Self-Assembled Nanomicelles of Affibody-Drug Conjugate with Excellent Therapeutic Property to Cure Ovary and Breast Cancers

Affibody molecules are small nonimmunoglobulin affinity proteins,which can precisely target to some cancer cells with specific overexpressed molecular signatures.However,the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy.Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy.As an example of the concept,the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of Z_(HHR2:342)-Cys with auristatin E derivate,where the affibody used is capable of binding to the human epidermal growth factor receptor 2(HER2).Such a nanodrug not only increased the blood circulation time,but also enhanced the tumor targeting capacity(abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor.As a result,this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models,which nearly eradicated both small solid tumors(about 100 mm^(3)) and large established tumors(exceed 500 mm^(3)).The relative tumor proliferation inhibition ratio reaches 99.8% for both models.

Highly efficient tumor-targeted nanomedicine assembled from affibody-drug conjugate for colorectal cancer therapy

Affibody is a new class of small non-immunoglobulin affinity proteins that possesses high affinity at the picomole level to several tumor overexpressed receptors.Owing to the simple framework,affibody is flexible for modification with payload,but the relatively low molecular weight of this construction simultaneously results in short half-life time which hinders its application in cancer therapy.In this work,we prepared a nanomedicine self-assembled from the conjugate of affibody(ZPDGFRβ:09591,PDGFRβ:platelet-derived growth factor receptorβ)with monomethyl auristatin E(MMAE)through cathepsin B cleavable dipeptide linker for targeted colorectal cancer therapy.The nanoscale characteristics of ZPDGFRβ:09591-MMAE affibody-drug conjugate nanomedicine(ZPDGFRβ:09591-M ADCN)resulted in enhanced pharmacokinetics,improved drug accumulation,and promoted biosecurity performance than those of free drugs.As a result,ZPDGFRβ:09591-M ADCN exhibited excellent antitumor efficacy with tumor inhibition rates(TIR)over 99.0%in PDGFRβ-positive tumor models with small solid tumors(~150 mm^(3))or large established tumors(~500 mm^(3)),indicating that ZPDGFRβ:09591-MMAE ADCN is promising for the clinic application in colorectal cancer therapy.

H_(2)O_(2)-responsive polymer prodrug nanoparticles with glutathione scavenger for enhanced chemo-photodynamic synergistic cancer therapy

The combination of chemotherapy and photodynamic therapy(PDT)based on nanoparticles(NPs)has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments.However,overexpressed glutathione(GSH)in tumor cells efficiently scavenges singlet oxygens(^(1)O_(2))generated from photosensitizers and results in the unsatisfactory efficacy of PDT.To address this obstacle,here we design H_(2)O_(2)-responsive polymer prodrug NPs with GSH-scavenger(Ce6@P(EG-a-CPBE)NPs)for chemo-photodynamic synergistic cancer therapy.They are constructed by the co-self-assembly of photosensitizer chlorin e6(Ce6)and amphiphilic polymer prodrug P(EG-a-CPBE),which is synthesized from a hydrophilic alternating copolymer P(EG-a-PD)by conjugating hydrophobic anticancer drug chlorambucil(CB)via an H_(2)O_(2)-cleavable linker 4-(hydroxymethyl)phenylboronic acid(PBA).Ce6@P(EG-a-CPBE)NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection.Upon internalization of Ce6@P(EG-a-CPBE)NPs by tumor cells,PBA is cleaved rapidly triggered by endogenous H_(2)O_(2)to release CB and Ce6.Ce6 can effectively generate abundant^(1)O_(2)under 660 nm light irradiation to synergistically kill cancer cells with CB.Concurrently,PBA can be transformed into a GSH-scavenger(quinine methide,QM)under intracellular H_(2)O_(2)and prevent the depletion of^(1)O_(2),which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis.Collectively,such H_(2)O_(2)-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment.

Cobalt and nitrogen codoped porous carbon as superior bifunctional electrocatalyst for oxygen reduction and hydrogen evolution reaction in alkaline medium

Cobalt and nitrogen codoped carbon materials(Co-N-C) were fabricated by pyrolysis of the mixture of poly(4-vinylpyridine) and cobalt chloride using SiO_2 nanoparticles as hard template, which were the first transition metal/nitrogen-codoped carbon bifunctional electrocatalyst derived from noncarbonizable polymer for ORR and HER. The as-made Co-N-C possessed hierarchical pore structure and high specific surface area, achieving excellent electrocatalytic performances for ORR and HER. Its ORR catalytic performances were comparable to those of Pt/C catalyst and its HER catalytic performances were superior to those of most doped carbon catalysts in KOH electrolyte. Moreover, its bifunctional electrocatalytic performances for ORR and HER were better than those of most bifunctional doped carbon catalysts in alkaline electrolyte.

Preparation of fluorescent hyperbranched polymer materials by end-capping approach

Two kinds of novel fluorescent hyperbranched polymers were synthesized by the end-capping approach. The fluorescent hyperbranched polyether (FPEOTM) was obtained by end capping the hyperbranched poly(hydroxyl ether) (PEOTM) with guest molecules N,N-dimethylaminobenzaldehyde (DMABA). In addition, in the presence of triethylamine, the hyperbranched polysulfone-amine with terminal double bonds (HPSA) was synthesized by polyaddition of a new AB2 type monomer (SAP, sulfone amine piperazine) at 40℃ for 60 h in chloroform solution. Then the fluorescent hyperbranched polysulfone-amine (FHPSA) was prepared by addition of guest molecules N,N-dimethylaminoanilines (DMAA) with the terminal double bonds of HPSA. The two resulting polymers fluoresce yellow-green color in both solid and solution states. The maximum emission wavelength is (460 ±10) nm and (470±10) nm, respectively. A novel 'complex quenching effect' for hyperbranched polymer was observed. The fluorescence can be quenched by transition metal

Intrinsic viscosity of polymer solutions: fresh ideas to an old problem

Intrinsic viscosity is one of the most fundamental properties of dilute polymer solutions; its study forms an integral part of the cornerstone of the modern macromolecular theory. However, a general theory applicable to any chain architectures and solvent conditions has remained elusive, due to the formidable challenges in the theoretical treatment of the long-range, many-body and accumulative hydrodynamic effects. Recently, Lijia An and coworkers at the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, has developed a new approach that largely overcomes these challenges. Their new theory provides a simple and unified theoretical framework for describing the intrinsic viscosity of polymers with arbitrary architectures under any solvent conditions and forms the theoretical basis for inferring the polymer chain structure from intrinsic viscosity measurements. Comparisons with existing experimental data yield extensive, quantitative agreement.

Amphiphilic drug-drug conjugate for cancer therapy with combination of chemotherapeutic and antiangiogenesis drugs

The progression and metastasis of solid tumors strongly rely on the process of forming nascent blood vessels.However,using angiogenesis inhibitors alone does not meet the cancer treatment needs.Herein,we used the amphiphilic drug-drug conjugate(ADDC)strategy to fabricate a new drug conjugate with the combination of chemotherapeutic drug and antiangiogenesis drug together.With one-step esterification of hydrophilic floxuridine(FUDR)and hydrophobic pseudolaric acid B(PAB),the conjugate was synthesized.The amphiphilic property of FUDR-PAB conjugate induced the self-assembly to form nanoparticles in water.From further in vitro and in vivo experiments,this FUDR-PAB conjugate does not only have a high antitumor effect,but also shows efficient antianiogenesis property.These results offer a promising ADDC strategy for designing drugs with combination of chemotherapeutic drug and antiangiogenesis drug together.

Synthesis and characterization of amphiphilc block copolymer poly(methyl acrylic acid)-block-polytetrahydrofuran

Under the specially designated condition the polymerization of both tetrahydrofuran (THF) and tert-butyl methacrylate (tBMA) is a living one. The diblock copolymer, poly(tert-butyl methacrylate)-block-polytetrahydrofuran (PtBMA-b-PTHF), was successfully synthesized by meansof the coupling reaction of living cationic PTHF+, SbF6 with living anionic PtBMA-, Li+. LiCI, whichhas a beneficial effect on the molecular weight distribution (MWD) in the anionic polymerization of (meth)acrylates, hinders the coupling reaction of living chains and cannot be used in the preparation of tBMA precursor. The hydrolysis of the aforementioned diblock copolymer under acid condition results in the amphiphilic diblock copolymer, i.e. poly(methyl acrylic acid)-block-polytetra-hydrofuran (PMAA-b-PTHF). The diblock copolymers were characterized with GPC and IR.

ROS-responsive thioether-containing hyperbranchede polymer micelles for light-triggered drug releas

As a kind of promising drug carriers,smart polymers have attracted much attention due to the effective and controlled drug release in target cells.Herein,a reactive oxygen species(ROS)-responsive thioether-containing amphiphilic hyperbranched polymer prepared from MTPA and TMPTGE(HBPMT)is synthesized from 3-(methylthio)propylamine(MTPA)and trimethylolpropane triglycidyl ether(TMPTGE)by the amine-epoxy click reaction via A2+B3 onepot approach.Benefiting from its inherent amphiphilic nature,HBPMT can selfassemble into stable micelles in water.Triggered by H_(2)O_(2),these micelles can be dissociated rapidly because hydrophobic thioether segments in their cores are oxidized into hydrophilic sulfoxide or sulfone groups.Additionally,the ROS produced by photosensitizer under light irradiation can also play the same role of H_(2)O_(2).Such HBPMT micelles can be utilized to encapsulate anticancer drug paclitaxel(PTX)and photosensitizer chlorin e6(Ce6)simultaneously for drug delivery and control release.The methyl thiazolyl tetrazolium assay toward MCF-7 tumor cells(a human breast adenocarcinoma cell line)indicates that these micelles encapsulated with PTX and Ce6 exhibit a significant combinational efficacy of cell proliferation inhibition,which means the promising potential for synergistic chemo-photodynamic cancer therapy.Such a novel nanocarrier based on amphiphilic to hydrophilic transition would provide a candidate for controlled drug release and cancer combination therapy.

Computer simulation studies of the influence of side alkyl chain on glass transition behavior of carbazole trimer

In this work,all-atom molecular dynamics simulations were employed to study the influence of the side alkyl chain on glass transition behavior of several carbazole trimers(CT) in a temperature range from 423 to 183 K.The glass transition temperatures were obtained from the break in the slope of the volume-temperature curves and found to agree with the experimental values.The short time dynamics of four CT molecules were probed by usingvelocity autocorrelation functions and mean-square displacements.The current studies showed that the dynamics of CT systems can be easily interpreted through the cage effect.Furthermore,the investigation of the torsional autocorrelation function and P_(2-state)/P_(3-state) functions showed that the rotational barriers of side chains can slow down the conformational relaxation and lead to stronger temperature dependence of conformational relaxation.The relaxation time,characteristic time of P_(2-state)(t) and P_(3-state)(t) functions were all found to have Arrhenius-type temperature dependence.

Endogenous nucleotide as drug carrier:base-paired guanosine-5’-monophosphate:pemetrexed vesicles with enhanced anticancer capability

Endogenous substance such as nucleotide as a drug carrier has been proposed as a novel drug delivery system.The nucleotide guanosine-5’-monophosphate(GMP) is used to transport an anticancer drug pemetrexed disodium heptahydrate(PMX) via specific base pairing.The endogenous nature of GMP helps to avoid biocompatibility issues that are generally accompanied with nanocarriers including cytotoxicity,immunogenicity and blood compatibility.Furthermore,the low-molecular weight of the GMP nucleotide carrier significantly boosts the drug loading capacity compared to traditional liposomes and high-molecular weight carriers.Hydrogen-bonding interaction between the carrier and drug realizes the controlled release of loaded drug,and also facilitates large scale manufacture since no additional chemical synthesis is required.More importantly,in vivo experiments reveal that the base-paired GMP:PMX nanovesicles improve the target specificity and pharmacokinetic properties of PMX,and exhibit remarkably enhanced anticancer abilities compared to standalone PMX without any carriers.We envision that this strategy could be extended to other endogenous substances and drugs bearing functional groups capable of specific interaction,and promote the construction of drug delivery systems with inherent biocompatibility,enhanced drug delivery efficacy,and a simplified preparation method.