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Novel pH responsive hesperidin nanoformulation exerts anticancer activity on lung adenocarcinoma cells by targeting Akt/mTOR and MEK/ERK pathways

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Abstract

Zinc oxide nanoparticle based drug delivery enhances bioavailability of anticancer drug to the tumor site. We developed novel biocompatible ZnO nanoparticles for the targeted delivery of hesperidin. UV, FT-IR, DLS analysis, SEM and XRD analyses were done to confirm hesperidin loading onto zinc oxide nanoparticles. We also performed crystal violet staining, ROS and live-dead staining assay to check toxicity of hesperidin nanoformulation on A549 lung adenocarcinoma cells. Effect of nanoformulation on protein and gene expression was evaluated. Particle size of formulated ZnO NPs was 3 nm, which increased to 104 nm after hesperidin loading. Hesperidin nanoformulation showed enhanced anticancer, antiproliferative and antimigratory effects on A549 cells with an IC50 concentration of 40 µg/mL. The nanoformulation reduced expression of Akt/mTOR and MEK/ERK signalling proteins and increased the expression of apoptotic markers. Hesperidin nanoformulation also upregulated the expression of apoptotic genes such as Bax, p53 and decreased the expression of anti-apoptotic gene Bcl2.

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Hesperidin nanoformulation and its biological activities.

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Acknowledgments

Pavan S R acknowledges the funding support in the form of Senior Research Fellowship from Indian Council of Medical Research (Grant No. 45/10/2022/NAN/BMS). This study was funded with Seed grant (YU/Seed grant/133-2022) from Yenepoya (Deemed to be University).

Funding

This study was funded by Indian Council of Medical Research, Grant No. 45/10/2022/NAN/BMS, awarded to Pavan S R. This study was supported with Seed Grant (YU/Seed grant/133-2022) from Yenepoya (Deemed to be University).

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  1. Division of Cancer Research and Therapeutics (CaRT), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India

    S. R. Pavan & Ashwini Prabhu

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SRP carried out the literature survey, performed experiments and drafted the manuscript. AP conceptualized and framed the outline of the study, along with critical revision of the manuscript.

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43578_2024_1304_MOESM1_ESM.tif

Supplementary Fig. S1: (A) UV absorption spectra of ZnO, ZnO–NH2, HSP and ZnO-HSP; (B) FT-IR analysis of ZnO–NH2, HSP and ZnO-HSP; (C, (D) DLS analysis of ZnO NPs and ZnO-HSP; (E) Zeta potential of ZnO NPs and ZnO-HSP. Supplementary file 1 (TIF 377 KB)

43578_2024_1304_MOESM2_ESM.tif

Supplementary Fig. S2: (A) SEM morphological analysis of ZnO NPs and ZnO-HSP; (B) XRD analysis of ZnO, HSP, ZnO-HSP; (C) Drug release studies at different pH conditions. Supplementary file 2 (TIF 604 KB)

43578_2024_1304_MOESM3_ESM.tif

Supplementary Fig. S3: (A) Decrease in the colony formation upon treatment; (B) Graphical representation of colonies number (ns: non-significant, ***p < 0.001, **p < 0.01,*p < 0.05). Supplementary file 3 (TIF 642 KB)

43578_2024_1304_MOESM4_ESM.tif

Supplementary Fig. S4: Cell cycle arrest analysis in A549 cells after treatment (A) Control; (B) ZnO NPs; (C) Cisplatin; (D) HSP; (E) ZnO-HSP; (F) Graphical representation of DNA content at different phases; (G) Immunoblotting of cyclin (B; H) Graphical representation of Cyclin B expression with respect to β-actin (ns: non-significant, ***p < 0.001, **p < 0.01,*p < 0.05). Supplementary file 4 (TIF 514 KB)

43578_2024_1304_MOESM5_ESM.tif

Supplementary Fig. S5: Gene expression study carried out in different treatment groups. (A) AKT; (B) ERK; (C) Bax; (D) Bcl2; (E) p53 (ns: non-significant, ***p < 0.001, **p < 0.01,*p < 0.05). Supplementary file 5 (TIF 433 KB)

43578_2024_1304_MOESM6_ESM.tif

Supplementary Fig. S6: A549 cells treated with hesperidin nanoformulation exhibit changes in the expression of proteins involved in apoptosis, cellular migration, AKT/mTOR and MEK/Erk signalling. It also regulates the expression of genes involved in cellular apoptosis (The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license). Supplementary file 6 (TIF 356 KB)

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Pavan, S.R., Prabhu, A. Novel pH responsive hesperidin nanoformulation exerts anticancer activity on lung adenocarcinoma cells by targeting Akt/mTOR and MEK/ERK pathways. Journal of Materials Research 39, 1217–1231 (2024). https://doi.org/10.1557/s43578-024-01304-w

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