Dataset Information

Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy.

ABSTRACT: This study investigates the use of camel milk-derived exosomes (CMEs) as carriers for ARV-825, an anticancer agent targeting bromodomain-containing protein 4 (BRD4), in oral chemotherapy. CMEs were isolated and characterized, and ARV-825-loaded CME formulations were prepared and evaluated through various in vitro and in vivo tests. The ARV-825-CME formulation exhibited an entrapment efficiency of 42.75 ± 5.05%, a particle size of 136.8 ± 1.94 nm, and a zeta potential of -32.75 ± 0.70 mV, ensuring stability and sustained drug release. In vitro studies showed a 5.4-fold enhancement in drug release kinetics compared to the free ARV-825 solution. Permeability studies indicated a 3.2-fold increase in apparent permeability, suggesting improved cellular uptake. Cytotoxicity assays demonstrated potent anticancer activity, with IC50 values decreasing by 1.5 to 2-fold in cancer cell lines SF8628 DIPG and H1975R (resistant to Osimertinib). In vivo pharmacokinetic studies in Sprague-Dawley rats revealed superior systemic absorption and bioavailability of ARV-825 from CMEs, with a 2.55-fold increase in plasma concentration and a 5.56-fold increase in AUC. Distribution studies confirmed absorption through the ileum. This research highlights the potential of CMEs as a promising delivery platform for ARV-825, enhancing its therapeutic efficacy and offering a novel approach to cancer treatment.

SUBMITTER: Nathani A

PROVIDER: S-EPMC11359469 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy.

Nathani Aakash A Aare Mounika M Sun Li L Bagde Arvind A Li Yan Y Rishi Arun A Singh Mandip M

Pharmaceutics 20240815 8

This study investigates the use of camel milk-derived exosomes (CMEs) as carriers for ARV-825, an anticancer agent targeting bromodomain-containing protein 4 (BRD4), in oral chemotherapy. CMEs were isolated and characterized, and ARV-825-loaded CME formulations were prepared and evaluated through various in vitro and in vivo tests. The ARV-825-CME formulation exhibited an entrapment efficiency of 42.75 ± 5.05%, a particle size of 136.8 ± 1.94 nm, and a zeta potential of -32.75 ± 0.70 mV, ensurin ...[more]

PMID: 39204415

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Project description:BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL.MethodsExpression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP).ResultsBRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo.ConclusionsBRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

Project description:BackgroundCamel milk is known to have hypoglycemic properties. Previous studies found that camel milk exosomes (CM-exo) may regulate cellular glucose metabolism through the inhibition of mitochondrial complex I, but this hypothesis has not been verified by other experiments. The objective of this study was to verify the hypothesis that CM-exo regulated glucose metabolism in hepatocytes by inhibiting mitochondrial complex I pathway. AML12 cells were treated with extracted exosomes from camel milk and the effect of the CM-exo on cell viability was examined by cell counting kit (CCK)-8 assays. The glucose content of the cell culture medium was measured to determine the glucose consumption of the cells. Lactate release from the cells was determined by measuring the lactate content in the cell culture medium. The glycogen content of AML12 cells was detected. The activity of complex I and the contents of ATP, NAD+ and NADH were measured. The protein expression levels of adenosine monophosphate-activated protein kinase (AMPK) and phosphorylated AMPK (p-AMPK) were detected by western blotting. The AML12 cells were treated with medium containing CM-exo and gluconeogenic substrates and the glucose content in the cells was determined. The protein expression levels of ten-eleven translocation methylcytosine dioxygenases (TET3), hepatocyte nuclear factor 4α-Promoter 2 (HNF4α-P2), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6PC), glycogen synthase kinase 3β (GSK3β) and phosphorylation of GSK3β (p-GSK3β) were detected by western blotting.ResultsThe results of this study showed that a high dose of CM-exo inhibited the viability of AML12 cells. It promoted glucose consumption, glycogen content and lactate release in AML12 cells, inhibited complex I activity, ATP content, NAD+ content, and NAD+/NADH ratio, and increased NADH content. The CM-exo increased the protein levels of p-AMPK, p-GSK3β, the protein expression ratio of p-AMPK/AMPK, p-GSK3β/GSK3β and decreased the glucose content and the protein expression levels of intracellular TET3, HNF4α-P2, PEPCK and G6PC.ConclusionsBy inhibiting the activity of mitochondrial complex I in hepatocytes, CM-exo inhibited oxidative phosphorylation, oxidation of NADH to NAD+ and synthesis of ATP, enhanced glycolysis, activated AMPK and resulted in decreased gluconeogenesis and increased glycogen synthesis.

Dataset Information

Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy.

Publications

Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy.

Similar Datasets

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