles. In vitro anti-tumor studies showed that ATO/TET@mPEG-PLGA had stronger cytotoxicity than ATO alone or ATO/TET intravenous emulsion and could induce apoptosis in HL-60 cells to a greater extent. Additionally, ATO/TET@mPEG-PLGA could induce G2/M cell cycle arrest. In conclusion, ATO/TET@mPEG-PLGA has excellent anti-tumor activity as a co-delivery system of ATO and TET.

A Facile Fabrication of Lysosome-Targeting pH Fluorescent Nanosensor Based on PEGylated Polyester Block Copolymer.

A novel lysosome-targeting PEGylated polyester-based fluorescent pH nanosensor is fabricated by the combination of ring-opening copolymerization (ROCOP), side-group modification and subsequent self-assembly. First, a key target amphiphilic copolymer carrier for rhodamine (Rh) pH indicator is synthesized in a facile manner by the ROCOP of phthalic anhydride with allyl glycidyl ether using mPEG-OH and t-BuP1/Et3B as the macroinitiator and binary catalyst, respectively. Subsequently, Rh moieties are covalently attached on the polymer chain with controllable grafting degree via an efficient thiol-ene click reaction. Concurrently, the effect of catalyst systems and reaction conditions on the catalytic copolymerization performance is presented, and the quantitative introduction of Rh is described in detail. Owing to its amphiphilic characteristics, the rhodamine-functionalized polyester-based block copolymer can self-assemble into micelles. With the covalent incorporation of Rh moieties, the as-formed micelles exhibit excellent absorption and fluorescence-responsive sensitivity and selectivity towards H+ in the presence of various metal cations. Moreover, the as-prepared micelles with favorable water dispersibility, good pH sensitivity and excellent biocompatibility also display appreciable cell-membrane permeability, staining ability and pH detection capability for lysosomes in living cells. This work provides a new strategy for the facile synthesis of novel biocompatible polymeric fluorescent pH nanosensors for the fluorescence imaging of lysosomal pH changes.

Polymerization-Induced Self-Assembly (PISA) for in situ drug encapsulation or drug conjugation in cancer application

HypothesisWe describe the possibility of using the same block copolymer carriers prepared by PISA for in situ drug encapsulation or drug conjugation. ExperimentsBlock copolymers containing poly((ethylene glycol) methacrylate)–co-poly(pentafluorophenyl methacrylate)-b-poly(hydroxypropyl methacrylate) (P((PEGMA-co-PFBMA)-b-PHPMA)) were synthesized at 10 wt% using PISA. The first approach involved in situ Doxorubicin (DOX) loading during PISA, while the second exhibited surface functionalization of PISA-made vesicles with dual drug therapies, N-acetyl cysteine (NAC) and DOX using para-fluoro-thiol reaction (PFTR) and carbodiimide chemistry, respectively. Cytotoxicity, cell uptake, and cell apoptosis were assessed on MDA-MB-231 cell lines. FindingsP((PEGMA-co-PFBMA)-b-PHPMA) nanocarriers were prepared, showing size and shape transformations from spheres, cylinders to raspberry-forming vesicles. DOX was readily loaded into NPs during PISA with relatively high encapsulation efficiency of 70 %, whereas the plain PISA-made vesicles could be functionalized with NAC and DOX at high yields. DOX-free NPs showed biocompatibility, whilst DOX-conjugated NPs imparted a concentration-dependent cytotoxicity, as well as an enhanced cell uptake compared to free DOX. The results demonstrated that the same PISA-derived self-assemblies enabled either in situ drug encapsulation, or post-polymerization surface engineering with useful functionalities upon tuning the macro-CTA block, thus holding promises for future drug delivery and biomedical applications.

Effect of Amphiphilic Graft Co-Polymer Carrier on Solubility and Dissolution Enhancement of Ambrisentan

Aim: Ambrisentan is a endothelin type A selective receptor antagonist used in the management of pulmonary arterial hypertension. Ambrisentan is BCS Class II drug haves very poor solubility in water and shows incomplete absorption after oral administration. The present work was aimed to study the effect of amphiphilic graft co-polymer carrier on enhancement of solubility and dissolution rate of poorly water soluble drug ambrisentan. To improve the aqueous solubility of ambrisentan solid dispersion was formulated by using novel carrier amphiphilic graft co-polymer (Soluplus® ).
 Materials and Methods: Solid dispersion was prepared by kneading technique by utilizing various ratios of carrier. Obtained solid dispersions ware evaluated for solubility, percentage yield, drug content and in vitro dissolution study. Powder characterization was performed by infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD).
 Results: FTIR spectroscopy shows no interaction between drug and polymer. DSC study showed that endothermic peak of drug was completely disappeared in Solid dispersion suggesting complete miscibility of drug in Soluplus®. XRD study suggest the conversion of crystalline ambrisentan in to amorphous form. All solid dispersions prepared with Soluplus® as a carrier showed increase in solubility. Solubility of ambrisentan was found to be increased 7.17 fold in optimized SD formulation ASD5. In vitro dissolution study showed the faster drug release from SD formulation compare to its pure form. All solid dispersion formulation’s release more than 50% of drug in first 10 min.
 Conclusion: This study conclude that the preparation of amphiphilic graft co-polymer based solid dispersion prepared by kneading technique is found to be useful in enhancement the solubility and dissolution rate of ambrisentan.

PH-Responsive Water-Soluble Polymer Carriers for Cell-Selective Metabolic Sialylation Labeling.

Cell-surface sialic acids can be metabolically labeled and subsequently modified using bioorthogonal chemistry. The method has great potential for targeted therapy and imaging; however, distinguishing the sialylation of specific cells remains a major challenge. Here, we described a cell-selective metabolic sialylation labeling strategy based on water-soluble polymer carriers presented with pH-responsive N-azidoacetylmannosamine (ManNAz) release. 2-Methacryloyloxyethyl phosphorylcholine contributed to increased water solubility and reduced nonspecific attachment to cells. Lactobionic acid residues, used for cell selectivity, recognized overexpressed receptors on target hepatoma cells and mediated cellular internalization. ManNAz caged by acidic pH-responsive carbonated ester linkage on the polymer was released inside target cells and expressed as azido sialic acid. Additionally, longer copolymer carriers enhanced the metabolic labeling efficiency of sialylation. This approach provides a platform for cell-selective labeling of sialylation and can be applied to high-resolution bioimaging and targeted therapy.

The development of a high-affinity conformation-sensitive antibody mimetic using a biocompatible copolymer carrier (iBody)

Peptide display methods are a powerful tool for discovering new ligands of pharmacologically relevant targets. However, the selected ligands often suffer from low affinity. Using phage display, we identified a new bicyclic peptide binder of prostate-specific membrane antigen (PSMA), a metalloprotease frequently overexpressed in prostate cancer. We show that linking multiple copies of a selected low-affinity peptide to a biocompatible water-soluble N-(2-hydroxypropyl)methacrylamide copolymer carrier (iBody) improved binding of the conjugate by several orders of magnitude. Furthermore, using ELISA, enzyme kinetics, confocal microscopy, and other approaches, we demonstrate that the resulting iBody can distinguish between different conformations of the target protein. The possibility to develop stable, fully synthetic, conformation-selective antibody mimetics has potential applications for molecular recognition, diagnosis and treatment of many pathologies. This strategy could significantly contribute to more effective drug discovery and design.

Polymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling

Drug repurposing is a promising strategy for identifying new applications for approved drugs. Here, we describe a polymer biomaterial composed of the antiretroviral drug ritonavir derivative (5-methyl-4-oxohexanoic acid ritonavir ester; RD), covalently bound to HPMA copolymer carrier via a pH-sensitive hydrazone bond (P-RD). Apart from being more potent inhibitor of P-glycoprotein in comparison to ritonavir, we found RD to have considerable cytostatic activity in six mice (IC50 ~ 2.3–17.4 μM) and six human (IC50 ~ 4.3–8.7 μM) cancer cell lines, and that RD inhibits the migration and invasiveness of cancer cells in vitro. Importantly, RD inhibits STAT3 phosphorylation in CT26 cells in vitro and in vivo, and expression of the NF-κB p65 subunit, Bcl-2 and Mcl-1 in vitro. RD also dampens chymotrypsin-like and trypsin-like proteasome activity and induces ER stress as documented by induction of PERK phosphorylation and expression of ATF4 and CHOP. P-RD nanomedicine showed powerful antitumor activity in CT26 and B16F10 tumor-bearing mice, which, moreover, synergized with IL-2-based immunotherapy. P-RD proved very promising therapeutic activity also in human FaDu xenografts and negligible toxicity predetermining these nanomedicines as side-effect free nanosystem. The therapeutic potential could be highly increased using the fine-tuned combination with other drugs, i.e. doxorubicin, attached to the same polymer system. Finally, we summarize that described polymer nanomedicines fulfilled all the requirements as potential candidates for deep preclinical investigation.

Nano-silica hybrid SDB carriers with high strength and hydrophobicity: synthesis, characterization and their application as sorbents of Ni2+

In Liquid Phase Catalytic Exchange (LPCE), the strength and hydrophobicity of styrene-divinylbenzene copolymer (SDB) carrier are key limitation factors for practical applications. In this paper, a surface-modified nano-SiO2 (KH570-SiO2) was used to improve the strength and hydrophobicity of SDB. Then, copolymerization of KH570SiO2 with St, DVB to produce KH570-SiO2/SDB, Divinyl benzene (DVB), styrene (St) glycidyl methacrylate (GMA) to produce KH570-SiO2/GMA/SDB. The two kinds of new carriers were characterized by scanning electron microscope, static water contact angle, N2 adsorption–desorption, transform infrared spectrometry and thermogravimetric analysis. Compared with SDB, both KH570-SiO2/SDB and KH570SiO2/GMA/SDB show better performances, such as a higher hydrophobicity(147° and 145°, respective), a higher strength(107.11 N and 115.37 N, respectively), a better thermal stability(373.8 and 435.67 ℃, respectively), and a larger specific surface area(487.253 and 463.673 m2/g, respective). The Nickel ion was uesd as the model ion of Platinum ion. And then the Ni2+ adsorption performances of KH570-SiO2/SDB and KH570-SiO2/GMA/SDB were studied. Experiments show that KH570-SiO2/GMA/SDB has a much higher adsorption rate and a bigger adsorption amount. Refinement indicates that the adsorption behaviors of SDB, KH570-SiO2/SDB and KH570-SiO2/GMA/SDB with Ni2+ are according to pseudo-first-order kinetic. The adsorption of SDB and KH570-SiO2/GMA/SDB obeyed Freundlich isotherm, while the adsorption of KH570-SiO2/SDB obeyed Langmuir isotherm.

Poly(L-Glutamic Acid)-Based Brush Copolymers: Fabrication, Self-assembly, and Evaluation as Efficient Nanocarriers for Cationic Protein Drug Delivery.

Protein drugs were considered to be the first choice to treat many human diseases, but their clinical application was usually limited by their short half-life and lack of validated targeted therapy. Here, a series of folate-functionalized poly(ethylene glycol)-b-(poly(2-aminoethyl-L-glutamate)-g-poly(L-glutamic acid))s (FA-PEG-b-(PELG-g-PLGA)s) were designed as tumor-targeted carriers for cationic protein delivery. Compared with traditional copolymers consisting of PEG and linear charged hydrophilic blocks, FA-PEG-b-(PELG-g-PLGA) with brush-like polyelectrolyte segments were beneficial to improving their electrostatic interactions with loading protein molecules, thus increasing drug-loading stability and protecting encapsulated proteins from degradation. The designed polymer brushes could efficiently encapsulate cytochrome C (CytC), a cationic model protein, to form polyion complex (PIC) micelles with an average particle size of approximately 200nm. An in vitro drug release study showed that the drug-loading stability of the formed PIC micelles was largely improved. The functionalization of the block copolymer carriers with a targeting folate group enhanced the tumor cell growth inhibition and total apoptotic rates induced by CytC. Our results shed light on the unique advantages of brush-like polymer carriers in delivering cationic proteins, and the poly(L-glutamic acid)-based linear-brush diblock copolymers could be applied as a versatile delivery platform for molecular targeting in cancer therapy.

Redox response, antibacterial and drug package capacities of chitosan-α-lipoic acid conjugates

Chitosan-α-lipoic acid (CS-LA) conjugates were prepared by amino reaction. The methotrexate (MTX) was successfully loaded within CS-LA copolymer by the ring-opening polymerizations of disulfide bond under the action of reducing agent. The obtained copolymer was investigated by fourier transform infrared spectrometer (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and nuclear magnetic resonance (1H NMR) analysis. The ring-opening polymerization process effected on rheological properties were studied. The graft of LA increased the apparent viscosity of CS-LA, and the loaded of MTX by redox reduced its apparent viscosity enormously. The load of MTX under the action of DTT decreased the apparent viscosity and moduli of CS-LA-MTX hydrogel. In dynamic oscillatory experiment, the package of MTX reduced the rigidity of CS-LA and damaged the gel structure of CS-LA. The antimicrobial ability of CS-LA against E. coli was processed by the inhibition zone and growth curves. The modification of LA raised the antibacterial activity of CS-LA. The cytotoxicity assay of CS-LA-MTX to prostate cancer cells (RM-1) was examined. The load of MTX within CS-LA-MTX greatly enhanced the cytotoxicity to RM-1 cells. In summary, CS-LA hydrogel may provide a new copolymer carrier for drug package in food and biomedical application.

Next-Generation Multimodality of Nanomedicine Therapy: Size and Structure Dependence of Folic Acid Conjugated Copolymers Actively Target Cancer Cells in Disabling Cell Division and Inducing Apoptosis.

Nanomedicine as a multimodality treatment of cancer utilizes the advantages of nanodelivery systems of drugs. They are superior to the clinical administration of different therapeutic agents in several aspects, including simultaneous delivery of drugs to the active site, precise ratio control of the loading drugs and overcoming multidrug resistance. The role of nanopolymer size and structural shape on the internalization process and subsequent intracellular toxicity is limited. Here, the size and shape dependent mechanism of a functionalized copolymer was investigated using folic acid (FA) covalently bonded to the copolymer poly (styrene-alt-maleic anhydride) (SMA) on its hydrophilic exterior via a biological linker 2,4-diaminobutyric acid (DABA) to target folic acid receptors (FR) overly expressed on cancer cells actively. We recently reported that unloaded FA-DABA-SMA copolymers significantly reduced cancer cell viability, suggesting a secondary therapeutic mechanism of action of the copolymer carrier post-internalization. Here, we investigated the size and shape dependent secondary mechanism of unloaded 350 kDa and 20 kDa FA-DABA-SMA. The 350 kDa and 20 kDa copolymers actively target folic acid receptors (FR) to initialize internationalization, but only the large size and sheet shaped copolymer disables cell division by intracellular disruptions of essential oncogenic proteins including p53, STAT-3 and c-Myc. Furthermore, the 350 kDa FA-DABA-SMA activates early and late apoptotic events in both PANC-1 and MDA-MB-231 cancer cells. These findings indicate that the large size and structural sheet shape of the 350 kDa FA-DABA-SMA copolymer facilitate multimodal tumor targeting mechanisms together with the ability to internalize hydrophobic chemotherapeutics to disable critical oncogenic proteins controlling cell division and to induce apoptosis. The significance of these novel findings reveals copolymer secondary cellular targets and therapeutic actions that extend beyond the direct delivery of chemotherapeutics. This report offers novel therapeutic insight into the intracellular activity of copolymers critically dependent on the size and structural shape of the nanopolymers.

Methionine Functionalized Biocompatible Block Copolymers for Targeted Plasmid DNA Delivery.

Reversible addition-fragmentation chain transfer (RAFT) polymerization integrates the advantages of radical polymerization and living polymerization. This work presents the preparation of methionine functionalized biocompatible block copolymers via RAFT polymerization. Firstly, N,N-bis(2-hydroxyethyl)methacrylamide-b-N-(3-aminopropyl)methacrylamide (BNHEMA-b-APMA, BA) was synthesized via RAFT polymerization using 4,4'-azobis(4-cyanovaleric acid) (ACVA) as an initiating agent and 4-cyanopentanoic acid dithiobenzoate (CTP) as the chain transfer agent. Subsequently, N,N-bis(2-hydroxyethyl)methacrylamide-b-N-(3-guanidinopropyl)methacrylamide (methionine grafted BNHEMA-b-GPMA, mBG) was prepared by modifying amine groups in APMA with methionine and guanidine groups. Three kinds of block polymers, mBG1, mBG2, and mBG3, were synthesized for comparison. A ninhydrin reaction was used to quantify the APMA content; mBG1, mBG2, and mBG3 had 21%, 37%, and 52% of APMA, respectively. Gel permeation chromatography (GPC) results showed that BA copolymers possess molecular weights of 16,200 (BA1), 20,900(BA2), and 27,200(BA3) g/mol. The plasmid DNA (pDNA) complexing ability of the obtained block copolymer gene carriers was also investigated. The charge ratios (N/P) were 8, 16, and 4 when pDNA was complexed completely with mBG1, mBG2, mBG3, respectively. When the N/P ratio of mBG/pDNA polyplexes was higher than 1, the Zeta potential of mBG was positive. At an N/P ratio between 16 and 32, the average particle size of mBG/pDNA polyplexes was between 100-200 nm. Overall, this work illustrates a simple and convenient protocol for the block copolymer carrier synthesis.

Multi-scale analysis of amorphous solid dispersions prepared by freeze drying of ibuprofen loaded acrylic polymer nanoparticles

Amorphous solid dispersions (ASDs) consisting of ibuprofen as a model drug, and Eudragit L100-55 as methacrylate copolymer carrier, were prepared by emulsification-diffusion method followed by freeze drying of nanoparticle suspensions. Subsequently, ibuprofen-loaded Eudragit L100-55 nanoparticles with different drug loadings were prepared. To understand the processing-structure-properties relationships, multi-scale analysis was performed. Average diameter of nanoparticles in all formulations was 234 ± 30 nm. Differential scanning calorimetry, X-ray diffraction and infrared spectroscopy showed that the formulations prepared from 9 to 16% of ibuprofen were fully amorphous while nano-crystalline domains localized inside the polymeric nanoparticles thanks to the atomic force microscopy analysis were detected in formulations prepared from higher content of ibuprofen (≥20%). Unexpected increase of the entrapment efficiency with the increase of ibuprofen loading was correlated with the increase of the viscosity of the organic phase. ASDs exhibited good dissolution profiles, characterized by sustained ibuprofen release, followed by supersaturation build-up. Physical stability tests performed on the ASDs showed that ibuprofen remained amorphous after 12 months of storage period. Therefore, Eudragit L100-55 plays a dual role in the ASDs, i.e. kinetic stabilization of ibuprofen in amorphous state during the storage period, and control of the drug release, and subsequent stabilization of the supersaturated state.

Study of target spacing of thermo-sensitive carrier on the activity recovery of immobilized penicillin G acylase.

The immobilized penicillin G acylase (PGA) is an important industrial catalyst, the activity recovery rate of it directly affects enterprise efficiency. How to improve the enzyme activity recovery rate has been a research focus in this field. Based on the above problems, this work further improved the activity recovery rate by adjusting the target spacing for the first time. Glycidyl methacrylate (GMA) was used as the immobilized target and methyl methacrylate (MMA) as the copolymer monomer. According to the copolymer composition equation of P(MMA-co-GMA), the thermo-sensitive copolymers, PDEA-b-PHEMA-b-P(MMA-co-GMA) with different target spacings, were synthesized rapidly and efficiently via reversible addition-fragmentation chain transfer (RAFT) polymerization method. The error range between the theoretical and actual values of MMA and GMA in the copolymers carrier was (0-4)%, which demonstrated that the reliability of using composition equation to accurately and quickly synthesize copolymers with specific spacing. Studies on the thermo-sensitive showed that the low critical solution temperature (LCST) of the copolymer carrier decreased with the increase of hydrophobic monomer. Most importantly, the activity recovery rate increased with the increase of target spacing, and when the molar ratio of MMA to GMA in the copolymer was 8.75:1, the recovery of activity of immobilized PGA could be up to 63.50%, which was 21.70% higher than that of pure GMA. This work provided an important idea for improving the activity of immobilized PGA.

The inactivation of the non-enveloped enterovirus 71 (EV71) by a novel disinfectant gel formulation for topical use

Background: Hand-foot-mouth disease may cause severe central nervous system complications and even death, that is induced mainly by enterovirus 71 (EV71), which is a non-enveloped virus. Inactivation of the EV71 on hands could effectively inhibit the transmission. However, the inactivations of the EV71 by conventional disinfectants including the alcohols are poor, due to the high stability of the EV71. A novel pyridyl imidazolidinone compound (TJAB1099) was designed to specifically inhibit EV71 replication in vitro. It may potentially be developed as formulations applied on hands for EV71 transmission control.Methods: The stress stability of TJAB1099 was first evaluated after storing in high temperature (60 °C, RH 10%), high humidity (25 °C, RH90%), and the high-intensity photolysis (4500 Lx ± 500 Lx) for 15 days, respectively. A wash-free antimicrobial gel containing the TJAB1099 was developed using the copolymer carrier. The antiviral activity, the acute oral toxicity, and the local irritation of the antimicrobial gel were evaluated accordingly.Results: The results indicated that the TJAB1099 was stable during the storage in high temperature and humidity. However, a significant change (p < .0001) was detected when TJAB1099 stored in the high-intensity photolysis. The antimicrobial gel containing 1 μM TJAB1099 could inhibit EV71 significantly higher than the ethanol (75%) (p < .0001) and commercialized disinfectant products (p < .0001). The results of acute oral toxicity and the local irritation suggest that the TJAB1099 containing antimicrobial gel was not causing skin irritations and acute oral toxicity symptoms.Conclusions: The results suggest that the antimicrobial gel containing TJAB1099 was safe and could effectively inhibit EV71 transmission in vitro.

Multifunctional Amine-Containing PVA-g-POEM Graft Copolymer Membranes for CO2 Capture

CO2 separation technology using polymeric membranes has emerged as a viable solution to mitigate the rapidly increasing anthropogenic CO2 emissions, which are directly linked to global warming and climate anomalies. However, in order to improve the gas separation performance, an intrinsic problem of polymeric membranes, i.e., a trade-off relationship between permeability and selectivity, needs to be addressed. In this study, a solid-state facilitated transport membrane is prepared by blending CO2-philic, amine-compatible poly(vinyl alcohol)-g-poly(oxyethylene methacrylate) (PVA-g-POEM) graft copolymer and diethylenetriamine (DETA) carriers. The graft copolymer consisting of PVA main chains and POEM side chains is synthesized via one-pot free radical polymerization and used as a polymer matrix. With the incorporation of 10 wt % of DETA into the polymer, the membrane exhibits a high CO2 permeance of 402.5 GPU (1 GPU = 10–6 cm3(STP)/(s·cm2·cmHg)) and CO2/N2 selectivity of 52.1. The enhanced performance of th...