Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical ...challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2' position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity.
Polybrominated diphenyl ethers（PBDEs） can be transferred to infants through the ingestion of breast milk, resulting in potential health risk. In this study, PBDEs, hydroxylated polybrominated ...diphenyl ethers（OH-PBDEs） and 2,2′,4,4′,5,6′-hexachlorobiphenyl（CB-153）in human milk from women living adjacent to e-waste recycling sites of Wenling,China, were investigated. The median level of PBDEs in samples from residents living in the e-waste recycling environment 〉 20 years（R20group, 19.5 ng/g lipid weight（lw））was significantly higher than that for residents living in Wenling 〈 3 years（R3group,3.88 ng/g lw）（p 〈 0.05）, likely ascribable to specific exposure to PBDEs from e-waste recycling activities. In the R20 group, most congeners（except for BDE-209） were correlated with each other（p 〈 0.05）. Moreover, CB-153 showed significant association with most PBDE congeners, rather than BDE-209. The relationship indicated that most BDE congeners other than BDE-209 shared common sources and/or pathways with CB-153, e.g., dietary ingestion. The correlations between BDE-209 and other congeners were different in the two groups, likely suggesting their different exposure sources and/or pathways for PBDEs.Although estimated dietary intake of PBDEs for infants via breast milk was lower than the minimum value affecting human health, the PBDE exposure of infants should be of great concern because of their potential effect on the development of neonates over long-term exposure. OH-PBDEs were not detected in the collected samples, which is in accordance with reports in published literature, likely indicating that they were not apt to be accumulated in human milk.
Prodrug Strategies for Paclitaxel Meng, Ziyuan; Lv, Quanxia; Lu, Jun ...
International journal of molecular sciences,
05/2016, Volume:
17, Issue:
5
Journal Article
Peer reviewed
Open access
Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low ...selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.
Monoclonal antibodies are the dominant agents used in inhibition of biological target molecules for disease therapeutics, but there are concerns of immunogenicity, production, cost and stability. ...Oligonucleotide aptamers have comparable affinity and specificity to targets with monoclonal antibodies whilst they have minimal immunogenicity, high production, low cost and high stability, thus are promising inhibitors to rival antibodies for disease therapy. In this review, we will compare the detailed advantages and disadvantages of antibodies and aptamers in therapeutic applications and summarize recent progress in aptamer selection and modification approaches. We will present therapeutic oligonucleotide aptamers in preclinical studies for skeletal diseases and further discuss oligonucleotide aptamers in different stages of clinical evaluation for various disease therapies including macular degeneration, cancer, inflammation and coagulation to highlight the bright commercial future and potential challenges of therapeutic oligonucleotide aptamers.
Breast cancer is the second leading cause of cancer death among women. Human epidermal receptor 2 (HER2) positive breast cancer (HER2+ BC) is the most aggressive subtype of breast cancer, with poor ...prognosis and a high rate of recurrence. About one third of breast cancer is HER2+ BC with significantly high expression level of HER2 protein compared to other subtypes. Therefore, HER2 is an important biomarker and an ideal target for developing therapeutic strategies for the treatment HER2+ BC. In this review, HER2 structure and physiological and pathological roles in HER2+ BC are discussed. Two diagnostic tests, immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), for evaluating HER2 expression levels are briefly introduced. The current mainstay targeted therapies for HER2+ BC include monoclonal antibodies, small molecule tyrosine kinase inhibitors, antibody-drug conjugates (ADC) and other emerging anti-HER2 agents. In clinical practice, combination therapies are commonly adopted in order to achieve synergistic drug response. This review will help to better understand the molecular mechanism of HER2+ BC and further facilitate the development of more effective therapeutic strategies against HER2+ BC.
Dechlorane Plus (DP), a flame retardant used as an alternative to decabromodiphenylether, has been frequently detected in organisms, indicating its bioaccumulation and biomagnification potential in ...aquatic and terrestrial species. However, little data is available on the bioaccumulation of DP in amphibians. Dechlorane Plus and its analogs (DPs) were detected in the liver, muscle and brain tissues of wild frogs (Rana limnocharis), which were collected from an e-waste recycling site, Southeast China. DP, Mirex, Dec 602 and a dechlorinated compound of DP (anti-Cl11-DP) varied in the range of 2.01–291, 0.650–179, 0.260–12.4, and not detected (nd)–8.67 ng/g lipid weight, respectively. No difference of tissue distribution was found for syn-DP, Mirex and Dec 602 between the liver and muscle tissue (liver/muscle concentration ratio close to 1, p > 0.05). However, higher retention was observed for anti-DP and anti-Cl11-DP in the frog muscle relative to the liver tissue (liver/muscle concentration ratio < 1, p < 0.05). Additionally, the blood-brain barrier was found to work efficiently to suppress these compounds entering brain tissues in this species (liver/brain concentration ratio > 1, p < 0.05), and the molecular weight was a key factor impacting the extent of the blood-brain barrier. Compared to levels in the muscle and brain tissue, a preferential enrichment of syn-DP was observed in the liver tissue, suggesting the occurrence of stereo-selective bioaccumulation in the wild frog.
Dechlorane Plus （DP）,a flame retardant used as an alternative to decabromodiphenylether, has been frequently detected in organisms, indicating its bioaccumulation and biomagnification potential in ...aquatic and terrestrial species. However, little data is available on the bioaccumulation of DP in amphibians. Dechlorane Plus and its analogs （DPs） were detected in the liver, muscle and brain tissues of wild frogs （Rana limnocharis）, which were collected from an e-waste recycling site, Southeast China. DP, Mirex, Dec 602 and a dechlorinated compound of DP （anti-Cll I-DP） varied in the range of 2.01-291, 0.650-179, 0.260-12.4, and not detected （nd）-8.67 ng/g lipid weight, respectively. No difference of tissue distribution was found for syn-DP, Mirex and Dec 602 between the liver and muscle tissue （liver/muscle concentration ratio close to 1, p 〉 0.05）. However, higher retention was observed for anti-DP and anti-Cll1-DP in the frog muscle relative to the liver tissue （liver/muscle concentration ratio 〈 1, p 〈 0.05）. Additionally, the blood-brain barrier was found to work efficiently to suppress these compounds entering brain tissues in this species （liver/brain concentration ratio 〉 l, p 〈 0.05）, and the molecular weight was a key factor impacting the extent of the blood-brain barrier. Compared to levels in the muscle and brain tissue, a preferential enrichment of syn-DP was observed in the liver tissue, suggesting the occurrence of stereo-selective bioaccumulation in the wild frog.
This study aimed to elucidate the potential causative links between inflammatory biomarkers and gastric cancer risk via a two-sample Mendelian randomization approach. Leveraging genome-wide ...association study (GWAS) data, we conducted a two-sample Mendelian randomization analysis. Instrumental variable selection for inflammatory markers - namely, tissue factor, monocyte chemotactic protein-1, E-selectin, interleukin 6 receptor, and fatty acid-binding protein 4 - was informed by SNP data from the IEU database. Strongly associated SNPs served as instrumental variables. We applied a suite of statistical methods, including Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger, and mode-based estimates, to compute the odds ratios (ORs) that articulate the impact of these markers on gastric cancer susceptibility. The IVW method revealed that the interleukin 6 receptor was inversely correlated with gastric cancer progression (OR = 0.86, 95% CI = 0.74-0.99, P = .03), whereas fatty acid-binding protein 4 was found to elevate the risk (OR = 1.21, 95% CI = 1.05-1.39, P = .03). Instrumental variables comprised 5, 4, 7, 2, and 3 SNPs respectively. Convergent findings from WME, MR-Egger, and mode-based analyses corroborated these associations. Sensitivity checks, including heterogeneity, horizontal pleiotropy assessments, and leave-one-out diagnostics, affirmed the robustness and reliability of our instruments across diverse gastric malignancy tissues without substantial bias. Our research suggests that the interleukin 6 receptor potentially mitigates, while fatty acid-binding protein 4 may contribute to the pathogenesis of gastric cancer (GC). Unraveling the intricate biological interplay between inflammation and oncogenesis offers valuable insights for preemptive strategies and therapeutic interventions in gastric malignancy management.
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