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Transmucosal Solid Lipid Nanoparticles to Improve Genistein Absorption via Intestinal Lymphatic Transport.

ABSTRACT: Genistein (GEN) is a soy-derived isoflavone that exhibits several biological effects, such as neuroprotective activity and the prevention of several types of cancer and cardiovascular disease. However, due to its poor water solubility and the extensive first-pass metabolism, the oral bioavailability of GEN is limited. In this work, solid lipid nanoparticles (SLN) were developed to preferentially reach the intestinal lymphatic vessels, avoiding the first-pass metabolism of GEN. GEN-loaded SLN were obtained by a hot homogenization process, and the formulation parameters were chosen based on already formulated studies. The nanoparticles were characterized, and the preliminary in vitro chylomicron formation was evaluated. The cell uptake of selected nanocarriers was studied on the Caco-2 cell line and intestinal mucosa. The SLN, characterized by a spherical shape, showed an average diameter (about 280 nm) suitable for an intestinal lymphatic uptake, good stability during the testing time, and high drug loading capacity. Furthermore, the intestinal mucosa and Caco-2 cells were found to uptake SLN. The approximately two-fold increase in particle size suggested a possible interaction between SLN and the lipid components of chylomicrons like phospholipid; therefore, the results may support the potential for these SLN to improve oral GEN bioavailability via intestinal lymphatic absorption.

SUBMITTER: Obinu A

PROVIDER: S-EPMC7920073 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Transmucosal Solid Lipid Nanoparticles to Improve Genistein Absorption via Intestinal Lymphatic Transport.

Obinu Antonella A Burrai Giovanni Pietro GP Cavalli Roberta R Galleri Grazia G Migheli Rossana R Antuofermo Elisabetta E Rassu Giovanna G Gavini Elisabetta E Giunchedi Paolo P

Pharmaceutics 20210216 2

Genistein (GEN) is a soy-derived isoflavone that exhibits several biological effects, such as neuroprotective activity and the prevention of several types of cancer and cardiovascular disease. However, due to its poor water solubility and the extensive first-pass metabolism, the oral bioavailability of GEN is limited. In this work, solid lipid nanoparticles (SLN) were developed to preferentially reach the intestinal lymphatic vessels, avoiding the first-pass metabolism of GEN. GEN-loaded SLN wer ...[more]

PMID: 33669306

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Project description:Because of the epidemic rise of obesity worldwide, the identification of novel target genes for pharmacological treatment of obesity and related disorders is becoming of high importance. IFRD1 and IFRD2 are members of a novel transcriptional regulators family. Intestinal over-expression of mouse homologue of IFRD1 promoted intestinal triglyceride uptake and induced whole body adiposity in mice. To further elucidate the role of IFRD1 and IFRD2 in vivo, we generated mice lacking both mouse homologues of IFRD1 (TIS7) and IFRD2 (SKMc15) genes. Here, we report that mice deficient in TIS7 and SKMc15 genes, despite normal calorie intake had severely reduced amount of adipose tissue, were resistant to diet-induced obesity and displayed high glucose tolerance. Lower dietary fat entry into the circulation suggested that this phenotype resulted from impaired intestinal lipid transport. We identified down-regulation of CD36, a fatty acid transporter, both on RNA and protein levels. Reporter assays indicated that TIS7 and SKMc15 transcriptionally regulated CD36 expression and CD36 overexpression partially restored fatty acid uptake in vitro. Hence, our study suggested that TIS7 and SKMc15 play an important role in the regulation of the lipid metabolism and might represent a novel strategy for treatment of disorders caused by excess fat intake. To determine whether decreased intestinal lipid absorption might be caused by changes in expression of lipid processing and transport molecules, we performed Affymetrix microarray analyses of total RNA samples isolated from the jejunum of HFD-fed WT type and dKO animals. The moderated t-test was used to calculate p-values for significance of differential gene expression between 3 dKO and 3 wild type mice. These raw p-values were adjusted for multiple hypothesis testing using the method from Benjamini and Hochberg for a strong control of the false discovery rate (FDR) and genes with thus adjusted p-values < 0.05 were considered significant. Age-matched (7-10 week old) male wild type and TIS7 (Ifrd1) SKMc15 (Ifrd2) double knock out mice (C57Bl6 background) were caged individually and maintained from 3 weeks up to 8 weeks on a synthetic high saturated fat (HFD) diet (Ssniff). Small intestines (jejunum) were harvested for total RNA isolation. RNAs from 3 WT and 3 dKO mice were subjected to Affymetrix based whole genome gene expression analysis (Mouse 430.2 GeneChip).

Dataset Information

Transmucosal Solid Lipid Nanoparticles to Improve Genistein Absorption via Intestinal Lymphatic Transport.

Publications

Transmucosal Solid Lipid Nanoparticles to Improve Genistein Absorption via Intestinal Lymphatic Transport.

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