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Chemistry (Weinheim An Der Bergstrasse,... Jun 2024Red fluorescent dyes are usually charged, lypophilic molecules with the relatively high molecular weight, which tend to localize in specific intracellular locations,...
Red fluorescent dyes are usually charged, lypophilic molecules with the relatively high molecular weight, which tend to localize in specific intracellular locations, e.g., a cyanine dye Cy5 is biased towards mitochondria. They are often used as markers of biomolecules including nucleic acids and proteins. Since molecular weight of the dyes is much smaller than that of the biomolecules, the labelling has a negligible effect on the properties of the biomolecules. In contrast, conjugation of the dyes to low molecular weight (pro)drugs can dramatically alter their properties. For example, conjugates of Cy5 with lysosome-targeting aminoferrocenes accumulate in mitochondria and exhibit no intracellular effects characteristic for the parent (pro)drugs. Herein we tested several neutral and negatively charged dyes for labelling lysosome-targeting aminoferrocenes 7 and 8 as well as a non-targeted control 3. We found that a BODIPY derivative BDP-TR exhibits the desired unbiased properties: the conjugation does not disturb the intracellular localization of the (pro)drugs, their mode of action and cancer cell specificity. We used the conjugates to clarify the mechanism of action of the aminoferrocenes. In particular, we identified new intermediates, explained why lysosome targeting aminoferrocenes are more potent than their non-targeted counterparts and evaluated their distribution in vivo.
PubMed: 38923064
DOI: 10.1002/chem.202401107 -
Drug Delivery and Translational Research Jun 2024The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug...
The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug (Cel-CSO) by conjugating chitosan oligosaccharides (CSO) to Cel for reversing Taxol resistance in chemotherapy, followed by self-assembly with Taxol into a novel nanoplatform of Cel-CSO/Taxol nanoparticles (termed NPs). NPs showed a suitable size (about 153 nm), excellent stability and prolonged release of Cel and Taxol in a manner that depended on both pH and time. NPs effectively inhibited the overexpression of multidrug resistance-related protein P-gp, hypoxia inducible factor-1α (HIF-1α), and triggered the MCF-7/Taxol cell apoptosis through inhibiting the PI3K/AKT/NF-κB/HIF-1α pathway. In tumor-bearing mice, NPs exhibited significant curative effects in inducing apoptosis of MCF-7/Taxol tumors which showed a low expression level of P-gp, microtubule-related proteins TUBB3 and Tau. The results indicated that NPs may be a promising strategy to overcome drug resistance caused by P-gp, which improve the antitumor effects in drug-resistant breast cancer.
PubMed: 38922561
DOI: 10.1007/s13346-024-01653-3 -
Pathogens (Basel, Switzerland) Jun 2024The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of...
The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm's digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals-which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as . Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.
PubMed: 38921780
DOI: 10.3390/pathogens13060482 -
Clinical Infectious Diseases : An... Jun 2024Remdesivir, an RNA-polymerase prodrug inhibitor approved for treatment of COVID-19, shortens recovery time and improves clinical outcomes. This prespecified analysis...
BACKGROUND
Remdesivir, an RNA-polymerase prodrug inhibitor approved for treatment of COVID-19, shortens recovery time and improves clinical outcomes. This prespecified analysis compared remdesivir plus standard-of-care (SOC) with SOC alone in adults hospitalized with COVID-19 requiring oxygen support in the early stage of the pandemic.
METHODS
Data for 10-day remdesivir treatment plus SOC from the extension phase of an open-label study (NCT04292899) were compared with real-world, retrospective data on SOC alone (EUPAS34303). Both studies included patients aged ≥18 years hospitalized with SARS-CoV-2 up to 30 May 2020, with oxygen saturation ≤94%, on room air or supplemental oxygen (all forms), and with pulmonary infiltrates. Propensity score weighting was used to balance patient demographics and clinical characteristics across treatment groups. The primary endpoint was time to all-cause mortality or end of study (day 28). Time-to-discharge, with a 10-day landmark to account for duration of remdesivir treatment, was a secondary endpoint.
RESULTS
1974 patients treated with remdesivir plus SOC, and 1426 with SOC alone, were included after weighting. Remdesivir significantly reduced mortality versus SOC (hazard ratio [HR]: 0.46, 95% confidence interval: 0.39-0.54). This association was observed at each oxygen support level, with the lowest HR for patients on low-flow oxygen. Remdesivir significantly increased the likelihood of discharge at day 28 versus SOC in the 10-day landmark analysis (HR: 1.64; 95% confidence interval: 1.43-1.87).
CONCLUSIONS
Remdesivir plus early-2020 SOC was associated with a 54% lower mortality risk and shorter hospital stays compared with SOC alone in patients hospitalized with COVID-19 requiring oxygen support.
CLINICAL TRIALS REGISTRATION
ClinicalTrials.gov NCT04292899 and EUPAS34303.
PubMed: 38920297
DOI: 10.1093/cid/ciae336 -
Acta Chimica Slovenica Jun 2024Diabetes mellitus is a chronic metabolic disorder marked by elevated blood sugar levels, leading to organ dysfunction. Curcumin, derived from turmeric, exhibits promise...
Diabetes mellitus is a chronic metabolic disorder marked by elevated blood sugar levels, leading to organ dysfunction. Curcumin, derived from turmeric, exhibits promise in managing type II diabetes. Nanomicelles were created by conjugating curcumin with chitosan through succinic anhydride. Succinyl-curcumin, the resultant compound, was esterified with chitosan to form a polymer prodrug conjugate. Nanomicelles, formed via dialysis, were spherical with a hydrodynamic size of 49.37 nm. In vitro release studies revealed 97% curcumin release at pH 5 in 7 days. A 21-day experiment on diabetic mice compared nanomicelles, standard drug, and free curcumin's impact on fasting blood glucose. The study showcased gradual, controlled curcumin release from nanomicelles, suggesting their potential in type II diabetes treatment.
Topics: Animals; Curcumin; Chitosan; Diabetes Mellitus, Type 2; Micelles; Mice; Mice, Inbred BALB C; Diabetes Mellitus, Experimental; Prodrugs; Nanoparticles; Male; Blood Glucose; Hypoglycemic Agents
PubMed: 38919100
DOI: 10.17344/acsi.2024.8658 -
Current Protein & Peptide Science Jun 2024Platinum (II) drugs, including cisplatin, carboplatin, and oxaliplatin, have achieved significant clinical success in cancer treatment. However, their clinical...
Platinum (II) drugs, including cisplatin, carboplatin, and oxaliplatin, have achieved significant clinical success in cancer treatment. However, their clinical application has been greatly hindered by various adverse factors such as non-specific activation and drug resistance. Compared with Pt(II) drugs, the axial ligands within Pt(IV) compounds can improve the pharmacokinetic properties, selectivity, and biological activity, implementing alternative cytotoxic mechanisms beyond DNA cross-linking and partially overcoming drug resistance. The controlled conversion of Pt(IV) prodrugs into Pt(II) agents at the tumor site has been extensively explored internationally. In this review, Pt(IV) prodrug modification strategies are first summarized, next the development of the predominant external and internal photosensitizers is listed. Finally, three representative photoreduction mechanisms and strategies for developing corresponding Pt(IV) prodrugs are discussed. This work provides constructive instruction for the subsequent molecular design of Pt(IV) prodrugs.
.PubMed: 38919078
DOI: 10.2174/0113892037297416240525155628 -
Current Pharmaceutical Design Jun 2024Hepatocellular Carcinoma (HCC) is a type of liver cancer known for its poor prognosis and high mortality. Teoptinib is a highly selective MET inhibitor that has been...
BACKGROUND & PURPOSE
Hepatocellular Carcinoma (HCC) is a type of liver cancer known for its poor prognosis and high mortality. Teoptinib is a highly selective MET inhibitor that has been used in the treatment of liver cancer. Although good progress has been made in clinical treatment, further improvement is still needed. In this study, a series of novel Teoptinib derivatives were synthesized and evaluated as anti-cancer agents for the treatment of liver cancer, and an oral nanodrug delivery system was also explored.
METHODS
A series of novel Teoptinib derivatives were synthesized, and an oral nanodrug delivery system was also explored. HPLC, high-resolution mass spectrometer and NMR were used to determine the structure and molecular formula of the synthesized compounds. Zeta potential assay was used to access the particle size distribution and zeta potential of the nanoparticles. MTT assay, cell colony formation assay, cell apoptosis inhibition assay, cell scratch assay, and the MHCC-97H xenograft model of nude mice assay were used to evaluate the in vitro and in vivo anti-tumor activity of the synthesized compounds.
RESULTS
Compound (R)-10 showed the best antitumor activity with 0.010 μM of the IC50 value against MHCC-97H, a human liver cancer cell line with high c-Met expression. The MHCC-97H xenograft model of nude mice assay showed that nano-prodrug of compound (R)-10 exhibited good in vivo activity with 87.67% of the TGI at the dosage of 8 mg/kg.
CONCLUSION
We designed and synthesized a series of c-Met inhibitors containing different side chains and chiral centers as anti-liver cancer agents. Among them, compound (R)-10 shows a promising effect as a lead molecule for further study in the treatment of liver cancer. The successful incorporation of (R)-10 into a novel oral nanodrug delivery system highlights the importance of effective drug delivery systems for enhanced therapeutic efficacy.
.PubMed: 38919077
DOI: 10.2174/0113816128314500240621071306 -
Hormones and Behavior Jun 2024Menopause is an endocrine shift leading to increased vulnerability for cognitive impairment and dementia risk factors, in part due to loss of neuroprotective circulating...
Menopause is an endocrine shift leading to increased vulnerability for cognitive impairment and dementia risk factors, in part due to loss of neuroprotective circulating estrogens. Systemic replacement of estrogen post-menopause has limitations, including risk for estrogen-sensitive cancers. A promising therapeutic approach therefore might be to deliver estrogen only to the brain. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in ovariectomized mice (a surgical menopause model). We treated mice with the prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17β-estradiol only in the brain. Young and middle-aged C57BL/6 J mice received ovariectomy and subcutaneous implant containing vehicle or DHED and underwent cognitive testing to assess memory after 1-3.5 months of treatment. Low and medium doses of DHED did not alter metabolic status in middle-aged mice. In both age groups, DHED treatment improved spatial memory in ovariectomized mice. Additional testing in middle-aged mice showed that DHED treatment improved working and recognition memory in ovariectomized mice. These results lay the foundation for future studies determining if this intervention is as efficacious in models of dementia with comorbid risk factors.
PubMed: 38917776
DOI: 10.1016/j.yhbeh.2024.105594 -
BioRxiv : the Preprint Server For... Jun 2024While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life....
While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by has the potential to diminish unwanted effects of fumarates while retaining efficacy.
PubMed: 38915544
DOI: 10.1101/2024.06.10.598291 -
Chemical Communications (Cambridge,... Jun 2024A nucleus-targeted nanocomposite was prepared by clickable amino acid-tuned one-step co-assembly of proteins and chemotherapeutics. The nanocomposite with favorable...
A nucleus-targeted nanocomposite was prepared by clickable amino acid-tuned one-step co-assembly of proteins and chemotherapeutics. The nanocomposite with favorable pharmacokinetic behavior can effectively accumulate in the nucleus, thereby significantly enhancing the anticancer therapeutic effect both and .
PubMed: 38915280
DOI: 10.1039/d4cc02377c