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DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models.

ABSTRACT: Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated αDR5 antibody (AMG 655). Binding and clustering of the DR5 is a prerequisite for efficient apoptosis initiation, and the αDR5-NPs were indeed found to activate apoptosis in multiple pancreatic cancer models, whereas the free antibody did not. The extent of apoptosis induced by αDR5-NPs was enhanced by down-regulating FLIP, a key modulator of death receptor-mediated activation of caspase-8. Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by αDR5-NPs. CPT-loaded αDR5-NPs significantly increased apoptosis and decreased cell viability in vitro in a caspase-8- and FADD-dependent manner consistent with their expected mechanism-of-action. Importantly, CPT-loaded αDR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that αDR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer.

SUBMITTER: Johnston MC

PROVIDER: S-EPMC7429293 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models.

Johnston Michael C MC Nicoll Julie A JA Redmond Kelly M KM Smyth Peter P Greene Michelle K MK McDaid William J WJ Chan Darren K W DKW Crawford N N Stott Katie J KJ Fox Jennifer P JP Straubinger Ninfa L NL Roche Sandra S Clynes Martin M Straubinger Robert M RM Longley Daniel B DB Scott Christopher J CJ

Journal of controlled release : official journal of the Controlled Release Society 20200603

Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advanta ...[more]

PMID: 32504778

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Project description:BACKGROUND:Pancreatic ductal adenocarcinoma (PDA) remains the most aggressive cancers with a 5-year survival below 10%. Systemic delivery of chemotherapy drugs has severe side effects in patients with PDA and does not significantly improve overall survival rate. It is highly desirable to advance the therapeutic efficacy of chemotherapeutic drugs by targeting their delivery and increasing accumulation at the tumor site. MUC1 is a membrane-tethered glycoprotein that is aberrantly overexpressed in > 80% of PDA thus making it an attractive antigenic target. METHODS:Poly lactic-co-glycolic acid nanoparticles (PLGA NPs) conjugated to a tumor specific MUC1 antibody, TAB004, was used as a nanocarrier for targeted delivery into human PDA cell lines in vitro and in PDA tumors in vivo. The PLGA NPs were loaded with fluorescent imaging agents, fluorescein diacetate (FDA) and Nile Red (NR) or isocyanine green (ICG) for in vitro and in vivo imaging respectively or with a chemotherapeutic drug, paclitaxel (PTX) for in vitro cytotoxicity assays. Confocal microscopy was used to visualize internalization of the nanocarrier in vitro in PDA cells with high and low MUC1 expression. The in vivo imaging system (IVIS) was used to visualize in vivo tumor targeting of the nanocarrier. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was used to determine in vitro cell survival of cells treated with PTX-loaded nanocarrier. One-sided t-test comparing treatment groups at each concentration and two-way ANOVAs comparing internalization of antibody and PLGA nanoparticles. RESULTS:In vitro, TAB004-conjugated ICG-nanocarriers were significantly better at internalizing in PDA cells than its non-conjugated counterpart. Similarly, TAB004-conjugated PTX-nanocarriers were significantly more cytotoxic in vitro against PDA cells than its non-conjugated counterpart. In vivo, TAB004-conjugated ICG-nanocarriers showed increased accumulation in the PDA tumor compared to the non-conjugated nanocarrier while sparing normal organs. CONCLUSIONS:The study provides promising data for future development of a novel MUC1-targeted nanocarrier for direct delivery of imaging agents or drugs into the tumor microenvironment.

Project description:The present study aimed to synthesize iron oxide nanoparticles loaded with quinine and alkaloids-rich Cinchona officinalis (Peruvian bark) stem bark extract, and further evaluate their cytotoxic effect and apoptosis mechanisms in MCF-7 breast cancer cells. Nanoparticles were prepared by biological reduction of iron oxide with Cinchona officinalis extract, using the green synthesis method. The nanoparticles were characterized by XRD, FT-IR, and UV-vis spectroscopy and transmission electron microscopy (TEM). In vitro cytotoxicity analyses of Cinchona officinalis extract, ferrous oxide, and Cinchona officinalis extract-loaded iron oxide nanoparticles (CO-NPs) were carried out using the MTT test for 24 h and 48 h. We found that CO-NPs reduced the MCF-7 cell viability with IC50 values of 16.2 and 9 µg/mL in 24 h and 48 h, respectively. In addition, CO-NPs were tested with normal hMSCs to determine their toxicity, and we did not find noticeable cytotoxicity. Confocal fluorescent microscopy revealed that CO-NPs efficiently increased the nuclear condensation and chromatin damage in propidium iodide staining; meanwhile, there was decreased mitochondrial membrane potential in CO-NPs-treated MCF-7 cells. In addition, AO-EB staining confirmed the late apoptotic and apoptotic morphology of cancer cells. Further gene expression analysis confirmed that the upregulation of tumor suppressors, Cdkn1A, Prb, and p53 was significantly increased, and inflammatory traits such as TNF-α and Nf-κb were increased in cancer cells treated with CO-NPs. Apoptotic stimulators such as Bax and caspase-3 expression were highly significantly increased, while mdm-2 and Bcl-2 were significantly decreased. Overall, the enhanced cytotoxic potential of the Cinchona officianlis stem bark extract loaded CO-NPs versus free Cinchona officianlis extract might be due to the functional stabilization of bioactive compounds, such as alkaloids, quinine, flavonoids, phenolics, etc., into the iron oxide, providing bioavailability and internalization of cinchona metabolites intracellularly.

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DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models.

Publications

DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models.

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