Oral Delivery of Multicompartment Nanomedicines for Colorectal Cancer Therapeutics: Combining Loco‐Regional Delivery with Cell‐Target Specificity

Background:: Several studies have suggested potential aptitude of polylactic-co-glycolic acid (PLGA)-derived nanoparticles (NPs) to improve the antitumor efficacy of anticancer drugs against colon cancer. Further, conjugation of lectins over the surface of the NPs may ameliorate interaction and thus enhance attachment of NPs with receptors. Objective:: The main goal of the study was to prepare and evaluate targeting potential (in vivo) of the optimized NPs against colorectal cancer. Methods:: The 5-fluorouracil (5-FU) loaded and wheat germ agglutinin (WGA)-conjugated PLGA-NPs (WFUNPs) were prepared and then they were evaluated in vivo for targeting aptitude of formulation using gamma scintigraphy after oral delivery. The WGA-conjugated and non-conjugated optimized NPs were compared for any significant results. Further, optimized formulations were also assessed for different parameters such as radiolabeling efficiency, sodium pertechnetate uptake, stability of NPs, and organ distribution study. Results:: Findings suggested prolonged retention of 99mTc-tagged WFUNPs in the colonic region after 24 h study. Eventually, the outcome from conjugated formulation revealed enhanced bioavailability of the drug in blood plasma for up to 24 h. Conclusion:: In conclusion, WGA-conjugation to NPs could improve the performance of the PLGA-NPs in the treatment of colorectal cancer.

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Adenovirus stripping: a versatile method to generate adenovirus vectors with new cell target specificity

Molecular Therapy ◽

10.1016/s1525-0016(03)00067-4 ◽

2003 ◽

Vol 7 (5) ◽

pp. 692-699 ◽

Cited By ~ 28

Author(s):

Saw See Hong ◽

Maria K Magnusson ◽

Petra Henning ◽

Leif Lindholm ◽

Pierre A Boulanger

Keyword(s):

Target Specificity ◽

Cell Target ◽

Adenovirus Vectors

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Oral delivery of pH-responsive alginate microbeads incorporating folic acid-grafted solid lipid nanoparticles exhibits enhanced targeting effect against colorectal cancer: A dual-targeted approach

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2020.02.132 ◽

2020 ◽

Vol 151 ◽

pp. 830-844 ◽

Cited By ~ 7

Author(s):

Kuldeep Rajpoot ◽

Sunil K. Jain

Keyword(s):

Colorectal Cancer ◽

Folic Acid ◽

Solid Lipid Nanoparticles ◽

Oral Delivery ◽

Lipid Nanoparticles ◽

Ph Responsive ◽

Solid Lipid ◽

Targeting Effect ◽

Targeted Approach

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RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer

Gut ◽

10.1136/gutjnl-2020-320652 ◽

2020 ◽

pp. gutjnl-2020-320652

Author(s):

Lei Sun ◽

Arabella Wan ◽

Zhuolong Zhou ◽

Dongshi Chen ◽

Heng Liang ◽

...

Keyword(s):

Colorectal Cancer ◽

Rna Binding ◽

Tumour Progression ◽

Binding Protein ◽

Rna Binding Protein ◽

Cancer Therapeutics ◽

Mitochondrial Metabolism ◽

The Cancer Genome Atlas ◽

Colorectal Tumour ◽

Specific Subset

ObjectiveDysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood.DesignWe analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models.ResultsWe identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m6A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models.ConclusionsCollectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.

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Somatic mutations in young-onset colorectal cancer unrelated to hereditary syndromes: A comparative study using high-depth targeted exome sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.623 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 623-623

Author(s):

Y. Nancy You ◽

Kyle Chang ◽

Ken Chen ◽

Amir Mehdizadeh ◽

Amanda Cuddy ◽

...

Keyword(s):

Colorectal Cancer ◽

Exome Sequencing ◽

Young Patients ◽

Cancer Therapeutics ◽

Metastatic Tumor ◽

Cancer Center ◽

Young Onset ◽

Targeted Exome Sequencing ◽

Hereditary Syndromes ◽

Depth Analysis

623 Background: Colorectal cancer (CRC) is being increasingly diagnosed among young adults, but known hereditary syndromes do not account for the majority of these cases. Young patients often present with metastatic disease and exhibit aggressive clinical courses. We aimed to elucidate the potentially unique biology of young-onset CRC. Methods: Patients diagnosed with metastatic CRC prior to age 40 without a known predisposing syndrome (young-onset) were compared to similar patients diagnosed after age 60 (later-onset). Primary and/or metastatic tumor tissues from 19 young- and 51 later-onset patients underwent targeted exome sequencing on a panel of 200 genes using Illumina HiSeq2000 performed by the Institute of Personalized Cancer Therapeutics of MD Anderson Cancer Center. Sequencing was to an average depth of 800x; single nucleotide variations (SNVs) were called according to in-house algorithms. Results: The median age of patients with young-onset CRCs was 34 years (interquartile range: 31-37), while that of later-onset CRCs was 66 years (IQR: 62- 72). The primary CRC was in the rectum in 30% of the young- vs. 16% of the later-onset cases. The overall mutational rate as measured by the number of SNVs per patient (median: 7 vs. 9) did not differ significantly between the groups. However, the median allelic frequency of SNVs was higher in the young-onset group (0.34 vs. 0.17%), suggesting differing patterns of tumor heterogeneity. Genes known to be associated with CRC carcinogenesis were mutated at different proportions (Table); SMAD4, mismatch repair genes (MSH6, MLH1, MSH2), ARID1A, IGF1R and KITappear to be more frequently mutated among the young. Conclusions: This exploratory study suggests that the somatic mutation profiles are distinct between young- vs. later-onset CRCs. More in-depth analysis of the genomic landscape of young-onset CRCs may reveal distinct and novel therapeutic avenues. [Table: see text]

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Comprehensive analysis of tumor microenvironment landscape and potential therapeutic agents based on tumor-infiltrating immune cells in colorectal cancer

10.21203/rs.3.rs-772603/v1 ◽

2021 ◽

Author(s):

Wenhui Zhong ◽

Feng Zhang ◽

Xin Lu ◽

Kaijun Huang ◽

Junming Bi ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Immune Cells ◽

Transforming Growth Factor ◽

Immune Cell ◽

Cancer Therapeutics ◽

The Cancer Genome Atlas ◽

Receptor Interaction ◽

Chemotherapy Drugs ◽

Drug Compounds

Abstract Background: Tumor-infiltrating immune cells (TIIC) are the major components of the tumor microenvironment (TME) and play vital roles in the tumorigenesis and progression of colorectal cancer (CRC). Increasing evidence has elucidated their significances in predicting prognosis and therapeutic efficacy. Nonetheless, the immune infiltrative landscape of CRC remains largely unknown. Methods: All the RNA-seq transcriptome data and full clinical annotation of 1213 colorectal cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO) database. The “CIBERSORT” and “estimate” R package were applied to calculate 22 infiltrated immune cell fractions and stromal and immune score. Three TIIC patterns were determined by Unsupervised clustering methods. Through using principal-component analysis, TIIC scores were established. Data for potential agents comes from the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) and Cancer Therapeutics Response Portal database (CTRP). Results：In this study, we identified three distinct TIIC patterns characterized by distinct immunological features in 1213 CRC samples from multiple platforms. Base on the TIIC-related gene signatures from three clusters, we constructed a scoring system to quantify the immune infiltration level of individual samples in the CRC cohort and the clinical benefits of different groups. The high TIIC score group was marked by increased immune activation status and favorable prognosis. Conversely, low TIIC score group was featured with immune-desert phenotype and poor prognosis, along with the activation of transforming growth factor-β (TGF-β), WNT, ECM receptor interaction, and VEGF signaling pathways. Meanwhile, the high TIIC score group was also correlated with enhanced efficacy of immunotherapy. Additional, four chemotherapy drugs, seven CTRP-derived drug compounds and six PRISM-derived drug compounds were identified as potential drug for CRC among high and low TIIC subgroups.Conclusions: Collectively, as an effective prognostic biomarker and predictive indicator, the TIIC score plays an important role in the evaluation of CRC prognosis and the response of immunotherapy. Investigation of the TIIC patterns might provide us a promising target for improving immunotherapeutic efficacy in CRC.

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