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. 2020 Jul 9;12(7):652.
doi: 10.3390/pharmaceutics12070652.

Chitosan-Based Microparticles Enhance Ellagic Acid's Colon Targeting and Proapoptotic Activity

Nabil A Alhakamy  1   2   3 , Osama A A Ahmed  1 , Mallesh Kurakula  4 , Giuseppe Caruso  5 , Filippo Caraci  5   6 , Hani Z Asfour  7 , Anas Alfarsi  1 , Basma G Eid  8 , Amir I Mohamed  9 , Nabil K Alruwaili  10 , Wesam H Abdulaal  11 , Usama A Fahmy  1 , Hani A Alhadrami  12   13 , Basmah M Eldakhakhny  14 , Ashraf B Abdel-Naim  8
Affiliations

Chitosan-Based Microparticles Enhance Ellagic Acid's Colon Targeting and Proapoptotic Activity

Nabil A Alhakamy et al. Pharmaceutics. .

Retraction in

Abstract

This study aimed at improving the targeting and cytotoxic effect of ellagic acid (EA) on colon cancer cells. EA was encapsulated in chitosan (CHIT) polymers then coated by eudragit S100 (ES100) microparticles. The release of EA double-coated microparticles (MPs) was tested at simulative pH values. Maximum release was observed at 24 h and pH 7.4. The cytotoxicity of EA MPs on HCT 116 colon cancer cells was synergistically improved as compared with raw EA. Cell-cycle analysis by flow cytometry suggested enhanced G2-M phase colon cancer cell accumulation. In addition, a significantly higher cell fraction was observed in the pre-G phase, which highlighted the enhancement of the proapoptotic activity of EA formulated in the double-coat mixture. Annexin-V staining was used for substantiation of the observed cell-death-inducing activity. Cell fractions were significantly increased in early, late, and total cell death. This was backed by high elevation in cellular content of caspase 3. Effectiveness of the double-coated EA to target colonic tissues was confirmed using real-time iohexol dye X-ray radiography. In conclusion, CHIT loaded with EA and coated with ES100 formula exhibits improved colon targeting as well as enhanced cytotoxic and proapoptotic activity against HCT 116 colon cancer when compared with the administration of raw EA.

Keywords: chitosan; colon targeting; drug release; ellagic acid; muco-adhesion.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
SEM images of microparticles (MPs) of chitosan loaded with ellagic acid (EA-CHIT) (A) and, additionally, coated with eudragit S100 (EA-CHIT-ES) at various magnifications: 180 X (B) 800 X (C) and 3000 X (D) showing EA-CHIT MPs entrapped within the ES100 coat.
Figure 2
Figure 2
Release profile of EA MPs at different pH values (1.2, 4.5, and 7.4).
Figure 3
Figure 3
IC50 of plain MPs, raw EA, and the EA MPs in (A) the HCT 116 cells and (B) EA.hy926 cells.
Figure 4
Figure 4
Impact of the EA MPs on the cell-cycle phases. (A) Control, (B) plain MPs, (C) raw EA, (D) EA MPs, (E) graphical presentation of each phase, and (F) graphical presentation of pre-G1 phase. * Significantly different from corresponding control at p < 0.05; # significantly different from plain MP at p < 0.05; $ significantly different from EA at p < 0.05.
Figure 5
Figure 5
Impact of the EA MPs on the annexin-V fluorescein isothiocyanate (FITC) positive-staining HTC 116 cells. (A) Control, (B) plain MPs, (C) raw EA, (D) EA MPs, and (E) graphical presentation of early and late apoptotic, necrotic, and total cell death. * Significantly different from corresponding control at p < 0.05. # significantly different from plain MP at p < 0.05; $ significantly different from EA at p < 0.05.
Figure 6
Figure 6
Effect of EA formulated in CHIT-ES100 double-coat on caspase 3 content in HCT 116 colon cancer cells. * Significantly different from control at p < 0.05; # significantly different from plain MPs at p < 0.05; $ significantly different EA at p < 0.05.
Figure 7
Figure 7
X-ray photographs of (A) EA-CHIT-ES100 MPs and (B) after 0.5 and 6 h.
See this image and copyright information in PMC

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