Redox-sensitive micelles for targeted intracellular delivery and combination chemotherapy of paclitaxel and all-trans-retinoid acid

The application of paclitaxel(PTX) in clinic has been restricted due to its poor solubility.Several traditional nano-medicines have been developed to improve this defect,while they are still lack of tumor targeting ability and rapid drug release. In this work,an amphiphilic polymeric micelle of hyaluronic acid(HA) – all-trans-retinoid acid(ATRA) with a disulfide bond,was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with selfassembling to micelles in water,the delivery system displayed satisfying drug loading capacities for both PTX(32.62% ± 1.39%) and ATRA,due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles(HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides,HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16 F10 cells. Due to these properties,cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly,HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore,redox-sensitive HASS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.

Pure redox-sensitive paclitaxelemaleimide prodrug nanoparticles: Endogenous albumininduced size switching and improved antitumor efficiency

A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer.However,its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier.Herein,we report an albumin-bound tumor redoxresponsive paclitaxel prodrugs nano-delivery strategy.Using diverse linkages(thioether bond and disulfide bond),paclitaxel(PTX)was conjugated with an albumin-binding maleimide(MAL)functional group.These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles(NPs)in aqueous solution without any excipients.By immediately binding to blood circulating albumin after intravenous administration,NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates in vivo,facilitating PTX prodrugs accumulation in the tumor region via albumin receptormediated active targeting.The tumor redox dual-responsive drug release property of prodrugs improves the selectivity of cytotoxicity between normal and cancer cells.Moreover,disulfide bond-containing prodrug/albumin nanoaggregates exhibit long circulation time and superior antitumor efficacy in vivo.This simple and facile strategy integrates the biomimetic characteristic of albumin,tumor redox-responsive on-demand drug release,and provides new opportunities for the development of the high-efficiency antitumor nanomedicines.

Preparation of polydopamine based redox-sensitive magnetic nanoparticles for doxorubicin delivery and MRI detection

To improve the water-dispersity of superparamagnetic iron oxide nanoparticles(SPIONs),a novel polydopamine based redox-sensitive copolymer modified SPIONs were prepared for the biomedical application to deliver doxorubicin(DOX)and magnetic resonance imaging(MRI)detection.The major components of this nanoparticle include SPIONs and the redox-sensitive polydopamine(rPDA)crosslinked copolymer,where N,N-Bis(acryloyl)cystamine served as cross-linker,dopamine methacrylamide and a long-chain polyethylene glyco methyl ether methacrylate acted as comonomers.Here the rPDA@SPIONs were formed by the ligand exchange reaction of dopamine moiety with the oleic acid layer capped on the surface of SPIONs,and the inner area of the nanoparticles formed a reservoir for DOX,while the hydrophilic PEG moiety helped the nanoparticles well-dispersible in aqueous solution.The DOX-loaded rPDA@SPIONs demonstrated a high drug loading efficiency of 857μg DOX per mg iron,and a strong T2 relaxivity of 123 mM-1•S^(-1)for MRI.The drug release analysis of drug-loaded nanoparticles showed a sustained and high cumulative drug release in GSH up to 73%within 48 h,rather than the relatively low release rate of 37%in PBS(pH 7.4)without GSH.All the results showed that the designed magnetic nanoparticle may be a promising vehicle for anticancer drug delivery with stimuli-triggered drug release behavior,and also a foundation for building smart theranostic formulations for efficient detection through MRI.

Redox-responsive biocompatible nanocarriers based on novel heparosan polysaccharides for intracellular anticancer drug delivery

Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be designed as anticancer drug carriers to increase tumor selectivity and improve the therapeutic effect. A novel redox-sensitive heparosancystamine-vitamin E succinate(KSV) micelle system was constructed for intracellular delivery of doxorubicin(DOX). Simultaneously, the redox-insensitive heparosan-adipic acid dihydrazide-vitamin E succinate copolymer(KV) was synthesized as control. DOX-loaded micelles(DOX/KSV) with an average particle size of 90–120 nm had good serum stability and redox-triggered depolymerization. In vitro drug release test showed that DOX/KSV micelles presented obvious redox-triggered release behavior compared with DOX/KV. Cytotoxicity and cell uptake were investigated using MGC80-3 tumor cells and COS7 fibroblast-like cells. The cell survival rate of blank micelles was more than 90%, and the cytotoxicity of DOX/KSV in MGC80-3 cells was higher than in COS7 cells, indicating that the carrier has better biocompatibility and less toxicity side effect. The cytotoxicity of DOX/KSV against MGC80-3 cells was significantly greater than that of free DOX and DOX/KV. Furthermore, compared with DOX/KV in MGC80-3 cells, DOX/KSV micelles uptook more anticancer drugs and then released DOX faster into the cell nucleus. The micelles were endocytosed by multiple pathways, but clathrin-mediated endocytosis was the main pathway. Therefore, heparosan polysaccharide could be a potential option as anticancer carrier for enhancing efficacy and mitigating toxicity.

Redox conditions in sediments and during sedimentation in the Ontong Java Plateau,west equatorial Pacific

Redox-sensitive elements in sediments, such as manganese （Mn）, vanadium （V）, molybdenum （Mo）, and uranium （U）, are promising indicators of past redox conditions during sedimentation and early diagenesis. However, in the Ontong Java Plateau, west equatorial Pacific, there are sparse datasets of redox-sensitive elements in sediment cores. Here, we present a 250 ka record of redox sensitive elements from a 460 cm gravity core at site WP7 （3~56＇S, 156^.E, water depth 1 800 m）, which was recovered from the southwest Ontong Java Plateau during the 1993 cruise of R/V Science I of the Institute of Oceanology, Chinese Academy of Sciences （IOCAS）. Relative to the Post-Archean Australian Shale （PAAS）, authigenic Mn, cobalt （Co）, nickel （Ni）, Mo, V, U, and cadmium （Cd） were found at constantly low levels except when peaks occurred at several depth intervals. Manganese, Co, Ni, and Mo concentrations were elevated at 25-35 cm due to Mn redox cycling. The core was divided into three distinct sections, the top 0-25 cm being oxic, a suboxic section at 25-35 cm and from 35-460 cm which was anoxic. Differential authigenic enrichments of Co, Ni, Mo, V, U, and Cd at the same depth intervals were observed indicating that the enrichments happened during sedimentation or diagenesis and suffered no post settlement redox changes. Therefore, no significant changes in redox conditions during sedimentation must have happened. The water at depth on the Ontong Java Plateau during past 250 ka must have been well oxygenated, possibly resulted from the more or less continuous presence of oxygen-rich deep water like the modem Antarctic Intermediate Water （AAIW） and Antarctic Circumpolar Water （ACW）; while it＇s slightly less oxygenated in glacial intervals, possibly due to ventilation weakening and/or the surface productivity increase.

Redox states of underground brine system along the southern coast of the Laizhou Bay

Underground brine samples were collected along the southern coast of the Laizhou Bay, Shangdong, China in two field investigations in 2003. The brines are confined in the Quaternary sediment and underwent a series of geochemical changes. The redox states of these brines were assessed qualitatively based on the measurements of Eh and redox-sensitive species such as DO, NO NO~, Mn2＋, Fe2＋, SO4^2- in the brines. The redox condition of the underground brine is anoxic, and the redox reactions that controlled the redox potential of brines should be Fe（Ⅲ） reduction and sulfate reduction.

A shift in redox conditions near the Ediacaran/Cambrian transition and its possible influence on early animal evolution,CorumbáGroup,Brazil

The Ediacaran-Cambrian transition witnessed some of the most important biological,tectonic,climatic and geochemical changes in Earth's history.Of utmost importance for early animal evolution is the likely shift in redox conditions of bottom waters,which might have taken place in distinct pulses during the late Ediacaran and early Paleozoic.To track redox changes during this transition,we present new trace element,total organic carbon and both inorganic and organic carbon isotopes,and the first iron speciation data on the Tamengo and Guaicurus formations of the CorumbáGroup in western Brazil,which record important paleobiological changes between 555 Ma to<541 Ma.The stratigraphically older Tamengo Formation is composed mainly of limestone with interbedded marls and mudrocks,and bears fragments of upper Ediacaran biomineralized fossils such as Cloudina lucianoi and Corumbella werneri.The younger Guaicurus Formation represents a regional transgression of the shallow carbonate platform and is composed of a homogeneous fine-grained siliciclastic succession,bearing meiofaunal bilateral burrows.The new iron speciation data reveal predominantly anoxic and ferruginous(non-sulfidic)bottom water conditions during deposition of the Tamengo Formation,with FeHR/FeT around 0.8 and FePy/FeHR below 0.7.The transition from the Tamengo to the Guaicurus Formation is marked by a stratigraphically rapid drop in FeHR/FeT to below 0.2,recording a shift to likely oxic bottom waters,which persist upsection.Redox-sensitive element(RSE)concentrations are muted in both formations,but consistent with non-sulfidic bottom water conditions throughout.We interpret the collected data to reflect a transition between two distinct paleoenvironmental settings.The Tamengo Formation represents an environment with anoxic bottom waters,with fragments of biomineralized organisms that lived on shallower,proba-bly mildly oxygenated surficial waters,and that were then transported down-slope.Similar to coeval suc-cessions(e.g.,the Nama Group in Namibia),our data support the hypothesis that late Ediacaran biomineralized organisms lived in a thin oxygenated surface layer above a relatively shallow chemocline.The Guaicurus Formation,on the other hand,records the expansion of oxic conditions to deeper waters during a sea level rise.Although the relationship between global biogeochemical changes and the activities of early bioturbators remains complex,these results demonstrate an unequivocal synchronous relationship between oxygenation of the Corumbábasin and the local appearance of meiofaunal bioturbators.