Project description:Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors, however its toxicity and side-effect limits its clinical efficacy. Herein, the docetaxel-loaded solid lipid nanoparticles (DSNs) were developed to reduce systemic toxicity while still keeping its anti-cancer activity. To evaluate its anti-cancer activity and toxicity and understand the molecular mechanisms of DSNs, different cellular, molecular and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel-Taxotere and induced more apoptosis at 24 h treatment in vitro. It can cause the treated cancer cells arrested at G2/M phase in a dose-depend manner as Taxotere. The DSNs can also suppress tumor growth very effectively in a murine breast cancer model. Systemic analysis of gene expression profiles by microarray and the following verification experiments suggested that both DSNs and Taxotere regulate expression of series genes and these genes functions involved in DNA replication, DNA damage response, cell proliferation, apoptosis and cell cycle regulation. Some of these genes expressed differentially at protein level although their transcription level was similar under TAX and DSNs treatment. Moreover, DSNs improved main side-effect of Taxotere by greatly lowering myelosuppression toxicity to bone marrow cells from mice. Taken together, our results expound the anti-tumor efficacy and the potential working mechanisms of DSNs in its anti-cancer activity and toxicity, which provide a theoretical foundation to develop and apply more efficient docetaxel formulation to treat cancer patients.
Project description:Hepatocellular carcinoma (HCC) is associated with high mortality rates despite the widespread application of radiofrequency ablation (RFA), which has limited therapeutic efficacy as a monotherapy. This study investigated ribonucleotide reductase M2 (RRM2) upregulation in post-RFA HCC tissues and developed a targeted nanoco-delivery system (red blood cell membrane/cRGD-modified pH-sensitive liposomes [sS@RBCM/cRGD-phLips]) to increase RFA efficacy through specific RRM2 knockout. RRM2 knockout synergistically amplified RFA-induced tumor cell death by promoting ferroptosis and immunogenic cell death. Mechanistically, RRM2 knockout upregulated the STAT1–IRF1–acyl-CoA synthetase long-chain family member 4 axis, which potentiated lipid peroxidation and ferroptosis. Furthermore, the nanocarrier system enhanced dendritic cell maturation and cytotoxic T cell infiltration, thereby remodeling the tumor immune microenvironment. In vivo experiments revealed that the combination of RFA- and RRM2-targeted nanoparticles significantly suppressed tumor growth and prolonged survival in HCC-bearing mice with minimal systemic toxicity. Notably, the dual-loaded nanoparticles also enhanced the efficacy of anti-programmed cell death protein 1 therapy, suggesting a promising combinatorial approach for HCC treatment. This study presents a novel therapeutic strategy that integrates RRM2-targeted gene editing with RFA, offering a robust and synergistic approach for improving HCC outcomes.
Project description:To further study the transcriptome of Caco-2 human colon epithelial-like cells after exposure to S-nitrosoglutathione (GSNO, 1.4 μM), or Eudragit RL PO polymeric nanoparticles (NP-ERL, 50 μg/mL) or GSNO loaded nanoparticles (NP-GSNO, 50 μg/mL corresponding to (1.4 μM GSNO) we investigate whole genome microarray to identify genes regulates by exposure or not to GSNO (1.4 μM) or Eudragit RL PO polymeric nanoparticles (NP-ERL, 50 μg/mL) or GSNO loaded nanoparticles (NP-GSNO, 50 μg/mL corresponding to (1.4 μM GSNO).
2015-12-31 | GSE69551 | GEO
Project description:Efficacious Suppression of Primary and Metastasized Liver Tumors by polyIC-Loaded Lipid Nanoparticles
Project description:To further study the transcriptome of THP-1 human monocytes after exposure to S-Nitrosoglutathione (GSNO), we investigate whole genome microarray expression to identify genes regulated by exposure or not to GSNO. To further study the transcriptome of THP-1 human monocytes after exposure for 4 h to 50 ug / mL of S-Nitrosoglutathione-loaded polymeric Eudragit RL nanoparticles (GSNO-loaded ENP), we investigate whole genome microarray expression to identify genes regulated by exposure or not to 50 ug / mL of GSNO-loaded ENP. To further study the transcriptome of THP-1 human monocytes after exposure for 4 h to 200 ug / mL of empty polymeric Eudragit RL nanoparticles (empty ENP), we investigate whole genome microarray expression to identify genes regulated by exposure or not to 200 ug / mL of empty ENP. To further study the transcriptome of THP-1 human monocytes after exposure for 24 h to 50 ug / mL of S-Nitrosoglutathione-loaded polymeric Eudragit RL nanoparticles (GSNO-loaded ENP), we investigate whole genome microarray expression to identify genes regulated by exposure or not to 50 ug / mL of GSNO-loaded ENP. To further study the transcriptome of THP-1 human monocytes after exposure for 24 h to 50 ug / mL of empty polymeric Eudragit RL nanoparticles (empty ENP), we investigate whole genome microarray expression to identify genes regulated by exposure or not to 50 ug / mL of empty ENP. To further study the transcriptome of THP-1 human monocytes after exposure for 4 h to 50 ug / mL of empty polymeric Eudragit RL nanoparticles (empty ENP), we investigate whole genome microarray expression to identify genes regulated by exposure or not to 50 ug / mL of empty ENP. To further study the transcriptome of THP-1 human monocytes after exposure for 4 h to 200 ug / mL of S-Nitrosoglutathione-loaded polymeric Eudragit RL nanoparticles (GSNO-loaded ENP), we investigate whole genome microarray expression to identify genes regulated by exposure or not to 200 ug / mL of GSNO-loaded ENP.
Project description:Perotein corona is formed surrouding interface of nanopsrticles upon administered in biological fluids. The quality of protein corona is recognized as the crucial factor for in vivo fate of the administered nanoparticles. In this project, Cas9 ribnonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) capable of robust gene knockout of hepatic genes of interest after single intravenous injection were developed. Compared with short interfering RNA (siRNA)-loaded LNPs, RNP-loaded LNPs showed different morphology, biodistribution, and mechanism of hepatic acccumulation. Therefore, proteome analysis of the corona proteins on the RNP and siRNA-loaded LNPs were performed to elucidate the impact of payloads on nano-bio interactions.
Project description:Purpose: To determine whether docetaxel therapy of advanced prostate cancer can be improved by using docetaxel in combination with Aneustat (OMN54), a multivalent botanical drug candidate undergoing a Phase-I Clinical Trial, and to identify the molecular action of this drug combination. Experimental Design: Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, either alone or in combination. Culture growth (at 48 hours) and xenograft size (at 3 weeks) were determined and animal health monitored. Xenografts were gene expression profiled using gene expression microarrays. Androgen receptor (AR) expression and AKT phosphorylation were examined. Results: Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner in vitro, reducing AR expression and AKT phosphorylation. Aneustat was not as effective as docetaxel in inhibiting LTL-313H xenograft growth. When combined, Aneustat and docetaxel markedly and synergistically enhanced anti-tumor activity without inducing major host toxicity, even leading to complete growth inhibition and tumor shrinkage not obtained with the single drugs. AR expression and AKT signalling in the xenografts were inhibited by docetaxel+Aneustat, but not by the single agents. Expression microarray analysis indicated that docetaxel+Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the drugs on their own. Conclusion: Our findings, obtained with a clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat.
Project description:To further study the transcriptome of Caco-2 human colon epithelial-like cells after exposure to S-nitrosoglutathione (GSNO, 1.4 μM), or Eudragit RL PO polymeric nanoparticles (NP-ERL, 50 μg/mL) or GSNO loaded nanoparticles (NP-GSNO, 50 μg/mL corresponding to (1.4 μM GSNO) we investigate whole genome microarray to identify genes regulates by exposure or not to GSNO (1.4 μM) or Eudragit RL PO polymeric nanoparticles (NP-ERL, 50 μg/mL) or GSNO loaded nanoparticles (NP-GSNO, 50 μg/mL corresponding to (1.4 μM GSNO). Changes in gene expression in Caco-2 cells incubated without (control) or with GSNO or nanoparticles for 4 h, were measured. Four biological replicates were performed as controls: S46_1_4 ; S46_1_3 ; S35_1_4 ; S35_1_3. Four biological replicates were performed for each conditions : wtih GSNO (1.4 µM) exposed cells (S46_2_2 ; S46_2_1 ; S35_2_2 ; S35_2_1), with NP-ERL (50 μg/mL) exposed cells (S46_1_2 ; S46_1_1 ; S35_1_2 ; S35_1_1) with NP-GSNO (50 μg/mL corresponding to 1.4 µM GSNO) exposed cells (S46_2_4 ; S46_2_3 ; S35_2_4 ; S35_2_3)