There is now little doubt that PEGylation is useful and is in widespread use because it provides a prolonged half-life,a higher stability and a lowerimmunogenicity[1].However,it is of concern that PEGylation may affec...There is now little doubt that PEGylation is useful and is in widespread use because it provides a prolonged half-life,a higher stability and a lowerimmunogenicity[1].However,it is of concern that PEGylation may affect the physicochemical and pharmacokinetic characteristics of protein-encapsulated liposome.Thus,we prepared the bovine serum albumin(BSA)-encapsulated liposome(BSA-liposome)with or without PEG and then compared their physicochemical and pharmacokinetic characteristics(Fig.1).BSA-liposomes were prepared by the thin-film hydration method.展开更多
Surface modification by poly(ethylene glycol)(PEGylation)has been acknowledged as a powerful strategy in minimizing non-specific reactions for biomedical devices.Once applied into manufacture of drug/gene delivery sys...Surface modification by poly(ethylene glycol)(PEGylation)has been acknowledged as a powerful strategy in minimizing non-specific reactions for biomedical devices.Once applied into manufacture of drug/gene delivery systems,PEGylation has demonstrated to significantly improve their biocompatibility and stealthiness in physiological environment.Nonetheless,reluctant cell membrane affinities thus cellular uptake efficiencies owing to PEGylation brought up further issues that are imperative to be resolved.Pertain to this PEGylation dilemma,we attempted to introduce peptide(GPLGVRG)linkage between block copolymer of PEG-poly{N’-[N-(2-aminoethyl)-2-aminoethyl]aspartamide}PAsp(DET),wherein the cationic PAsp(DET)could self-assemble with pDNA into nanoscaled complex core.Noteworthy was the peptide linkage whose amino acids sequence could be specifically recognized and degraded by matrix metalloproteinases(MMPs)(overexpressed in extracellular milieu of tumors).Therefore,our subsequent studies validated facile detachment of PEGylation from the aforementioned polyplex micelles upon treatment of MMPs,which elicited improved cytomembrane affinities and cellular uptake efficiencies.In addition,promoted escape from endosome entrapment was also confirmed through direct endosome membrane destabilization by PAsp(DET),which was further elucidated to be attributable to dePEGylation as well as elevated charged density of PAsp(DET)in acidic endosomes.These benefits from dePEGylation eventually contributed to promoted gene expression at the affected cells and potent tumor growth suppression based on anti-angiogenic approach.Therefore,our developed strategy has provided a facile approach in overcoming the dilemma of PEGylation,which could be informative in design of drug/gene delivery systems.展开更多
Although surface PEGylation of nanomedicines can decrease serum protein adsorption in vivo,it also blocks uptake by tumor cells.This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extr...Although surface PEGylation of nanomedicines can decrease serum protein adsorption in vivo,it also blocks uptake by tumor cells.This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extracellular microenvironment to achieve improved cellular uptake while prolonged circulation times.Herein,the amphiphilic graft copolymers with p H-sensitive ortho ester-linked m PEG in side chains and polyurethanes in backbone,can self-assemble into the free and doxorubicin(DOX)-loaded micelles.The p H-sensitive micelles could undergo several characteristics as follows:(i)PEGylated shells for stability in sodium dodecyl sulfonate(SDS)solution;(ii)De PEGylation via degradation of ortho ester linkages at tumoral extracellular pH(6.5)for gradually dynamic size changes and effective release of DOX;and(iii)enhanced cellular uptake and cytotoxicity via positive DOX.Moreover,the dynamic micelles with detachable PEGylation could quickly penetrate the centers of SH-SY5 Y multicellular spheroids(MCs)and strongly inhibit tumor growth in vitro and in vivo,and might be considered as promising and effective drug carriers in tumor therapy.展开更多
Hirudin is the most anticoagulant drug found in nature, but its short serum half-life significantly inhibits its clinical anpplication. The PEGvlation of hirudin, the most promising anticoagulant drug, was performed i...Hirudin is the most anticoagulant drug found in nature, but its short serum half-life significantly inhibits its clinical anpplication. The PEGvlation of hirudin, the most promising anticoagulant drug, was performed in this paper. The optimal reaction conditions for PEG ylated hirudin were investigated, wh.en the PEGylation react, on.wasconducted under 4℃ after 10h, in the borate buffer at pH 8.5 .with the molar ratio 230 ： 1 of PEG to hirudin, a higher modification extent was achieved. Finally, the bioactivity of PEGylated hirudin was measured in vitro.Compared with unmodified hirudin, 26% of anti-thrombin activity was retained.展开更多
Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performanc...Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performance owing to limited tumor retention.The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity.Therefore,a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed.Here,we developed a PEGylation-enabled peptide multidisplay platform(PEGibody)for PR_b,anα5β1 targeting peptide.PEGibody generation involved PEGylation and self-assembly.[^(64)Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter.Compared with non-PEGylated radioligands,[^(64)Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability.Importantly,the biodistribution analysis confirmed rapid clearance of[^(64)Cu]QM-2303 from the bloodstream.Administration of a single dose of[^(177)Lu]QM-2303 led to robust antitumor efficacy.Furthermore,[^(64)Cu]/[^(177)Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice.Therefore,this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime.The PEGibody-based radiopharmaceutical[^(64)Cu]/[^(177)Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy forα5β1-overexpressing tumors.展开更多
In this study,N-terminal site-specific mono-PEGylation of the recombinant lidamycin apoprotein(r LDP) of lidamycin(LDM) was prepared using a polyethyleneglycol(PEG) derivative(Mw20 k Da) through a reactive terminal al...In this study,N-terminal site-specific mono-PEGylation of the recombinant lidamycin apoprotein(r LDP) of lidamycin(LDM) was prepared using a polyethyleneglycol(PEG) derivative(Mw20 k Da) through a reactive terminal aldehyde group under weak acidic conditions(p H 5.5).The biochemical properties of m PEG-r LDP-AE,an enediyne-integrated conjugate,were analyzed by SDSPAGE,RP-HPLC,SEC-HPLC and MALDI-TOF.Meanwhile,in vitro and in vivo antitumor activity of m PEG-r LDP-AE was evaluated by MTT assays and in xenograft model.The results indicated that m PEGr LDP-AE showed significant antitumor activity both in vitro and in vivo.After PEGylation,m PEG-r LDP still retained the binding capability to the enediyne AE and presented the physicochemical characteristics similar to that of native LDP.It is of interest that the PEGylation did not diminish the antitumor efficacy of LDM,implying the possibility that this derivative may function as a payload to deliver novel tumortargeted drugs.展开更多
PEGylation, the attachment of poly（ethylene glycol） （PEG）, has been adopted to improve the pharmacokinetic properties of oligonucleotide therapeutics for nearly 30 years. Prior efforts mainly focused on the invest...PEGylation, the attachment of poly（ethylene glycol） （PEG）, has been adopted to improve the pharmacokinetic properties of oligonucleotide therapeutics for nearly 30 years. Prior efforts mainly focused on the investigation of linear or slightly branched PEG having different molecular weights, terminal functional groups, and possible oligonucleotide sites for functionalization. Recent studies on highly branched PEG （including brush, star, and micellar structures） indicate superior properties in several areas including cellular uptake, gene regulation efficac~ reduction of side effects, and biodistribution. This review focuses on comparing the effects of PEG architecture on the physiochemical and biological properties of the PEGylated oligonucleotide.展开更多
BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despi...BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.展开更多
PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect,which consequently improves the intratumoral accumulation.However,cell uptake of PEGylated nanoformu...PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect,which consequently improves the intratumoral accumulation.However,cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG,which limits their therapeutic effect.To this end,we designed and prepared two kinds of poly(L-glutamic acid)-cisplatin(PLG-CDDP)nanoformulations with detachable PEG,which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization.The extracellular pH(pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride(CDM)-derived amide bond and matrix metalloproteinases-2/9(MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG,yielding pHe-responsive PEG-pHe-PLG and MMP-sensitive PEG-MMP-PLG.The corresponding smart nanoformulations PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin(CDDP).The circulation half-lives of PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt,respectively.Upon reaching tumor tissue,PEG on the surface of nanomedicines was detached as triggered by pHe or MMP,which increased intratumoral CDDP retention,enhanced cell uptake,and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer(HGSOC)mouse model,indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.展开更多
Current treatment options for hepatitis D are limited,with pegylated interferonalpha(PEG-IFNα)being the only therapy available in the Asia-Pacific region.However,PEG-IFNαhas limited efficacy and significant side eff...Current treatment options for hepatitis D are limited,with pegylated interferonalpha(PEG-IFNα)being the only therapy available in the Asia-Pacific region.However,PEG-IFNαhas limited efficacy and significant side effects.Pegylated interferon lambda acts on interferon-lambda(Type III)receptors predominantly expressed in hepatocytes.In 2023,bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D.This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide receptor on liver cells,which is the primary entry point for the virus.Recently,several new drugs have entered various stages of development,offering hope for improved hepatitis D virus(HDV)management.Two more viral entry inhibitors are HH003 and tobevibart.Other agents include nucleic acid polymers(REP 2139-Mg),prenylation inhibitors(lonafarnib),and RNA interference-based therapies(elebsiran).Emerging trials are now considering combination therapies,such as SOLSTICE,a Phase 2 clinical trial evaluating tobevibart alone or combined with elebsiran.The combination dosed monthly achieved>50%virologic and biochemical response at 24 weeks of therapy.The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1,2,and 3 trials.With these new treatments on the horizon,the prospects for improved HDV patient outcomes are promising.展开更多
To investigate the risk and influencing factors of long-term liver adverse events in chronic hepatitis B patients achieving hepatitis B surface antigen(HBsAg)clearance after pegylated interferonα(Peg-IFNα)treatment,...To investigate the risk and influencing factors of long-term liver adverse events in chronic hepatitis B patients achieving hepatitis B surface antigen(HBsAg)clearance after pegylated interferonα(Peg-IFNα)treatment,a retrospective analysis was conducted on 456 patients at Beijing Ditan Hospital from 2008 to 2023 who achieved HBsAg clearance and discontinued Peg-IFNαtreatment.The baseline was defined as the time of HBsAg clearance and treatment cessation.The endpoint was the first occurrence of liver adverse events(hepatocellular carcinoma or ascites)or last follow-up.Subsequently,we evaluated the incidence and risk factors of liver adverse events,along with changes in liver fibrosis,cirrhosis,and liver function indicators.During a median follow-up of 70 months,the incidence of liver adverse events was 2.30%,hepatocellular carcinoma 1.76%,and ascites 0.55%.Older age and cirrhosis were significant risk factors(HR 1.075 and 41.393,both P<0.01).The APRI score significantly improved at follow-up compared to baseline(0.53 vs.0.25,P<0.001),and cirrhosis prevalence decreased from 5.70%to 0.88%(P<0.001).In conclusion,patients who achieved HBsAg clearance and discontinued Peg-IFNαtreatment have a low risk of liver adverse events,while advanced age and cirrhosis remain major risk factors.展开更多
As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effective...As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effectively mitigated the immunogenicity of PEGylated liposomes and enhanced their in vivo performance by tolerating splenic marginal zone B cells.FA specifically inhibited the internalization of PEGylated liposomes by splenic marginal zone B cells,thereby reducing splenic lymphocyte proliferation and specific IgM secretion.This modulation alleviated Ig M-mediated accelerated blood clearance and adverse accumulation of the PEGylated liposomes in the skin.These findings provide new insights into the immunomodulatory effects of FA and promising avenues to enhance the efficacy and safety of PEGylated liposomal nanomedicines.展开更多
Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor vaccines.The targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delive...Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor vaccines.The targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delivery systems.Whether the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains unclear.Here,we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths(100/400/1000/2000)(MPn-LPX).The top candidate MP_(400)-LPX(the linker was PEG400)showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by DCs.Furthermore,MP_(400)-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse model.Collectively,these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA vaccines.Our findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.展开更多
The treatment of hepatitis C has undergone a significant boom since the advent of direct acting antivirals (DAA). Indeed, the interferon-ribavirin combination that has been used to treat hepatitis C has a virological ...The treatment of hepatitis C has undergone a significant boom since the advent of direct acting antivirals (DAA). Indeed, the interferon-ribavirin combination that has been used to treat hepatitis C has a virological response in only 45% of cases with significant side effects. The advent of direct-acting antivirals has changed the prognosis of cirrhotic patients with hepatitis C. DAAs have ensured a sustained viral response in the majority of patients. Our work aims to see the evolution of hepatitis C patients at the cirrhosis stage under DAA. We conducted a retrospective study over 15 years (January 2009, January 2024) including all patients with post-viral cirrhosis C, whom we divided into two groups: group A, cirrhotic patients who received ribavirin and interferon, and group B, patients on DAA. From January 2009 to January 2024, we conducted a study of 182 patients with viral hepatitis C, including 102 cirrhotic patients. The mean age was 55 years. 66% of patients were initially treated with the ribavirin interferon combination, while 34% received direct-acting antivirals (DAAs). Since the introduction of DAAs, the most commonly used regimens have been sofosbuvir/daclatasvir with or without ribavirin and sofosbuvir/ledipasvir with or without ribavirin. Group A achieved sustained virological response (SVR) in 60% of cases, with notable side effects. In Group B, SVR was 98.18%, with improved tolerability and fewer side effects than previous treatments. Fifteen patients developed hepatocellular carcinoma (HCC), with a significantly lower mortality rate in those treated with DAAs compared with pegylated dual therapy (p: 0.001).展开更多
Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions.Alzheimer’s disease ...Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions.Alzheimer’s disease is associated with dementia and a progressive decline in memory,thinking,and social skills,eventually leading to a point that the individual can no longer perform daily activities independently.Currently available drugs on the market temporarily alleviate the symptoms,however,they are not successful in slowing down the progression of Alzheimer’s disease.Treatment and cures have been constricted due to the difficulty of drug delivery to the blood-brain barrier.Several studies have led to identification of vesicles to transport the necessary drugs through the blood-brain barrier that would typically not achieve the targeted area through systemic delivered medications.Recently,liposomes have emerged as a viable drug delivery agent to transport drugs that are not able to cross the blood-brain barrier.Liposomes are being used as a component of nanoparticle drug delivery;due to their biocompatible nature;and possessing the capability to carry both lipophilic and hydrophilic therapeutic agents across the blood brain barrier into the brain cells.Studies indicate the importance of liposomal based drug delivery in treatment of neurodegenerative disorders.The idea is to encapsulate the drugs inside the properly engineered liposome to generate a response of treatment.Liposomes are engineered to target specific diseased moieties and also several surface modifications of liposomes are under research to create a clinical path to the management of Alzheimer’s disease.This review deals with Alzheimer’s disease and emphasize on challenges associated with drug delivery to the brain,and how liposomal drug delivery can play an important role as a drug delivery method for the treatment of Alzheimer’s disease.This review also sheds some light on variation of liposomes.Additionally,it emphasizes on the liposomal formulations which are currently researched or used for treatment of Alzheimer’s disease and also discusses the future prospect of liposomal based drug delivery in Alzheimer’s disease.展开更多
PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,...PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.展开更多
Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol （PEG） were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were in...Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol （PEG） were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scuteUarin were obtained, and the results showed that these conjugates were potential prodrugs for the oral delivery of scuteUarin.展开更多
Background:Endostatin(ES) is a well-established potent endogenous antiangiogenic factor.An ES variant,called zinc-binding protein-ES(ZBP-ES),is clinically available;however,its use is limited by rapid renal clearance ...Background:Endostatin(ES) is a well-established potent endogenous antiangiogenic factor.An ES variant,called zinc-binding protein-ES(ZBP-ES),is clinically available;however,its use is limited by rapid renal clearance and short residence time.PEGylation has been exploited to overcome these shortcomings,and mono-PEGylated ES(called M_2ES) as well as mono-PEGylated ZBP-ES(MZBP-ES) are developed in our study.This study aimed to compare the biophysical properties and biological effects of M_2ES and MZBP-ES to evaluate their druggability.Methods:Circular dichroism and tryptophan emission fluorescence were used to monitor the conformational changes of M_2ES and MZBP-ES.Their resistance to trypsin digestion and guanidinium chloride(GdmCl)-induced unfolding was examined by Coomassie staining and tryptophan emission fluorescence,respectively.The biological effects of M_2ES and MZBP-ES on endothelial cell migration were evaluated using Transwell migration and wound healing assays,and the uptake of M_2ES and MZBP-ES in endothelial cells was also compared by Western blotting and immunofluorescence.Results:Structural analyses revealed that M_2ES has a more compact tertiary structure than MZBP-ES.Moreover,M_2ES was more resistant to trypsin digestion and GdmCI-induced unfolding compared with MZBP-ES.In addition,although M_2ES and MZBP-ES showed comparable levels of inhibiting transwell migration and wound healing of endothelial cells,M_2ES displayed an increased ability to enter cells compared with MZBP-ES,possibly caused by the enhanced interaction with nucleolin.Conclusions:M_2ES has a more compact tertiary structure,is more stable for trypsin digestion and GdmCI-induced unfolding,exhibits increased cellular uptake and shows equivalent inhibitory effects on cell migration relative to MZBP-ES,indicating that M_2ES is a more promising candidate for anticancer drug development compared with MZBP-ES.展开更多
Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic cancer.In addition,enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer.Furthermore,the occurrence of intensive desmo...Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic cancer.In addition,enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer.Furthermore,the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic cancer.In this study,a novel FR-directed,macropinocytosis-enhanced,and highly cytotoxic bioconjugate folate(F)-human serum albumin(HSA)-apoprotein of lidamycin(LDP)-active enediyne(AE)derived from lidamycin was designed and prepared.F-HSA-LDP-AE consisted of four moieties:F,HSA,LDP,and AE.F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer cells.Its uptake in wild-type cells was more extensive than in K-Ras mutant-type cells.By in vivo optical imaging,F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice,showing clear and lasting tumor localization for 360 h.In the MTT assay,F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell lines.It also induced apoptosis and caused G2/M cell cycle arrest.F-HSALDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic mice.At well-tolerated doses of 0.5 and 1 mg/kg,(i.v.,twice),the inhibition rates were 91.2%and 94.8%,respectively(P<0.01).The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.展开更多
This study aimed to investigate the ability of the novel materials D-α-tocopheryl poly(2-ethyl-2-oxazoline) succinate(TPOS) to construct pH-sensitive liposomes. TPOS was initially synthesized and characterized by TLC...This study aimed to investigate the ability of the novel materials D-α-tocopheryl poly(2-ethyl-2-oxazoline) succinate(TPOS) to construct pH-sensitive liposomes. TPOS was initially synthesized and characterized by TLC, FTIR, and ~1H-NMR. The buffering capacity of polyethylene glycol-distearoyl phosphatidylethanolamine(PEG-DSPE) and TPOS was determined by acid-base titration, and TPOS displayed a slower downtrend and gentler slope of titration curve than PEG-DSPE within pH 7.4–5.0. Studies on the in vitro drug release demonstrated that TPOS modified docetaxel(DOC) liposomes(TPOS-DOC-L) had a slower drugrelease rate at pH 7.4 similar to PEGylated-DOC liposomes(PEG-DOC-L), whereas the release rate reached approximately 86.92% ± 1.69% at pH 6.4. In vitro cellular uptake assays by microplate reader, and flow cytometry revealed that TPOS modified coumarin 6 liposomes(TPOS-C6-L) had stronger cellular uptake at pH 6.4 than that at pH 7.4( P < 0.01). Conversely, for PEGylated C6 liposomes(PEG-C6-L) and conventional C6 liposomes(C6-L), very similar cellular uptakes were exhibited at different pH values. Confocal laser scanning microscopy images showed that PEG-C6-L and C6-L were mainly located in lysosomes. By contrast, TPOS-C6-L showed broader cytoplasmic release and distribution at 4 h. MTT assay showed that the cytotoxicity of TPOS-DOC-L was similar to that of PEG-DOC-L and conventional DOC liposomes(DOC-L) at the same DOC concentration and at pH 7.4, but was much lower than those at pH 6.4 after 48 h of incubation. The apoptosis of PEG-DOC-L and DOC-L had no remarkable improvement with decreased pH from 7.4 to 6.4. Meanwhile, TPOS-DOC-Lsignificantly induced the apoptosis of HeLa cells with decreased pH. Therefore, TPOS can be a biomaterial for the construction of a pH-sensitive drug delivery system.展开更多
文摘There is now little doubt that PEGylation is useful and is in widespread use because it provides a prolonged half-life,a higher stability and a lowerimmunogenicity[1].However,it is of concern that PEGylation may affect the physicochemical and pharmacokinetic characteristics of protein-encapsulated liposome.Thus,we prepared the bovine serum albumin(BSA)-encapsulated liposome(BSA-liposome)with or without PEG and then compared their physicochemical and pharmacokinetic characteristics(Fig.1).BSA-liposomes were prepared by the thin-film hydration method.
基金the National Natural Science Foundation of China(No.21878041)the funding support from Talent Project of Revitalizing Liaoning(No.XLYC1807184)Dalian Science&Technology Innovation Fund(Nos.2020JJ26SN050,2020JJ26GX025)。
文摘Surface modification by poly(ethylene glycol)(PEGylation)has been acknowledged as a powerful strategy in minimizing non-specific reactions for biomedical devices.Once applied into manufacture of drug/gene delivery systems,PEGylation has demonstrated to significantly improve their biocompatibility and stealthiness in physiological environment.Nonetheless,reluctant cell membrane affinities thus cellular uptake efficiencies owing to PEGylation brought up further issues that are imperative to be resolved.Pertain to this PEGylation dilemma,we attempted to introduce peptide(GPLGVRG)linkage between block copolymer of PEG-poly{N’-[N-(2-aminoethyl)-2-aminoethyl]aspartamide}PAsp(DET),wherein the cationic PAsp(DET)could self-assemble with pDNA into nanoscaled complex core.Noteworthy was the peptide linkage whose amino acids sequence could be specifically recognized and degraded by matrix metalloproteinases(MMPs)(overexpressed in extracellular milieu of tumors).Therefore,our subsequent studies validated facile detachment of PEGylation from the aforementioned polyplex micelles upon treatment of MMPs,which elicited improved cytomembrane affinities and cellular uptake efficiencies.In addition,promoted escape from endosome entrapment was also confirmed through direct endosome membrane destabilization by PAsp(DET),which was further elucidated to be attributable to dePEGylation as well as elevated charged density of PAsp(DET)in acidic endosomes.These benefits from dePEGylation eventually contributed to promoted gene expression at the affected cells and potent tumor growth suppression based on anti-angiogenic approach.Therefore,our developed strategy has provided a facile approach in overcoming the dilemma of PEGylation,which could be informative in design of drug/gene delivery systems.
基金financially supported by the National Natural Science Foundation of China(No.51803001,51603001 and 51503001)the Research Foundation of Education Department of Anhui Province of China(No.KJ2018ZD003 and KJ2018A0006)the Academic and Technology Introduction Project of Anhui University(AU02303203)。
文摘Although surface PEGylation of nanomedicines can decrease serum protein adsorption in vivo,it also blocks uptake by tumor cells.This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extracellular microenvironment to achieve improved cellular uptake while prolonged circulation times.Herein,the amphiphilic graft copolymers with p H-sensitive ortho ester-linked m PEG in side chains and polyurethanes in backbone,can self-assemble into the free and doxorubicin(DOX)-loaded micelles.The p H-sensitive micelles could undergo several characteristics as follows:(i)PEGylated shells for stability in sodium dodecyl sulfonate(SDS)solution;(ii)De PEGylation via degradation of ortho ester linkages at tumoral extracellular pH(6.5)for gradually dynamic size changes and effective release of DOX;and(iii)enhanced cellular uptake and cytotoxicity via positive DOX.Moreover,the dynamic micelles with detachable PEGylation could quickly penetrate the centers of SH-SY5 Y multicellular spheroids(MCs)and strongly inhibit tumor growth in vitro and in vivo,and might be considered as promising and effective drug carriers in tumor therapy.
文摘Hirudin is the most anticoagulant drug found in nature, but its short serum half-life significantly inhibits its clinical anpplication. The PEGvlation of hirudin, the most promising anticoagulant drug, was performed in this paper. The optimal reaction conditions for PEG ylated hirudin were investigated, wh.en the PEGylation react, on.wasconducted under 4℃ after 10h, in the borate buffer at pH 8.5 .with the molar ratio 230 ： 1 of PEG to hirudin, a higher modification extent was achieved. Finally, the bioactivity of PEGylated hirudin was measured in vitro.Compared with unmodified hirudin, 26% of anti-thrombin activity was retained.
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04,China)+6 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-026(2023),2022-I2M-2-002-2,and 2021-I2M-3-001(2023),China)the National Key Research and Development Program of China(No.2022YFE0111700)the Beijing Nova Program to Kuan Hu(No.0104002,China)supported by the Beijing Natural Science Foundation(No.L234044,China)the Fundamental Research Funds for the Central Universities(Nos.3332023044 and 3332023151,China)the CIRP Open Fund of Radiation Protection Laboratories(No.ZHYLYB2021005,China)the China National Nuclear Corporation Young Talent Program.
文摘Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performance owing to limited tumor retention.The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity.Therefore,a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed.Here,we developed a PEGylation-enabled peptide multidisplay platform(PEGibody)for PR_b,anα5β1 targeting peptide.PEGibody generation involved PEGylation and self-assembly.[^(64)Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter.Compared with non-PEGylated radioligands,[^(64)Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability.Importantly,the biodistribution analysis confirmed rapid clearance of[^(64)Cu]QM-2303 from the bloodstream.Administration of a single dose of[^(177)Lu]QM-2303 led to robust antitumor efficacy.Furthermore,[^(64)Cu]/[^(177)Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice.Therefore,this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime.The PEGibody-based radiopharmaceutical[^(64)Cu]/[^(177)Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy forα5β1-overexpressing tumors.
基金supported by the National Science and Technology Major Project for Major New Drug Innovation (Nos.2013ZX09102064 and 2014ZX09201042-003)
文摘In this study,N-terminal site-specific mono-PEGylation of the recombinant lidamycin apoprotein(r LDP) of lidamycin(LDM) was prepared using a polyethyleneglycol(PEG) derivative(Mw20 k Da) through a reactive terminal aldehyde group under weak acidic conditions(p H 5.5).The biochemical properties of m PEG-r LDP-AE,an enediyne-integrated conjugate,were analyzed by SDSPAGE,RP-HPLC,SEC-HPLC and MALDI-TOF.Meanwhile,in vitro and in vivo antitumor activity of m PEG-r LDP-AE was evaluated by MTT assays and in xenograft model.The results indicated that m PEGr LDP-AE showed significant antitumor activity both in vitro and in vivo.After PEGylation,m PEG-r LDP still retained the binding capability to the enediyne AE and presented the physicochemical characteristics similar to that of native LDP.It is of interest that the PEGylation did not diminish the antitumor efficacy of LDM,implying the possibility that this derivative may function as a payload to deliver novel tumortargeted drugs.
基金Financial support by the National Institute of General Medical Sciences Award Number 1R01GM121612-01, the National Science Foundation （CAREER Award Number 1453255）, and the American Chemical Society Petroleum Research Fund （No. PRF 54905-DNI5）, is acknowledged.
文摘PEGylation, the attachment of poly（ethylene glycol） （PEG）, has been adopted to improve the pharmacokinetic properties of oligonucleotide therapeutics for nearly 30 years. Prior efforts mainly focused on the investigation of linear or slightly branched PEG having different molecular weights, terminal functional groups, and possible oligonucleotide sites for functionalization. Recent studies on highly branched PEG （including brush, star, and micellar structures） indicate superior properties in several areas including cellular uptake, gene regulation efficac~ reduction of side effects, and biodistribution. This review focuses on comparing the effects of PEG architecture on the physiochemical and biological properties of the PEGylated oligonucleotide.
基金Supported by Changsha Science and Technology Program,No.kq2022397Natural Science Foundation of Hunan Province(Departmental Joint Fund),No.2023JJ60440+2 种基金Research Program of Health Commission of Hunan Province,No.202303088786Clinical Medical Research Center for Viral Hepatitis of Hunan Province,No.2023SK4009the Scientific Research Program of FuRong Laboratory,No.2023SK2108.
文摘BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.
基金The study was financially supported by the National Natural Science Foundation of China(Grant Nos.52073280,51973216,and 51673187).
文摘PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect,which consequently improves the intratumoral accumulation.However,cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG,which limits their therapeutic effect.To this end,we designed and prepared two kinds of poly(L-glutamic acid)-cisplatin(PLG-CDDP)nanoformulations with detachable PEG,which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization.The extracellular pH(pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride(CDM)-derived amide bond and matrix metalloproteinases-2/9(MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG,yielding pHe-responsive PEG-pHe-PLG and MMP-sensitive PEG-MMP-PLG.The corresponding smart nanoformulations PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin(CDDP).The circulation half-lives of PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt,respectively.Upon reaching tumor tissue,PEG on the surface of nanomedicines was detached as triggered by pHe or MMP,which increased intratumoral CDDP retention,enhanced cell uptake,and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer(HGSOC)mouse model,indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.
文摘Current treatment options for hepatitis D are limited,with pegylated interferonalpha(PEG-IFNα)being the only therapy available in the Asia-Pacific region.However,PEG-IFNαhas limited efficacy and significant side effects.Pegylated interferon lambda acts on interferon-lambda(Type III)receptors predominantly expressed in hepatocytes.In 2023,bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D.This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide receptor on liver cells,which is the primary entry point for the virus.Recently,several new drugs have entered various stages of development,offering hope for improved hepatitis D virus(HDV)management.Two more viral entry inhibitors are HH003 and tobevibart.Other agents include nucleic acid polymers(REP 2139-Mg),prenylation inhibitors(lonafarnib),and RNA interference-based therapies(elebsiran).Emerging trials are now considering combination therapies,such as SOLSTICE,a Phase 2 clinical trial evaluating tobevibart alone or combined with elebsiran.The combination dosed monthly achieved>50%virologic and biochemical response at 24 weeks of therapy.The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1,2,and 3 trials.With these new treatments on the horizon,the prospects for improved HDV patient outcomes are promising.
基金funded by the Beijing Research Ward Ecxellence Program,BRWEP(BRWEP2024W102170101)the capital health research and development of special public health project(2022-1-2172)+3 种基金the National Key Research and Development Program(2022YFC2603500,2022YFC2603505,2023YFC2306901,2023YFC2308105,2023YFC2308105)the Beijing Municipal Health Commission high-level public health technical personnel construction project,discipline leader-03-26Beijing Hospitals Authority"peak"talent training program(DFL20241803)the Beijing Hospitals Authority Clinical medicine Development of special funding support(ZLRK202301).
文摘To investigate the risk and influencing factors of long-term liver adverse events in chronic hepatitis B patients achieving hepatitis B surface antigen(HBsAg)clearance after pegylated interferonα(Peg-IFNα)treatment,a retrospective analysis was conducted on 456 patients at Beijing Ditan Hospital from 2008 to 2023 who achieved HBsAg clearance and discontinued Peg-IFNαtreatment.The baseline was defined as the time of HBsAg clearance and treatment cessation.The endpoint was the first occurrence of liver adverse events(hepatocellular carcinoma or ascites)or last follow-up.Subsequently,we evaluated the incidence and risk factors of liver adverse events,along with changes in liver fibrosis,cirrhosis,and liver function indicators.During a median follow-up of 70 months,the incidence of liver adverse events was 2.30%,hepatocellular carcinoma 1.76%,and ascites 0.55%.Older age and cirrhosis were significant risk factors(HR 1.075 and 41.393,both P<0.01).The APRI score significantly improved at follow-up compared to baseline(0.53 vs.0.25,P<0.001),and cirrhosis prevalence decreased from 5.70%to 0.88%(P<0.001).In conclusion,patients who achieved HBsAg clearance and discontinued Peg-IFNαtreatment have a low risk of liver adverse events,while advanced age and cirrhosis remain major risk factors.
基金supported by the National Natural Science Foundation of China(Nos.82373817 and 82003659)Shanghai Natural Science Foundation(No.23ZR1477500)Pudong Health Bureau of Shanghai(No.YC-2023-0401)。
文摘As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effectively mitigated the immunogenicity of PEGylated liposomes and enhanced their in vivo performance by tolerating splenic marginal zone B cells.FA specifically inhibited the internalization of PEGylated liposomes by splenic marginal zone B cells,thereby reducing splenic lymphocyte proliferation and specific IgM secretion.This modulation alleviated Ig M-mediated accelerated blood clearance and adverse accumulation of the PEGylated liposomes in the skin.These findings provide new insights into the immunomodulatory effects of FA and promising avenues to enhance the efficacy and safety of PEGylated liposomal nanomedicines.
基金financially supported by National Key S&T Special Projects(No.2018ZX09201018-024)Henan Medical Science and Technology Joint Building Program(No.SBGJ202102132)+3 种基金China Postdoctoral Science Foundation(No.2020TQ0282)Henan Province Youth Talent Promoting Project(No.2022HYTP047)Key Research and Development Project of Henan Province(No.232102311224)Sichuan Provincial Science and Technology Innovation(Seedling Project)Cultivation Projects(No.MZGC20230034).
文摘Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor vaccines.The targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delivery systems.Whether the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains unclear.Here,we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths(100/400/1000/2000)(MPn-LPX).The top candidate MP_(400)-LPX(the linker was PEG400)showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by DCs.Furthermore,MP_(400)-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse model.Collectively,these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA vaccines.Our findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.
文摘The treatment of hepatitis C has undergone a significant boom since the advent of direct acting antivirals (DAA). Indeed, the interferon-ribavirin combination that has been used to treat hepatitis C has a virological response in only 45% of cases with significant side effects. The advent of direct-acting antivirals has changed the prognosis of cirrhotic patients with hepatitis C. DAAs have ensured a sustained viral response in the majority of patients. Our work aims to see the evolution of hepatitis C patients at the cirrhosis stage under DAA. We conducted a retrospective study over 15 years (January 2009, January 2024) including all patients with post-viral cirrhosis C, whom we divided into two groups: group A, cirrhotic patients who received ribavirin and interferon, and group B, patients on DAA. From January 2009 to January 2024, we conducted a study of 182 patients with viral hepatitis C, including 102 cirrhotic patients. The mean age was 55 years. 66% of patients were initially treated with the ribavirin interferon combination, while 34% received direct-acting antivirals (DAAs). Since the introduction of DAAs, the most commonly used regimens have been sofosbuvir/daclatasvir with or without ribavirin and sofosbuvir/ledipasvir with or without ribavirin. Group A achieved sustained virological response (SVR) in 60% of cases, with notable side effects. In Group B, SVR was 98.18%, with improved tolerability and fewer side effects than previous treatments. Fifteen patients developed hepatocellular carcinoma (HCC), with a significantly lower mortality rate in those treated with DAAs compared with pegylated dual therapy (p: 0.001).
文摘Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions.Alzheimer’s disease is associated with dementia and a progressive decline in memory,thinking,and social skills,eventually leading to a point that the individual can no longer perform daily activities independently.Currently available drugs on the market temporarily alleviate the symptoms,however,they are not successful in slowing down the progression of Alzheimer’s disease.Treatment and cures have been constricted due to the difficulty of drug delivery to the blood-brain barrier.Several studies have led to identification of vesicles to transport the necessary drugs through the blood-brain barrier that would typically not achieve the targeted area through systemic delivered medications.Recently,liposomes have emerged as a viable drug delivery agent to transport drugs that are not able to cross the blood-brain barrier.Liposomes are being used as a component of nanoparticle drug delivery;due to their biocompatible nature;and possessing the capability to carry both lipophilic and hydrophilic therapeutic agents across the blood brain barrier into the brain cells.Studies indicate the importance of liposomal based drug delivery in treatment of neurodegenerative disorders.The idea is to encapsulate the drugs inside the properly engineered liposome to generate a response of treatment.Liposomes are engineered to target specific diseased moieties and also several surface modifications of liposomes are under research to create a clinical path to the management of Alzheimer’s disease.This review deals with Alzheimer’s disease and emphasize on challenges associated with drug delivery to the brain,and how liposomal drug delivery can play an important role as a drug delivery method for the treatment of Alzheimer’s disease.This review also sheds some light on variation of liposomes.Additionally,it emphasizes on the liposomal formulations which are currently researched or used for treatment of Alzheimer’s disease and also discusses the future prospect of liposomal based drug delivery in Alzheimer’s disease.
基金financially supported by National Natural Science Foundation of China (no. 81872816)Doctoral Scientific Research Staring Foundation of Liaoning Province (no. 2021BS-130)General Program of Department of Education of Liaoning Province (no. LJKZ0953)
文摘PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.
基金supported by the National Natural Science Foundation of China(No.30070935,30271614)
文摘Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol （PEG） were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scuteUarin were obtained, and the results showed that these conjugates were potential prodrugs for the oral delivery of scuteUarin.
基金supported by the General Programs of the National Natural Science Foundation of China(No.81171998,81472667,and 81461148021)the National Science and Technology Major Project for "Major New Drugs Innovation and Development"(No.2013ZX09509103)supported by the General Programs of the National Natural Science Foundation of China(No. 81272529)
文摘Background:Endostatin(ES) is a well-established potent endogenous antiangiogenic factor.An ES variant,called zinc-binding protein-ES(ZBP-ES),is clinically available;however,its use is limited by rapid renal clearance and short residence time.PEGylation has been exploited to overcome these shortcomings,and mono-PEGylated ES(called M_2ES) as well as mono-PEGylated ZBP-ES(MZBP-ES) are developed in our study.This study aimed to compare the biophysical properties and biological effects of M_2ES and MZBP-ES to evaluate their druggability.Methods:Circular dichroism and tryptophan emission fluorescence were used to monitor the conformational changes of M_2ES and MZBP-ES.Their resistance to trypsin digestion and guanidinium chloride(GdmCl)-induced unfolding was examined by Coomassie staining and tryptophan emission fluorescence,respectively.The biological effects of M_2ES and MZBP-ES on endothelial cell migration were evaluated using Transwell migration and wound healing assays,and the uptake of M_2ES and MZBP-ES in endothelial cells was also compared by Western blotting and immunofluorescence.Results:Structural analyses revealed that M_2ES has a more compact tertiary structure than MZBP-ES.Moreover,M_2ES was more resistant to trypsin digestion and GdmCI-induced unfolding compared with MZBP-ES.In addition,although M_2ES and MZBP-ES showed comparable levels of inhibiting transwell migration and wound healing of endothelial cells,M_2ES displayed an increased ability to enter cells compared with MZBP-ES,possibly caused by the enhanced interaction with nucleolin.Conclusions:M_2ES has a more compact tertiary structure,is more stable for trypsin digestion and GdmCI-induced unfolding,exhibits increased cellular uptake and shows equivalent inhibitory effects on cell migration relative to MZBP-ES,indicating that M_2ES is a more promising candidate for anticancer drug development compared with MZBP-ES.
基金supported by grants from CAMS Innovation Fund for Medical Sciences(Grant No.:2021-I2M-1-026)Scientific Research Project of Tianjin Education Commission(Grant No.:2020KJ140)Tianjin Health Research Project(Grant No.:KJ20017)。
文摘Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic cancer.In addition,enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer.Furthermore,the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic cancer.In this study,a novel FR-directed,macropinocytosis-enhanced,and highly cytotoxic bioconjugate folate(F)-human serum albumin(HSA)-apoprotein of lidamycin(LDP)-active enediyne(AE)derived from lidamycin was designed and prepared.F-HSA-LDP-AE consisted of four moieties:F,HSA,LDP,and AE.F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer cells.Its uptake in wild-type cells was more extensive than in K-Ras mutant-type cells.By in vivo optical imaging,F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice,showing clear and lasting tumor localization for 360 h.In the MTT assay,F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell lines.It also induced apoptosis and caused G2/M cell cycle arrest.F-HSALDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic mice.At well-tolerated doses of 0.5 and 1 mg/kg,(i.v.,twice),the inhibition rates were 91.2%and 94.8%,respectively(P<0.01).The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.
基金supported by National Natural Science Foundation of China (81102394)Natural Science Foundation of Liaoning Province (20170540575)
文摘This study aimed to investigate the ability of the novel materials D-α-tocopheryl poly(2-ethyl-2-oxazoline) succinate(TPOS) to construct pH-sensitive liposomes. TPOS was initially synthesized and characterized by TLC, FTIR, and ~1H-NMR. The buffering capacity of polyethylene glycol-distearoyl phosphatidylethanolamine(PEG-DSPE) and TPOS was determined by acid-base titration, and TPOS displayed a slower downtrend and gentler slope of titration curve than PEG-DSPE within pH 7.4–5.0. Studies on the in vitro drug release demonstrated that TPOS modified docetaxel(DOC) liposomes(TPOS-DOC-L) had a slower drugrelease rate at pH 7.4 similar to PEGylated-DOC liposomes(PEG-DOC-L), whereas the release rate reached approximately 86.92% ± 1.69% at pH 6.4. In vitro cellular uptake assays by microplate reader, and flow cytometry revealed that TPOS modified coumarin 6 liposomes(TPOS-C6-L) had stronger cellular uptake at pH 6.4 than that at pH 7.4( P < 0.01). Conversely, for PEGylated C6 liposomes(PEG-C6-L) and conventional C6 liposomes(C6-L), very similar cellular uptakes were exhibited at different pH values. Confocal laser scanning microscopy images showed that PEG-C6-L and C6-L were mainly located in lysosomes. By contrast, TPOS-C6-L showed broader cytoplasmic release and distribution at 4 h. MTT assay showed that the cytotoxicity of TPOS-DOC-L was similar to that of PEG-DOC-L and conventional DOC liposomes(DOC-L) at the same DOC concentration and at pH 7.4, but was much lower than those at pH 6.4 after 48 h of incubation. The apoptosis of PEG-DOC-L and DOC-L had no remarkable improvement with decreased pH from 7.4 to 6.4. Meanwhile, TPOS-DOC-Lsignificantly induced the apoptosis of HeLa cells with decreased pH. Therefore, TPOS can be a biomaterial for the construction of a pH-sensitive drug delivery system.
