Disulfide-Linked Amphiphilic Polymer-Docetaxel Conjugates Assembled Redox-Sensitive Micelles for Efficient Antitumor Drug Delivery.

Here, we prepared novel redox-sensitive drug delivery system based on copolymer-drug conjugates methoxy poly(ethylene glycol)-poly(γ-benzyl l-glutamate)-disulfide-docetaxel (mPEG-PBLG-SS-DTX) to realize the desirable cancer therapy. First, copolymers of methoxy poly(ethylene glycol)-poly(γ-benzyl l-glutamate) (mPEG-PBLGs) with different molecular weight (mPEG2000-PBLG1750 and mPEG5000-PBLG1750) were synthesized via the ring open polymerization (ROP) of 5-benzyl-l-glutamate-N-carboxyanhydride (γ-Bzl-l-Glu-NCA) initiated by monoamino-terminated mPEG (mPEG-NH2). Then, the docetaxel (DTX) was conjugated to the block polymers through a linkage containing disulfide bond to obtain mPEG-PBLG-SS-DTXs, including mPEG2000-PBLG1750-SS-DTX and mPEG5000-PBLG1750-SS-DTX. The obtained copolymer-drug conjugates mPEG2000-PBLG1750-SS-DTX and mPEG5000-PBLG1750-SS-DTX could self-assemble into nanosized micelles in aqueous environment via dialysis method with a low critical micelle concentration (CMC, 3.98 and 6.94 µg/mL, respectively). The size of the micelles was approximately 101.3 and 148.9 nm, respectively, with a narrow size distribution. They released approximately 40% DTX in a sustained way in the presence of 50 mM DTT after 120 h in comparison with only approximately 10% DTX released from micelles in the absence of DTT. The high cytotoxicity was identified for mPEG-PBLG-SS-DTXs micelles against MCF-7/ADR and A549 cells, and the IC50 of mPEG-PBLG-SS-DTXs micelles against MCF-7/ADR for 24 h was roughly a 15th of the value of free DTX. Moreover, the mPEG-PBLG-SS-DTXs micelles could be efficiently uptaken by MCF-7/ADR and A549 cells. Thus, the present constructed mPEG-PBLG-SS-DTXs micelles were very promising for effective cancer therapy.

Faceted fatty acid vesicles formed from single-tailed perfluorinated surfactants.

The aggregation behavior and rheological properties of two mixtures of perfluorononanoic acid (PFNA)/NaOH and perfluorodecanoic acid (PFDA)/NaOH were investigated in aqueous solutions. Interestingly, pH-sensitive polyhedral fatty acid vesicles were spontaneously formed in both systems, which were determined by freeze-fracture transmission electron microscopy (FF-TEM) measurements. Especially, a phase transition from faceted vesicles to the L3 phase with the increase of pH was observed in the PFNA/NaOH system while it was not observed in the PFDA/NaOH system. Differential scanning calorimetry (DSC) and wide angle X-ray scattering (WAXS) measurements confirmed that the bilayers of the faceted vesicles were in the crystalline station indicating that the crystallization of fluorocarbon chains was the main driving force for their formation. Besides, the two systems of faceted perfluorofatty acid vesicles exhibit interesting rheological properties, for instance, they showed high viscoelasticity and shear-thinning behaviour, and the elastic modulus (G') and viscous modulus (G'') of PFDA/NaOH vesicles were much higher than those of PFNA/NaOH vesicles. Conversely, the solution of the L3 phase with fluid bilayers did not present viscoelastic properties. Therefore, the viscoelastic properties of vesicles resulted from the crystalline fluorinated alkyl chains with high rigidity at room temperature and the dense packing of vesicles. As far as we know, such faceted fatty acid vesicles formed from single-tailed perfluorinated surfactants have been rarely reported. Our work successfully constructs polyhedral fatty acid vesicles and proposes their formation mechanism, which should be a great advance in the fundamental research of fatty acid vesicles.

Polymorphic transient glycolipid assemblies with tunable lifespan and cargo release.

HYPOTHESIS: In living systems, dynamic processes like dissipative assembly, polymorph formation, and destabilization of hydrophobic domains play an indispensable role in the biochemical processes. Adaptation of biological self-assembly processes to an amphiphilic molecule leads to the fabrication of intelligent biomaterials with life-like behavior. EXPERIMENTS: An amphiphilic glycolipid molecule was engineered into various dissipative assemblies (vesicles and supramolecular nanotube-composed hydrogels) by using two activation steps, including heating-cooling and shear force in method-1 or boric acid/glycolipid complexation and shear force in method-2. The influence of number of activation steps on vesicle to nanotube phase transitions and activation method on the properties of hydrogels were investigated, where the morphological transformations and destabilization of hydrophobic domains resulted from a bilayer to a higher-order crystal structure. FINDINGS: Hydrophobic and hydrophilic cargos encapsulated in the dissipative assemblies (vesicles and injectable hydrogels) can be released in a controlled manner via changing the activation method. The reported adaptive materials engineered by dual activation steps are promising self-assembled systems for programmed release of loaded cargos at a tunable rate.

Pegylated Interferon Treatment for the Effective Clearance of Hepatitis B Surface Antigen in Inactive HBsAg Carriers: A Meta-Analysis.

Background: Expanding antiviral therapy to benefit more populations and optimizing treatment to improve prognoses are two main objectives in current guidelines on antiviral therapy. However, the guidelines do not recommend antiviral therapy for inactive hepatitis B surface antigen (HBsAg) carriers (IHCs). Recent studies have shown that antiviral therapy is effective with good treatment outcomes in IHC populations. We conducted a systematic review and meta-analysis of HBsAg clearance and conversion in IHCs. Methods: We searched PubMed, Embase, Medline, and Web of Science to retrieve articles on HBsAg clearance in IHCs published between January 2000 and August 2021. Data were collected and analysed using the random-effects model for meta-analysis. Results: A total of 1029 IHCs from 11 studies were included in this analysis. The overall HBsAg clearance rate was 47% (95% confidence interval (CI): 31% - 64%), with a conversion rate of 26% (95% CI: 15% - 38%) after 48 weeks of Pegylated interferon (Peg-IFN) treatment. In the control group (including nucleos(t)ide analogue (NA) treatment or no treatment), the overall HBsAg clearance rate was only 1.54% (95% CI: 0.56% - 3.00%), which was markedly lower than that in the Peg-IFN group. Further analysis showed that a low baseline HBsAg level and long treatment duration contributed to a higher HBsAg clearance rate. Conclusion: This study showed that treatment of IHCs can be considered to achieve a clinical cure for chronic hepatitis B virus (HBV) infection. After Peg-IFN treatment, the HBsAg clearance rate was 47%, and the conversion rate was 26%, which are markedly higher than those reported by previous studies on Peg-IFN treatment in patients with chronic hepatitis B (CHB). A low baseline HBsAg level and long treatment duration were associated with HBsAg clearance in IHCs. Therefore, antiviral therapy is applicable for IHCs, a population who may be clinically cured. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO, CRD): CRD42021259889.

Effect of hydrophilic groups of Ca surfactants and hydrophobic chains of C(n)DMAO on coordinated vesicle formation.

The effects of hydrophilic headgroups of Ca surfactants, calcium dodecylsulfate (Ca(DS)(2)), calcium dodecylsulfonate (Ca(DSA)(2)), and calcium laurate (CaL(2)) and hydrophobic chains of alkyldimethylamine oxide (C(n)DMAO, n = 12, 14, 16) on the formation of Ca(2+)-ligand coordinated vesicles was investigated in detail. On the basis of phase behavior studies, rheological properties and freeze-fracture transmission electron microscope (FF-TEM) images were measured. Quite different phase behaviors were observed in different surfactant systems. For a Ca surfactant with a highly polar group, Ca(DS)(2), vesicles were observed in all Ca(DS)(2)/C(n)DMAO (n = 12, 14, and 16) systems, whereas for Ca surfactant with lower polar group, Ca(DSA)(2), vesicles can form in Ca(DSA)(2)/C(n)DMAO systems of n = 14 and 16 but not for n = 12. For CaL(2), the surfactant with the least polar group, vesicles form only in the CaL(2)/C(16)DMAO system. The results demonstrate that in the systems formed by Ca surfactants and C(n)DMAO, the formation of vesicles is driven not only by interaction between Ca(2+) and the N → O groups of C(n)DMAO but also by electrostatic and hydrophobic interactions. Vesicles prefer to form in Ca surfactants with highly polar headgroups and C(n)DMAO with long chain length.

Metal-ligand-coordinated vesicles and vesicle-assisted preparation of calcium oxalate.

A Ca(2+) -ligand-coordinated vesicle phase was prepared from a mixture of tetradecyldimethylamine oxide (C14DMAO) and calcium tetradecylamidomethyl sulfate [(CH3(CH2)13NHCOCH2OSO3)2Ca] in aqueous solution. At the appropriate mixing ratios, Ca(2+) -ligand coordination results in the formation of molecular bilayers because Ca(2+) can firmly bind to the head groups of C14DMAO and (CH3(CH2)13NHCOCH2OSO3)2Ca by complexation which reduces the area of head group. In this system, no counterions in aqueous solution exist because of the Ca(2+) -ligand coordination, and the bilayer membranes are not shielded by salts, i.e., a salt-free but charged molecular bilayer. The structures of the birefringent solutions of (CH3(CH2)13NHCOCH2OSO3)2Ca and C14DMAO mixtures were determined by transmission electron microscopy (TEM) images and rheological measurements, demonstrating that the birefringent sample solutions consist of vesicles. The Ca(2+) -ligand complex vesicle phase was used as a microreactor to prepare calcium oxalate (CaC2O4) crystals. Dimethyl oxalate, as a precursor, can hydrolyze to oxalic acid and methanol. Oxalic acid should precipitate Ca(2+) ions binding to the head groups of C14DMAO and (CH3(CH2)13NHCOCH2OSO3)2Ca to produce CaC2O4 crystals (Ca(2+) + H2C2O4 --> CaC2O4 (downward arrow) + 2H+). The obtained particles were CaC2O4 monohydrate, which were dominated by (020) faces. CaC2O4 precipitates were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared (FT-IR) analysis. After removal of CaC2O4 precipitates, a new cationic and anionic (catanionic) vesicle phase was constructed through electrostatic interaction between cationic C14DMAOH+ (C14DMAO + H+ --> C14DMAOH+) and anionic CH3(CH12)13 NHCOCH2OSO3-.

Redox-sensitive micelles assembled from amphiphilic mPEG-PCL-SS-DTX conjugates for the delivery of docetaxel.

Docetaxel (DTX) can produce anti-tumor effects by inhibiting cell growth and inducing apoptosis. However, the poor solubility of DTX restricts its application and its clinical formulation has caused serious adverse reaction due to the use of Tween-80. In the present study, DTX was conjugated to an amphiphilic di-block polymer to solve these problems. Methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was selected as the polymer skeleton and a redox sensitive disulfide bond was used as the linker between DTX and mPEG-PCL. The synthesized mPEG-PCL-SS-DTX conjugates were characterized by (1)H-nuclear magnetic resonance ((1)H NMR) and Fourier transform infrared spectroscopy (FTIR). Interestingly, the mPEG-PCL-SS-DTX conjugates could self-assemble into micelles in aqueous solution. The critical micelle concentration (CMC) of mPEG-PCL-SS-DTX micelles was about 2.3mgL(-1) determined using pyrene molecule fluorescent probe method while the size of mPEG-PCL-SS-DTX micelles was determined to be ca. 17.6nm and 116.0nm with a bimodal distribution by dynamic light scattering (DLS). The in vitro release results indicated that the as-prepared micelles exhibited a sustained release profile with good redox sensitive properties. In particular, the hemolytic toxicity test indicated the as-prepared mPEG-PCL-SS-DTX micelles had negligible hemolytic activity, demonstrating their safety in drug delivery system. Cytotoxicity assay of the mPEG-PCL-SS-DTX micelles verified their highly enhanced cytotoxicity to MCF-7/A and A549 cells. These results thus demonstrated that the present redox-sensitive mPEG-PCL-SS-DTX micelle was an efficient and safe sustained drug delivery system in the biomedical area.

Active targeting co-delivery system based on pH-sensitive methoxy-poly(ethylene glycol)2K-poly(ε-caprolactone)4K-poly(glutamic acid)1K for enhanced cancer therapy.

In this paper, we successfully synthesized folate-modified pH-sensitive copolymer methoxy-poly(ethylene glycol)2K-poly(ε-caprolactone)4K-poly(glutamic acid)1K (mPEG2K-PCL4K-PGA1K-FA), which could form the polymeric assembly in an aqueous solution, for co-delivering hydrophilic drugs doxorubicin hydrochloride (DOX) and verapamil hydrochloride (VER) (FA-poly(DOX+VER)). Since VER was an effective P-glycoprotein inhibitor, the combination of DOX and VER could reverse the multidrug resistance efficiently and enhance the therapeutic effect. Therefore, the inhibition ratios of MCF-7/ADR resistant cancer cell treated by FA-poly (DOX+VER) were almost more than 30% higher than those of FA-polyDOX after 48h and 72h. Furthermore, the conjugation of FA could lead the co-delivery systems actively targeting into the FA receptor over-expressing cancer cells in addition to the passive accumulation of the assembly in tumor tissues. Importantly, the prepared mPEG2K-PCL4K-PGA1K-FA assembly showed high pH-sensitive property, which made the drugs mostly released in tumor tissue (acid environment) than in physiological environment (neutral environment). In summary, the as-prepared co-delivery system FA-poly(DOX+VER) demonstrated a high efficiency in reversing the multidrug resistance and targeting FA receptor to improve the anticancer effect of DOX in MCF-7/ADR resistant cells.

Fluorescent oligomer as a chemosensor for the label-free detection of Fe(3+) and dopamine with selectivity and sensitivity.

In this article, a sensitive and selective turn-off fluorescence chemosensor, Tyloxapol (one kind of water soluble oligomer), was developed for the label-free detection of Fe(3+) ions in aqueous solution. Fluorescence (FL) experiments demonstrated that Tyloxapol was a sensitive and selective fluorescence sensor for the detection of Fe(3+) directly in water over a wide range of metal cations including Na(+), K(+), Ag(+), Hg(2+), Cd(2+), Co(2+), Cu(2+), Cr(3+), Mn(2+), Ba(2+), Zn(2+), Ni(2+), Mg(2+), Ca(2+), and Pb(2+). Moreover, the fluorescence intensity of Tyloxapol has shown a linear response to Fe(3+) in the concentration range of 0-100 µmol L(-1) with a detection limit of 2.2 µmol L(-1) in aqueous solution. Next, based on a competition mechanism, another turn-on sensing application of the Tyloxapol/Fe(3+) platform to probe dopamine (DA) against various other biological molecules such as other neurotransmitters or amino acids (norepinephrine bitartrate, acetylcholine chloride, alanine, valine, phenylalanine, tyrosine, leucine, glycine, histidine) were also investigated. It is expected that our strategy may offer a new approach for developing simple, cost-effective, rapid and sensitive sensors in biological and environmental applications.

Two routes to vesicle formation: metal-ligand complexation and ionic interactions.

Two routes to vesicle formation were designed to prepare uni- and multilamellar vesicles in salt-free aqueous solutions of surfactants. The formation of a surfactant complex between a double-chain anionic surfactant with a divalent-metal ion as the counterion and a single-chain zwitterionic surfactant with the polar group of amine-oxide group is described for the first time as a powerful driving force for vesicle-phases constructed from salt-free mixtures of aqueous surfactant solutions. As a typical example, a Zn(2+)-induced charged complex fluid, vesicle-phase has been studied in aqueous mixtures of tetradecyldimethylamine oxide (C(14)DMAO) and zinc 2,2-dihydroperfluorooctanoate [Zn(OOCCH(2)C(6)F(13))(2)]. This ionically charged vesicle-phase formed due to surfactant complexation has interesting rheological properties and is not shielded by excess salts because there are no counterions in the solution. Such a vesicle-phase of surfactant complex is important for many applications; for example, the vesicle-phase was further used to produce in situ the vesicle-phase of the salt-free cationic/anionic (catanionic) surfactants, C(14)DMAOH(+)-(-)OOCCH(2)C(6)F(13). The salt-free catanionic vesicle-phase could be produced through injecting H(2)S gas into the C(14)DMAO/Zn(OOCCH(2)C(6)F(13))(2) vesicle-phase, because the zwitterionic surfactant C(14)DMAO can be charged by the H(+) released from H(2)S to become a cationic surfactant and Zn(2+) was precipitated as ZnS. After the ZnS precipitates were removed from C(14)DMAO/Zn(OOCCH(2)C(6)F(13))(2) solutions, the final mixed solution does not contain excess salts as do other cationic/anionic surfactant systems. Both the C(14)DMAO-Zn(OOCCH(2)C(6)F(13))(2) complex and the resulting catanionic C(14)DMAOH(+)-(-)OOCCH(2)C(6)F(13) solution are birefringent Lalpha-phase solutions that consist of uni- and multilamellar vesicles. Ring-shaped semiconductor ZnS materials with encapsulated ZnS precipitates and regular spherical ZnS particles were prepared, which resulted in a transition from vesicles composed of metal-ligand complexes to vesicles held together by ionic interactions in the salt-free aqueous systems. This strategy should provide a new method to prepare inorganic materials. The present routes to form vesicles solve a problem: how to prepare nanomaterials using surfactant self-assembly, with structure controlled not by the growing material, but by the phase behavior of the surfactants.

Room-temperature super hydrogel as dye adsorption agent.

Supramolecular hydrogels were prepared in the mixtures of a chiral amphiphilic lithocholic acid (LCA) and a nonionic surfactant, dodecyldimethylamine oxide (C(12)DMAO), in water. With the addition of LCA to C(12)DMAO micellar solutions, a transition from micelles to gels occurs at room temperature. Hydrogels can form at very low concentrations (below 0.1 wt %), exhibiting a super gelation capability. The rheological measurements show a strong mechanical strength with an elastic modulus exceeding 5000 Pa and a yield stress exceeding 100 Pa. Microstructures determined by TEM, SEM, and AFM observations demonstrate that the gels are formed by intertwined helical fibrils. The formation of fibrils is induced by enormous cycles of units composed of two LCA molecules and four C(12)DMAO molecules driven by comprehensive noncovalent interaction, especially the hydrogen bonds produced in two reversed LCA molecules and the C(12)DMAOH(+)-C(12)DMAO pairs. The xerogels show excellent adsorption capability of the toxic dye with a maximum adsorption value of 202 mg·g(-1).

Huperzine A-phospholipid complex-loaded biodegradable thermosensitive polymer gel for controlled drug release.

The huperzine A-phospholipid complex loaded biodegradable thermosensitive PLGA-PEG-PLGA polymer gel was studied as injectable implant system for controlled release of huperzine-A (HA). First, HA molecules were successfully incorporated into the soybean phosphatidylcholine (SP) molecules to form the huperzine-A-soybean phosphatidylcholine complexes (HA-SPC), which was proved by FT-IR, DSC, XRD, solubility study, TEM, etc. The results indicated that hydrogen bonds and electrostatic interaction between HA and SP molecules play an important role in the formation of HA-SPC. Secondly, the HA-SPC was loaded into biodegradable PLGA-PEG-PLGA thermosensitive gel as injectable implant material to control the release of HA. The in vitro and in vivo drug release behaviors of the prepared products were studied. The in vitro release studies demonstrated that the HA-SPC-loaded gel significantly reduced the initial burst of drug release and extended the release period to about 2 weeks. The in vivo pharmacokinetics study of HA-SPC-loaded gel in rabbits showed that plasma concentration of HA (2.54-0.15ng/mL) was detected for nearly 2 weeks from delivery systems upon single subcutaneous injection. What's more, the in vitro release pattern correlated well with the in vivo pharmacokinetics profile. The present study indicates that HA-SPC loaded PLGA-PEG-PLGA thermal gel may be an attractive candidate vehicle for controlled HA release.

Mg2+-induced vesicles of tetradecyldimethylamine oxide and magnesium dodecyl sulfate.

A Mg2+-induced vesicle phase was prepared from a mixture of tetradecyldimethylamine oxide (C14DMAO) and magnesium dodecyl sulfate [Mg(DS)2] in aqueous solution. Study of the phase behavior shows that at the appropriate mixing ratios, Mg2+-ligand coordination between C14DMAO and Mg(DS)2 results in the formation of molecular bilayers, in which Mg2+ can firmly bind to the head groups of the two surfactants. The area of the head group can be reduced because of the complexation. In this case, no counterions exist in aqueous solution because of the fixation of Mg2+ ions to the bilayer membranes. Therefore, the charges of the bilayer membranes are not shielded by salts. The birefringent solutions of Mg(DS)2 and C14DMAO mixtures consist of vesicles which were determined by transmission electron microscopy (TEM) images and rheological measurements. Magnesium oxide (MgO) nanoplates were obtained via the decomposition of Mg(OH)2 which were synthesized in Mg2+-induced vesicle phase which was used as the microreactor under the existence of ammonia hydroxide. The morphologies and structures of the obtained MgO nanoplates have been characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The results indicate that the crystal growth is along the (111) direction which can be affected by the presence of a vesicle phase having a fixation of Mg2+ ions to the bilayer membranes.

Ca2+- and ba2+-ligand coordinated unilamellar, multilamellar, and oligovesicular vesicles.

Ca(2+)- and Ba(2+)-coordinated vesicle phases were prepared in mixed aqueous solutions of tetradecyldimethylamine oxide (C(14)DMAO) and calcium oleate (Ca(OA)(2)) or barium oleate (Ba(OA)(2)). At the right mixing ratios, metal-ligand coordination between Ca(OA)(2) or Ba(OA)(2) and C(14)DMAO results in the formation of molecular bilayers due to the reduction in area per head group. Ca(2+) and Ba(2+) tightly associate to the head groups of surfactants and in this system the bilayer membranes are not shielded by excess salts. The structures of the birefringent samples of the Ca(OA)(2)/C(14)DMAO/H(2)O and Ba(OA)(2)/C(14)DMAO/H(2)O systems were determined by freeze-fracture transmission electron microscopy (FF-TEM), small-angle X-ray scattering (SAXS), and rheological measurements to consist of unilamellar, multilamellar, and oligovesicular vesicles. The coordination between C(14)DMAO and Ba(OA)(2) or Ca(OA)(2) plays an important role in the formation of the vesicles, which was easily confirmed by studying the phase behavior of the KOA/C(14)DMAO/H(2)O system in which only the L(1) phase forms, due to the absence of coordination between KOA and C(14)DMAO. A mechanism is proposed that accounts for the formation of these new metal-ligand coordinated vesicles.