Cited by 106Nanoparticle-Based Drug DeliveryMesoporous Materials and CatalysisRNA Interference and Gene Delivery

The DOI matches its Crossref record; 101 of the 102 references it cites were found in a registry or an index; none of the 109 sources its claims cite is checked for support yet.

Targeted Nano-Drug Delivery of Colchicine against Colon Cancer Cells by Means of Mesoporous Silica Nanoparticles

Open access
AbouAitah, Khaled, Hassan, Heba A., Swiderska-Sroda, Anna, Gohar, Lamiaa, Shaker, Olfat G., Wojnarowicz, Jacek, Opalinska, Agnieszka, Smalc-Koziorowska, Julita, Gierlotka, Stanislaw, Lojkowski, Witold·2020·Cancers

Abstract

Antimitotics are important anticancer agents and include the natural alkaloid prodrug colchicine (COL). However, a major challenge of using COL as an anticancer drug is its cytotoxicity. We developed a novel drug delivery system (DDS) for COL using mesoporous silica nanoparticles (MSNs). The MSNs were functionalized with phosphonate groups, loaded with COL, and coated with folic acid chitosan-glycine complex. The resulting nanoformulation, called MSNsPCOL/CG-FA, was tested for action against cancer and normal cell lines. The anticancer effect was highly enhanced for MSNsPCOL/CG-FA compared to COL. In the case of HCT116 cells, 100% inhibition was achieved. The efficiency of MSNsPCOL/CG-FA ranked in this order: HCT116 (colon cancer) > HepG2 (liver cancer) > PC3 (prostate cancer). MSNsPCOL/CG-FA exhibited low cytotoxicity (4%) compared to COL (~60%) in BJ1 normal cells. The mechanism of action was studied in detail for HCT116 cells and found to be primarily intrinsic apoptosis caused by an enhanced antimitotic effect. Furthermore, a contribution of genetic regulation (metastasis-associated lung adenocarcinoma transcript 1 (MALAT 1), and microRNA (mir-205)) and immunotherapy effects (angiopoietin-2 (Ang-2 protein) and programmed cell death protein 1 (PD-1) was found. Therefore, this study shows enhanced anticancer effects and reduced cytotoxicity of COL with targeted delivery compared to free COL and is a novel method of developing cancer immunotherapy using a low-cost small-molecule natural prodrug.

Overview

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Written from the paper’s full text.

TL;DR

The paper reports a mesoporous silica nanoparticle delivery system for colchicine, MSNsPCOL/CG-FA, functionalized with phosphonate groups and coated with a folic acid–chitosan–glycine complex, which enhanced anticancer effects and reduced normal-cell toxicity compared with free colchicine. In HCT116 colon cancer cells it achieved 100% inhibition at 200 μg/mL and acted mainly through intrinsic apoptosis, with additional effects on genetic and immune markers.

Key findings

  • MSNsPCOL/CG-FA inhibited cancer cells in the order HCT116 > HepG2 > PC3. In HCT116 cells, 200 μg/mL produced 100% inhibition at 24, 48, and 72 h; IC50 values for MSNsPCOL/CG-FA were 19.7 μg/mL at 24 h, 17.4 μg/mL at 48 h, and 17.0 μg/mL at 72 h. In normal BJ1 cells, MSNsPCOL/CG-FA inhibited only 4% after 72 h versus ~60% for free COL.
  • Mechanistically, MSNsPCOL/CG-FA inhibited tubulin by ~90% at 50 μg/mL, increased G2/M arrest to 14.8% versus 12.4% for 5-FU and 8.7% for COL, induced total apoptosis of 15.0% versus 10.6% for COL, and produced caspase-3 activity >1000 pg/mL. It enhanced Bax to ~14 FLD and inhibited Bcl-2 to ~0.1 FLD, inhibited BRAF by ~90% at 50 μg/mL, and reduced CD44 to 33.3 ± 3.5 ng/mL versus 185.5 ± 15.4 ng/mL in control cells.
  • The nanoformulation also reduced MALAT-1 to 0.3 ± 0.05-fold change versus ~160-fold in control cells, reduced mir-205 to 0.53 ± 0.05-fold change versus 14-fold in control cells, lowered Ang-2 to 174.0 ± 0.75 ng/mL versus 213.3 ± 3.0 ng/mL in control cells, and lowered PD-1 to 9.8 ± 0.3 ng/mL versus 14 ± 0.5 ng/mL in control cells, close to the normal BJ1 level of 9.6 ± 0.5 ng/mL.

Methods

  • MSNs of KCC-1 type were synthesized, functionalized with phosphonate groups, loaded with colchicine, and coated with chitosan-glycine conjugated to folic acid. Characterization included FE-SEM, STEM, BET surface area, EDS, NTA, FTIR, STA-DSC, XRD, and zeta potential measurements.
  • In vitro assays used HCT116 colon cancer, HepG2 liver cancer, PC3 prostate cancer, and BJ1 normal fibroblast cells. Cytotoxicity was measured by MTT assay at 24, 48, and 72 h; mechanism studies used flow cytometry for cell cycle, apoptosis, and mitochondrial membrane potential, ELISA for tubulin, caspase-3, BRAF, cytochrome c, CD44, Ang-2, and PD-1, and RT-PCR for Bax/Bcl-2, MALAT1, and miR-205.
  • Data are expressed as mean ± SD, with significance tested by Student t-test, Mann-Whitney U test, and ANOVA at p < 0.05; measurements were performed in triplicate.

Limitations

  • The paper has no formal limitations section. The authors state that the MALAT1, mir-205, and PD-1 results with COL and its delivery in HCT116 cells were obtained for the first time and that further deep investigations are needed.
  • Evident from the text: all anticancer and mechanistic data are in vitro cell-line experiments; no in vivo animal tumor model, pharmacokinetic, biodistribution, or clinical data are reported.
  • Evident from the text: the immunotherapy/immune-checkpoint interpretation is based on marker levels in HCT116 cells rather than immune-cell functional assays, and long-term safety or targeting specificity is not established.

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Integrity signals

Registry

Crossref · 10.3390/cancers12010144

Cites

101 of 101 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 109 cited sources checked · 0 supported · 0 flagged

Show all 139 claims

  • It may state two separate claims as one. 59
  • Probably not a substantial claim. 46
88 of 88
  • The authors state this as an assumption.

    No data are available yet on the effects of COL on MALAT1 inhibition or promotion.

    “To the best of our knowledge, no data are available yet on the effects of COL on MALAT1 inhibition or promotion.”
  • The authors state this as an assumption.

    No data are available yet on the effects of COL in either downregulating or upregulating mir-205 in cancer.

    “To the best of our knowledge, there are no data available yet on the effects of COL in either downregulating or upregulating mir-205 in cancer.”
  • The paper relies on this without support.

    These are the first results for COL or a DDS as a small drug molecule.

    “These are the first results for COL or a DDS as a small drug molecule.”
  • The authors state this as an assumption.

    The results for MALAT1, mir-205, and PD-1 with COL and its delivery in HCT116 cancer cells were obtained for the first time.

    “To the best of our knowledge, the results for MALAT1, mir-205, and PD-1 with COL and its delivery in HCT116 cancer cells were obtained for the first time.”
  • The paper relies on this without support.

    Ang-2 is a pro-angiogenic cytokine that maintains angiogenesis and restricts the antitumor immune response from attacking cancer cells.

    “Ang-2 is a pro-angiogenic cytokine that maintains angiogenesis and restricts the antitumor immune response from attacking cancer cells.”
  • The paper relies on this without support.

    Arresting cells at the G2/M phase results in apoptosis.

    “Arresting cells at the G2/M phase results in apoptosis.”
  • The paper relies on this without support.

    NanoDrop2000 is very accurate for measuring even the smallest quantities of RNA.

    “The concentration of RNA was determined using NanoDrop2000, which is very accurate for measuring even the smallest quantities of RNA (NanoDrop2000, Thermo Scientific, Wilmington, NC, USA).”
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Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting BJ1 cytotoxicity values for the nanoformulation

    Major

    The paper reports 4% inhibition of normal BJ1 cells after 72 hours, but its summary of the same comparison gives 10% toxicity for MSNsPCOL/CG-FA.

  • Claim of superior inhibition at every concentration conflicts with equal inhibition

    Minor

    The paper says MSNsPCOL/CG-FA was more efficient than COL at all concentrations in HCT116 cells, immediately after reporting equal, 100% inhibition at 200 μg/mL.

  • Explanation says average particle size increased when the reported size decreased

    Minor

    The proposed explanation says coating led to an increase in average size, but the same paragraph reports a decrease from 391 nm for MSNsPCOL to 330 nm for MSNsPCOL/CG-FA.

  • Conclusion reverses the order of phosphonate modification and drug loading

    Minor

    The methods say the MSNs were first modified to obtain MSNsP and COL was then loaded into MSNsP. The conclusion instead describes loading COL followed by phosphonate modification.

  • HepG2 treatment ranking repeats the same formulation

    Minor

    The stated ranking places MSNsPCOL/CG-FA both above and below COL, despite the preceding comparison identifying MSNsPCOL as the other nanoformulation.

5 of 5

Citations

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Metadata

Authors
AbouAitah, K., Hassan, H. A., Swiderska-Sroda, A., Gohar, L., Shaker, O. G., Wojnarowicz, J., Opalinska, A., Smalc-Koziorowska, J., Gierlotka, S., & Lojkowski, W.
Affiliations
  • Institute of High Pressure Physics (PL)
  • National Research Centre (EG)
  • Laboratory of Nanostructures, Institute of High Pressure Physics, Polish Academy of Sciences, Sokolowska 29/37, 01-142 Warsaw, Poland
  • Cairo University (EG)
  • Laboratory of Semiconductor Characterization, Institute of High Pressure Physics, Polish Academy of Sciences, Sokolowska 29/37, 01-142 Warsaw, Poland
Corresponding author
AbouAitah, Khaled
Venue
Cancers
Publisher
MDPI AG
Published
2020-01-07
Volume
12
Issue
1
Pages
144
ISSN
2072-6694 (ISSN-L)
OpenAlex
W3000634096
Cited by
105
References
102
Citations by year
2026: 11 · 2025: 13 · 2024: 20 · 2023: 19 · 2022: 16 · 2021: 17 · 2020: 9
FWCI
3.69
Type
journal article
Language
en
Open access
Locations
  • Cancers (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Research Centre (NRC, Egypt) (Internal funding)
  • National Center for Research and Development, Poland (STRATEGMED3/306888/3/ NCBR/2017, project iTE, Poland)
  • European Regional Development Fund within the Operational Programme “Innovative Economy” (CePT project, reference: POIG.02.02.00-14-024/08)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Physical Sciences › Materials Science › Materials Chemistry › Mesoporous Materials and Catalysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
colchicine, mesoporous silica nanoparticles, targeted drug delivery, colon cancer, antimitotic agents, folic acid, phosphonate functionalization, HCT116 cells, apoptosis, MALAT1, microRNA-205, angiopoietin-2, PD-1, cancer immunotherapy, cytotoxicity reduction

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