Albumin-mediated Delivery of Therapeutic Peptides for Pancreatic Cancer Therapy
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PROVIDER: PRJNA629118 | ENA |
REPOSITORIES: ENA
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Project description:Bioactive peptides are promising agents for therapeutic applications, however their small size results in poor stability, low bioavailability and rapid renal clearance, so its widespread use is limited. To address these issues, fusing or conjugating peptides to suitable molecular scaffolds is required. In this study, human serum albumin (HSA) is used as a delivery carrier for human β-defensin-2 peptides (HBD2) in the production of HSA-delivered defensin complex (ADDC) to facilitate its cellular uptake and transport to intracellular targets. Conjugation can improve the stability of HBD2, while extend the circulation time and promote its accumulation within tumor, thereby improving the therapeutic efficacy. Herein, ADDC provides a protective structure against the harsh external environment and serves as a passive tumor-targeted system. Our data showed that the combination of ADDC with clinically relevant drugs, such as Doxorubicin, Gemcitabine, Cisplatin, and Cetuximab can significantly increase the cytotoxicity of ADDC on human pancreatic cancer cells. The results of bioinformatics analysis also revealed that ADDC may affect the metabolic processes, gene transcription and apoptosis of pancreatic cancer cells. Collectively, ADDC exhibited specific tumor targeting capabilities, low systemic toxicity, and enhanced antitumor efficacy in a mouse model of pancreatic cancer.
2020-12-23 | GSE149557 | GEO
Project description:Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate (Albumin-binding siMMP13<(EG18L)2) was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of post-traumatic OA (PTOA) and RA (K/BxN) joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin ‘hitchhiking’ for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA.
2023-05-30 | GSE233714 | GEO
Project description:Therapeutic Delivery of Targeted Nanoparticle Cannabinoid Equivalents
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Project description:Nanoparticles and nano delivery systems are continuously being refined and developed as means of treating numerous human diseases by site-specific, and target-oriented delivery of medicines. The nanoparticles can carry therapeutic cargo or be medicinal themselves by virtue of their constitutional structural components. Here we report the ability of synthetic N-acylethanolamides, linoleoylethanolamide (LEA) and oleoylethanolamide (OEA), with endocannabinoid-like activity, to form spherical colloidal nanoparticles that when conjugated with tissue specific homing molecules, can localise to specific areas of the body, and reduce inflammation. The opportunities to mediate pharmacological effects of endocannabinoids at targeted sites provides a novel drug delivery system with increased medicinal potential to treat many diseases in many areas of medicine.
2022-10-19 | GSE206164 | GEO
Project description:Therapeutic delivery of transcription factor HNF4A mRNA attenuates liver fibrosis
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Project description:Human serum albumin is the most abundant plasma protein with a large number of lysine and arginine residues. Hence, it is highly susceptible to glycation in vivo. In hyperglycemic conditions, such as diabetes, the level of HSA glycation increases. Here we quantified glycated HSA peptides in a subject population of healthy and type 2 diabetes with and without nephropathy to assess its performance for the diagnosis of diabetic nephropathy compared to HbA1c.
2023-07-20 | PXD040028 | Pride
Project description:The mRNA-based therapeutics such as COVID-19 vaccines are rapidly progressing into the clinic with a tremendous potential of benefiting millions of people worldwide. Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive aspect, however until recently, it has remained poorly explored. In this study, we examined for the first time therapeutic utility of mRNA delivery in liver fibrosis and cirrhosis, which contributes to millions of deaths, annually. Here, demonstrated the therapeutic efficacy of the human transcription factor hepatic nuclear factor alpha (HNF4A) encoding mRNA in murine chronically injured liver leading to fibrosis and cirrhosis. We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNP) encapsulating HNF4A mRNA. To identify potential mechanism, we performed microarray-based gene expression profiling, single cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for further functional validation. Expression of HNF4A encoding mRNA led to restoration of metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of HNF4A mRNA encapsulated-LNP induced a robust inhibition of fibrogenesis in four independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver.
2021-09-01 | GSE165277 | GEO
Project description:Therapeutic Delivery of CCL2 Modulates Immune Response and Restores Host-microbe Homeostasis
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Project description:Many studies have sought to circumvent the protective qualities of the blood brain barrier to deliver therapeutic proteins to the brain for the treatment of neurodegenerative diseases. Yet, brain specific uptake, peripheral toxicity, off-target effects, and repeated dosing continue to present considerable challenges. As proof of principle, we sought to determine whether human iPSC-microglia (iMG) could be genetically engineered ex vivo to enable pathology-responsive delivery of amyloid-targeting proteins to the brain. Human iPSCs were CRISPR-edited to express the beta-amyloid degrading enzyme neprilysin (NEP) or secreted neprilysin (sNEP) under control of the endogenous CD9 promoter, a microglial gene that is specifically upregulated in plaque-associated microglia. Following adult-transplantation into xenotolerant, amyloid-accumulating mice (5x-MITRG), beta-amyloid peptides, synaptic markers, and off-target substrate levels were examined. To further determine whether increased engraftment of therapeutic microglia could provide additional disease-modifying efficacy, sNEP iMGs were further modified to confer resistance to CSF1R antagonists, enabling brain-wide engraftment of human microglia. Amyloid pathology and synaptic, inflammatory, and neurodegeneration biomarkers were then assessed. We demonstrate that microglia can be engineered to enable pathology-responsive delivery of therapeutic proteins to the brain. NEP and sNEP xenografted microglia reduced levels of amyloid peptides and oligomers, prevented pathology-associated reductions in synaptic markers, and lowered astrogliosis within the hippocampus and overlying cortex of 5x-MITRG mice without off-target degradation. Surprisingly, sNEP delivery by microglia adjacent to the injection site alone was sufficient to achieve almost all disease-modifying outcomes as effectively as CNS-wide sNEP-microglia engraftment. However, significant reductions in amyloid pathology, dystrophic neurites, and perineuronal nets within the plaque-dense subiculum of 5x-MITRG mice was only achieved following CNS-wide microglial replacement. Taken together, these results demonstrate that human microglia can be engineered as a promising new immune cell therapeutic platform to provide widespread and pathology-responsive delivery of biological therapeutics for the treatment of neurodegenerative disease.
2025-07-01 | GSE282917 | GEO
Project description:Physiologically, albumin is produced by hepatocytes. It remains largely unknown how patients are capable of maintaining essential albumin levels even in the condition of liver failure. Here, we delineate a hierarchical regulatory network that controls albumin transcription under different pathophysiological conditions. The ALB core promoter possesses a TATA box and nucleosome-free area, which allows constitutive binding of RNA Pol II and thus initiation of transcription. In normal conditions, HNF4α and C/EBPα facilitate albumin transcription through binding to its promoter. In severely damaged livers, hepatocellular HNF4α and C/EBPα expression is often inhibited. The absence of HNF4 and C/EBPα increases hedgehog ligand biosynthesis. Hedgehog upregulates FOXA2 expression through transcription factor GLI2 binding to the FOXA2 promoter. Subsequently, FOXA2 maintains albumin expression in the hepatocytes lacking HNF4α and C/EBPα. In patients with massive hepatocyte loss, the expression of albumin is activated in liver progenitor cells. Albumin transcription in these cells is regulated by HNF4α or FOXA2. Taken together, HNF4α, C/EBPα and FOXA2 form a hierarchical regulatory network that ensures stable albumin expression even in pathophysiological conditions.
2022-04-06 | GSE181201 | GEO