The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate wi...The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and myelotoxicity.Due to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse reactions.Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects.In this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.展开更多
AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment ...AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.展开更多
AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (...AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.展开更多
Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Trea...Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn' s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?展开更多
The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not s...The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not subject to interference from environmental factors, and exhibit enhanced precision and accuracy. Therefore, a novel RF sensor for the selective detection of 6-MP was developed. The present work reports a sensitive and selective RF sensor for the detection of 6-mercaptopurine, by hybridizing carbon nanodots (CDots) and gold nanoclusters (AuNCs) capped with bovine serum albumin (BSA). The CDots serve as the reference signal and the AuNCs as the reporter. On addition of the 6-MP, AuNCs formed aggregates, because the existing cross-links within the AuNCs and BSA structure were broken in favour of the Au-S bonds, which can enhance the fluorescence of AuNCs, while the fluorescence of CDots is stable against 6-MP, leading to distinct ratiometric fluorescence changes when exposed to 6-MP. 6-MP could be detected in the range of 0 - 30.22 μM with a detection limit of 54 nM. The developed sensor was applied for the determination of 6-MP in human serum samples and satisfactory results were obtained.展开更多
<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Me...<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Methods: The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed. Results: The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved. Conclusion: This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.展开更多
The Ag clusters have been investigated widely theoretically and experimentally. In particular, it has recently shown that the neutral Ag8 clusters embedded in an argon matrix have a strong fluorescence signal. As we c...The Ag clusters have been investigated widely theoretically and experimentally. In particular, it has recently shown that the neutral Ag8 clusters embedded in an argon matrix have a strong fluorescence signal. As we can know, the metal clusters may have important effects on the structures and properties of biomolecules. More and more attention is paid to the interaction between nanomaterials and biomolecules. In this work, the B3LYP method in density functional theory was used on the complexes between the 6-mercaptopurine（6MP） and Ag8 clusters combined with 6-311＋＋G＊＊ as well as LANL2DZ base sets. The geometries of all the complexes were optimized with full degree of freedom and the structures, chemical bonds, orbital properties as well as Mulliken charges for ten possible complexes were analyzed based on the same theory level. In addition, the influence of temperature and pressure on the stabilities of the four complexes was further explored using standard statistical thermodynamic methods ranging from 50 to 500 K and at 100 kPa or 100 bar. The results show that the complex Ag8-6 MP-7-5 can be the most stable one among the investigated complexes, in which the Ag（11） atom interacts with the S（10） atom forming the strong chemical bond. The Mulliken charges also show that the Ag–S chemical bond is formed and the related charge has transferred. Additionally, the temperature and pressure can significantly influence the stability of the four stable complexes.展开更多
The Polarographic and voltammetric behavior of 6-mercaptopurine were studied by several electrochemical techniques There are two reduction peaks in HAC buffer solution at PH 4.0. The characteriatics of the second Pea...The Polarographic and voltammetric behavior of 6-mercaptopurine were studied by several electrochemical techniques There are two reduction peaks in HAC buffer solution at PH 4.0. The characteriatics of the second Peak(P2) were studied in detail. The relationship between P: current(ip2 and concentration of 6-mercaptopurine is linear in the range of lx10-7-lx10 mol/L It has beeb applied to quantitative analysis of an anticancer tablet with satisfying results.The mechaniam,of the electrode reaction was proposed alao.展开更多
An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic d...An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic drug 6-mercaptopurine and a hydrophilic β-CD grafted carboxymethyl chitosan were synthesized. Then, a novel amphiphilic inclusion complex was prepared with the dimer being partially embedded into the cavity of β-CD moiety. It self-assembled into pH/redox responsive core-shell micelles in distilled water. TEM confirmed that the micelles possessed a spherical core-shell configuration with a mean size of about 160 nm. DLS showed that the micelles were stable in aqueous solution. Their particle diameters altered with pH values as well as glutathione (GSH) concentrations and respectively attained a maximum value at pH 6.0 and 20 mM GSH. Release profiles of 6-mercaptopurine showed a low release rate (about 27 wt% after 48 h) in pH 7.4 medium with 10 μM GSH, and a marked increase (over 88 wt% after 48 h) in pH 5.0 medium with 20 mM GSH. In vitro cytotoxicity test showed that the micelles had a dose-dependent toxicity for HeLa cells, indicating a great potential for controlled release of 6-mercaptopurine in tumor cells.展开更多
Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects.This situation can be improved by drug delivery systems or drug modification strategies.Herei...Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects.This situation can be improved by drug delivery systems or drug modification strategies.Herein,to improve the therapeutic efficacy and safety of the traditional anticancer drug 6-mercaptopurine(6-MP),we dimerized 6-MP to form a disulfide bond-containing drug dimer and prepared a cysteine-based poly(disulfide amide)with redox-responsive capability as a drug carrier.Briefly,dimeric 6-MP(DMP)was synthesized via the oxidization of iodine and self-assembled with the poly(disulfide amide)to form dual redox-responsive DMP-loaded NPs(DMP-NPs).The 6-MP itself could hardly be loaded into nanoparticles(NPs)owing to its hydrophobicity,while the DMP-NPs showed a higher drug loading capacity over 6-MP,small particle size,and favorable stability.With abundant disulfide bonds in polymer backbones and drug payloads,DMP-NPs could rapidly respond to high levels of glutathione(GSH)and release drugs in a controllable manner.More importantly,both cellular and animal experiments demonstrated the enhanced anticancer efficacy of DMP-NPs against lymphoma and their high safety.Overall,this drug dimer-loaded dual redox-responsive drug delivery system provides new options for improving the applications of traditional drugs and developing drug delivery systems with enhanced drug effects and high safety.展开更多
目的本研究旨在探讨涎液化糖链抗原-6(krebs von den lungen-6,KL-6)在特发性肺含铁血黄素沉着症(idiopathic pulmonary hemosiderosis,IPH)患儿辅助诊断中的临床应用价值。方法收集2014年6月至2024年7月期间于广州医科大学附属第一医...目的本研究旨在探讨涎液化糖链抗原-6(krebs von den lungen-6,KL-6)在特发性肺含铁血黄素沉着症(idiopathic pulmonary hemosiderosis,IPH)患儿辅助诊断中的临床应用价值。方法收集2014年6月至2024年7月期间于广州医科大学附属第一医院就诊的140例患儿,分为病例组与对照组,其中病例组根据疾病类型细分为IPH组(32例)、间质性肺炎(interstitial lung disease,ILD)组(22例)、肺炎(pneumonia,PN)组(60例),对照组为非肺部疾病(non-pulmonary disease,NPD)组(26例)。以上患儿检测血清KL-6水平,分析KL-6在各组患儿中的表达差异。结果KL-6阳性率在各组患儿中从高到低分别为IPH(68.75%)、ILD(45.45%)、PN(1.69%)和NPD(0.00%),组间阳性率差异有统计学意义(χ^(2)=66.10,P<0.001)。IPH组患儿血清KL-6平均水平高于PN组患儿(Ζ=-6.92,P<0.001)。诊断试验结果显示ROC曲线下面积为0.940(95%CI:0.89~1.00,P<0.001),截断值为392.00 U/mL,灵敏度为81.30%,特异度为95.00%。结论KL-6在鉴别IPH患儿与PN和NPD患儿中具有较高的诊断价值,可作为IPH辅助诊断的血液生物标志物。展开更多
基金Supported by Grant from Inflammatory Bowel and Immunobiology Research Institute,Cedars-Sinai Medical Center
文摘The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and myelotoxicity.Due to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse reactions.Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects.In this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.
文摘AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.
文摘AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.
文摘Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn' s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?
文摘The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not subject to interference from environmental factors, and exhibit enhanced precision and accuracy. Therefore, a novel RF sensor for the selective detection of 6-MP was developed. The present work reports a sensitive and selective RF sensor for the detection of 6-mercaptopurine, by hybridizing carbon nanodots (CDots) and gold nanoclusters (AuNCs) capped with bovine serum albumin (BSA). The CDots serve as the reference signal and the AuNCs as the reporter. On addition of the 6-MP, AuNCs formed aggregates, because the existing cross-links within the AuNCs and BSA structure were broken in favour of the Au-S bonds, which can enhance the fluorescence of AuNCs, while the fluorescence of CDots is stable against 6-MP, leading to distinct ratiometric fluorescence changes when exposed to 6-MP. 6-MP could be detected in the range of 0 - 30.22 μM with a detection limit of 54 nM. The developed sensor was applied for the determination of 6-MP in human serum samples and satisfactory results were obtained.
文摘<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Methods: The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed. Results: The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved. Conclusion: This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.
基金supported by the National Natural Science Foundation of China(No.21643014)the Special Natural Science Foundation of Science and Technology Bureau of Xi’an City Government(No.2016CXWL02 and SGH17H249)
文摘The Ag clusters have been investigated widely theoretically and experimentally. In particular, it has recently shown that the neutral Ag8 clusters embedded in an argon matrix have a strong fluorescence signal. As we can know, the metal clusters may have important effects on the structures and properties of biomolecules. More and more attention is paid to the interaction between nanomaterials and biomolecules. In this work, the B3LYP method in density functional theory was used on the complexes between the 6-mercaptopurine（6MP） and Ag8 clusters combined with 6-311＋＋G＊＊ as well as LANL2DZ base sets. The geometries of all the complexes were optimized with full degree of freedom and the structures, chemical bonds, orbital properties as well as Mulliken charges for ten possible complexes were analyzed based on the same theory level. In addition, the influence of temperature and pressure on the stabilities of the four complexes was further explored using standard statistical thermodynamic methods ranging from 50 to 500 K and at 100 kPa or 100 bar. The results show that the complex Ag8-6 MP-7-5 can be the most stable one among the investigated complexes, in which the Ag（11） atom interacts with the S（10） atom forming the strong chemical bond. The Mulliken charges also show that the Ag–S chemical bond is formed and the related charge has transferred. Additionally, the temperature and pressure can significantly influence the stability of the four stable complexes.
文摘The Polarographic and voltammetric behavior of 6-mercaptopurine were studied by several electrochemical techniques There are two reduction peaks in HAC buffer solution at PH 4.0. The characteriatics of the second Peak(P2) were studied in detail. The relationship between P: current(ip2 and concentration of 6-mercaptopurine is linear in the range of lx10-7-lx10 mol/L It has beeb applied to quantitative analysis of an anticancer tablet with satisfying results.The mechaniam,of the electrode reaction was proposed alao.
文摘An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic drug 6-mercaptopurine and a hydrophilic β-CD grafted carboxymethyl chitosan were synthesized. Then, a novel amphiphilic inclusion complex was prepared with the dimer being partially embedded into the cavity of β-CD moiety. It self-assembled into pH/redox responsive core-shell micelles in distilled water. TEM confirmed that the micelles possessed a spherical core-shell configuration with a mean size of about 160 nm. DLS showed that the micelles were stable in aqueous solution. Their particle diameters altered with pH values as well as glutathione (GSH) concentrations and respectively attained a maximum value at pH 6.0 and 20 mM GSH. Release profiles of 6-mercaptopurine showed a low release rate (about 27 wt% after 48 h) in pH 7.4 medium with 10 μM GSH, and a marked increase (over 88 wt% after 48 h) in pH 5.0 medium with 20 mM GSH. In vitro cytotoxicity test showed that the micelles had a dose-dependent toxicity for HeLa cells, indicating a great potential for controlled release of 6-mercaptopurine in tumor cells.
基金This work was supported by the National Natural Science Foundation of China(Nos.51973243 and 52173150)International Cooperation and Exchange of the National Natural Science Foundation of China(No.51820105004)+1 种基金China Postdoctoral Science Foundation(No.2020M683058),the Science and Technology Planning Project of Shenzhen(No.JCYJ20190807155801657)Guangdong Innovative and Entrepreneurial Research Team Program(No.2016ZT06S029).
文摘Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects.This situation can be improved by drug delivery systems or drug modification strategies.Herein,to improve the therapeutic efficacy and safety of the traditional anticancer drug 6-mercaptopurine(6-MP),we dimerized 6-MP to form a disulfide bond-containing drug dimer and prepared a cysteine-based poly(disulfide amide)with redox-responsive capability as a drug carrier.Briefly,dimeric 6-MP(DMP)was synthesized via the oxidization of iodine and self-assembled with the poly(disulfide amide)to form dual redox-responsive DMP-loaded NPs(DMP-NPs).The 6-MP itself could hardly be loaded into nanoparticles(NPs)owing to its hydrophobicity,while the DMP-NPs showed a higher drug loading capacity over 6-MP,small particle size,and favorable stability.With abundant disulfide bonds in polymer backbones and drug payloads,DMP-NPs could rapidly respond to high levels of glutathione(GSH)and release drugs in a controllable manner.More importantly,both cellular and animal experiments demonstrated the enhanced anticancer efficacy of DMP-NPs against lymphoma and their high safety.Overall,this drug dimer-loaded dual redox-responsive drug delivery system provides new options for improving the applications of traditional drugs and developing drug delivery systems with enhanced drug effects and high safety.
文摘目的本研究旨在探讨涎液化糖链抗原-6(krebs von den lungen-6,KL-6)在特发性肺含铁血黄素沉着症(idiopathic pulmonary hemosiderosis,IPH)患儿辅助诊断中的临床应用价值。方法收集2014年6月至2024年7月期间于广州医科大学附属第一医院就诊的140例患儿,分为病例组与对照组,其中病例组根据疾病类型细分为IPH组(32例)、间质性肺炎(interstitial lung disease,ILD)组(22例)、肺炎(pneumonia,PN)组(60例),对照组为非肺部疾病(non-pulmonary disease,NPD)组(26例)。以上患儿检测血清KL-6水平,分析KL-6在各组患儿中的表达差异。结果KL-6阳性率在各组患儿中从高到低分别为IPH(68.75%)、ILD(45.45%)、PN(1.69%)和NPD(0.00%),组间阳性率差异有统计学意义(χ^(2)=66.10,P<0.001)。IPH组患儿血清KL-6平均水平高于PN组患儿(Ζ=-6.92,P<0.001)。诊断试验结果显示ROC曲线下面积为0.940(95%CI:0.89~1.00,P<0.001),截断值为392.00 U/mL,灵敏度为81.30%,特异度为95.00%。结论KL-6在鉴别IPH患儿与PN和NPD患儿中具有较高的诊断价值,可作为IPH辅助诊断的血液生物标志物。
