β-Glucan-Mediated Oral Codelivery of 5FU and Bcl2 siRNA Attenuates Stomach Cancer

Humayra Afrin, Stephanie Vargas Esquivel, Raj Kumar, Md Ikhtiar Zahid, Beu Oporeza, Md Fashiar Rahman, Thomas Boland, Md Nurunnabi

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Based on cancer-related deaths, stomach cancer is ranked fifth, and first among Hispanics. Lack of technologies for early diagnosis and unavailability of target-specific therapeutics are largely the causes of the poor therapeutic outcomes from existing chemotherapeutics. Currently available therapeutic modalities are invasive and require systemic delivery, although the cancer is localized in the stomach at its early stage. Therefore, we hypothesize that an oral local delivery approach can extend the retention duration of the therapeutics modalities within the stomach and thereby enhance therapeutic efficacy. To accomplish this, we have developed a ß-glucan (BG)-based oral delivery vehicle that can adhere to the mucus lining of the stomach for an extended period while controlling the release of Bcl2 siRNA and 5-fluorouracil (5FU) payload for over 6 h. We found that Bcl2 siRNA selectively knocked down the Bcl2 gene in a C57BL/6 stomach cancer mouse model followed by upregulation of apoptosis and remission of cancer. BG was found to be very effective in maintaining the stability of siRNA for at least 6 h, when submerged in simulated gastric juice tested in vitro. To investigate the potential therapeutic effects in vivo, we used a stomach cancer mouse model, where C57BL/6 mice were treated with 5FU, BG/5FU, siRNA, BG/siRNA, and BG/5FU/siRNA. Higher inhibition of Bcl2 and therapeutic efficacy were observed in mice treated with BG/5FU/siRNA confirmed with Western blotting and a TUNEL assay. Significant reduction in the tumor region was observed with histology (H&E) and immunohistochemistry (Ki67, TUNEL, and Bcl2) analyses. Overall, the oral formulation shows improved efficacy with nonsignificant side effects compared to the conventional treatment tested in the gastric cancer mouse model.

Original languageEnglish
Pages (from-to)32188-32200
Number of pages13
JournalACS applied materials & interfaces
Volume15
Issue number27
DOIs
StatePublished - 12 Jul 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society

Funding

We acknowledge funding by the Cancer Prevention Research Institute of Texas (CPRIT) through a Texas Regional Excellence in Cancer Award (TREC) under Award No. PR210153, and the National Institutes of Health (NIH) under Award No. R03OD032624. The contents of this paper are solely the authors’ responsibility and do not necessarily represent the official views of NIH. Contents for graphics and cartoons including table of contents were obtained from smart.servier.com and Microsoft PowerPoint.

FundersFunder number
Microsoft PowerPoint
Texas Regional Excellence in Cancer AwardPR210153
National Institutes of HealthR03OD032624
Cancer Prevention and Research Institute of Texas

    Keywords

    • oral biologics
    • oral local delivery
    • stomach cancer
    • stomach specific

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