Aqueous Self-Assembly of Block Copolymers to Form Manganese Oxide-Based Polymeric Vesicles for Tumor Microenvironment-Activated Drug Delivery

Molecular self-assembly is crucially fundamental to nature.However,the aqueous self-assembly of polymers is still a challenge.To achieve self-assembly of block copolymers [(polyacrylic acid-block-polyethylene glycol-block-polyacrylic acid(PAA68-b-PEG86-b-PAA68)] in an aqueous phase,manganese oxide(MnO2) is first generated to drive phase separation of the PAA block to form the PAA68-b-PEG68-b-PAA68/MnO2 polymeric assembly that exhibits a stable structure in a physiological medium.The polymeric assembly exhibits vesicular morphology with a diameter of approximately 30 nm and high doxorubicin(DOX) loading capacity of approximately 94%.The transformation from MnO2 to Mn2+caused by endogenous glutathione(GSH)facilitates the disassembly of PAA68-b-PEG68-b-PAA68/MnO2 to enable its drug delivery at the tumor sites.The toxicity of DOXloaded PAA68-b-PEG68-b-PAA69/MnO2 to tumor cells has been verified in vitro and in vivo.Notably,drug-loaded polymeric vesicles have been demonstrated,especially in in vivo studies,to overcome the cardiotoxicity of DOX.We expect this work to encourage the potential application of polymer self-assembly.

Simulated annealing-based optimal design of energy efficient ternary extractive dividing wall distillation process for separating benzene-isopropanol-water mixtures

This article investigates the performances of different extractive distillation processes intensified with dividing-wall column for separating benzene-isopropanol-water ternary mixtures.All the processes with ethylene glycol as solvent are optimized with the minimal total annual cost(TAC)as target.In order to get the global optimal solution intelligently,an improved simulated annealing algorithm is adopted,which is programmed in MATLAB and linked to Aspen Plus.The results show that the extractive dividing wall column-solvent(EDWC-S)process consisting of an extractive dividing wall column and a solvent recovery column is the best scheme.It can reduce the TAC by 28.65%and CO_(2) emissions by 32.84% compared to the conventional triple-column extractive distillation process.

RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma

Dysregulation of mTORCl/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types;however,the mechanism of mTORC2 in tumorigenesis is still obscure.Here,we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma(ESCC)and its effects on the sensitivity of cells to mTOR inhibitors.We demonstrated that RICTOR,the key factor of mTORC2,and p-AKT(Ser473)were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis(TNM)phase of ESCC patients.Furthermore,we found that mTORCl/mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal.Another,we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis.Noteworthy,knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling,and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40,thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo.Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.

Discovery of [1,2,3]triazolo[4,5-d]pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors

Ubiquitin specific peptidase 28(USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date,only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28(IC50=1.10 ± 0.02 μmol/L, Kd=40 nmol/L), showing selectivity over USP7 and LSD1(IC50> 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition(EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.

Discovery of WS-157 as a highly potent,selective and orally active EGFR inhibitor

EGFR tyrosine kinase inhibitor(EGFR-TKI)has been used successfully in clinic for the treatment of solid tumors.In the present study,we reported the discovery of WS-157 from our inhouse diverse compound library,which was validated to be a potent and selective EGFR-TKI.WS-157 showed excellent inhibitory activities against EGFR(IC50=0.81 nmol/L),EGFR[d746-750](IC50=1.2 nmol/L)and EGFR[L858R](IC50=1.1 nmol/L),but was less effective or even inactive against other nine kinases.WS-157 also displayed excellent antiproliferative activities against a panel of human cancer cell lines,and exhibited the ability to reduce colony formation and wound healing the same as gefitinib.We found that WS-157 upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib.In addition,WS-157 showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species.These studies indicate that WS-157 has strong antitumor activity in vitro and in vivo,and could be used for the development of anti-lung cancer agent targeting EGFR.

Plasma from healthy donors protects blood-brain barrier integrity via FGF21 and improves the recovery in a mouse model of cerebral ischaemia

Background Healthy plasma therapy reverses cognitive deficits and promotes neuroplasticity in ageing brain disease.However,whether healthy plasma therapy improve blood-brain barrier integrity after stroke remains unknown.Methods Here,we intravenously injected healthy female mouse plasma into adult female ischaemic stroke C57BL/6 mouse induced by 90 min transient middle cerebral artery occlusion for eight consecutive days.Infarct volume,brain atrophy and neurobehavioural tests were examined to assess the outcomes of plasma treatment.Cell apoptosis,blood-brain barrier integrity and fibroblast growth factor 21 knockout mice were used to explore the underlying mechanism.Results Plasma injection improved neurobehavioural recovery and decreased infarct volume,brain oedema and atrophy after stroke.Immunostaining showed that the number of transferase dUTP nick end labelling+/NeuN+cells decreased in the plasma-injected group.Meanwhile,plasma injection reduced ZO-1,occluding and claudin-5 tight junction gap formation and IgG extravasation at 3 days after ischaemic stroke.Western blot results showed that the FGF21 expression increased in the plasma-injected mice.However,using FGF21 knockout mouse plasma injecting to the ischaemic wild-type mice diminished the neuroprotective effects.Conclusions Our study demonstrated that healthy adult plasma treatment protected the structural and functional integrity of blood-brain barrier,reduced neuronal apoptosis and improved functional recovery via FGF21,opening a new avenue for ischaemic stroke therapy.