Targeted modulation of cell differentiation in distinct regions of the gastrointestinal tract via oral administration of differently PEG-PEI functionalized mesoporous silica nanoparticles

Abstract

Targeted delivery of drugs is required to efficiently treat intestinal diseases such as colon cancer and inflammation. Nanoparticles could overcome challenges in oral administration caused by drug degradation at low pH and poor permeability through mucus layers, and offer targeted delivery to diseased cells in order to avoid adverse effects. Here, we demonstrate that functionalization of mesoporous silica nanoparticles (MSNs) by polymeric surface grafts facilitates transport through the mucosal barrier and enhances cellular internalization. MSNs functionalized with poly(ethylene glycol) (PEG), poly(ethylene imine) (PEI), and the targeting ligand folic acid in different combinations are internalized by epithelial cells in vitro and in vivo after oral gavage. Functionalized MSNs loaded with γ-secretase inhibitors of the Notch pathway, a key regulator of intestinal progenitor cells, colon cancer, and inflammation, demonstrated enhanced intestinal goblet cell differentiation as compared to free drug. Drug-loaded MSNs thus remained intact in vivo, further confirmed by exposure to simulated gastric and intestinal fluids in vitro. Drug targeting and efficacy in different parts of the intestine could be tuned by MSN surface modifications, with PEI coating exhibiting higher affinity for the small intestine and PEI–PEG coating for the colon. The data highlight the potential of nanomedicines for targeted delivery to distinct regions of the tissue for strict therapeutic control.

Keywords:

• intestinal targeting
• PEG-PEI copolymer
• Notch inhibition

Acknowledgments

The Cell Imaging Core at Turku Centre for Biotechnology, Helena Saarento, Catharina Alam, M Nadeem Asghar, Joel Nyström, and Julia Misiorek (Cell Biology/Biosciences, ÅAU) are thanked for technical support and advice. We are grateful to Dr Jussi Meriluoto, Biochemistry/Biosciences, ÅAU, for performing the HPLC analysis. Microscopy Service of Universidad Rey Juan Carlos (Spain) and Antonio Martín Rengel (Department of Chemical and Environmental Technology, Universidad Rey Juan Carlos, Madrid, Spain) are acknowledged for providing the TEM images. This work was financed by the Academy of Finland #140759/126161 (DT), #218062 (CS) and #137101/140193/260599/278812 (DD, DSK, NP, JMR), Sigrid Jusélius Foundation (DT, CS) and Liv och Hälsa foundation (DT), EU FP7 IRG (DT), Cancer Society of Finland and ÅAU Center of Excellence of Cell Stress and Molecular Aging (DT, CS). ERASMUS Experts III programme (DD), Centre of Excellence for Functional Materials (FunMat) (DSK), Doctoral Network in Materials Research at ÅAU (NP), and Turku Doctoral Programme in Molecular Biosciences at ÅAU and Swedish cultural foundation (IAKL) are greatly acknowledged for financial support.

Disclosure

The authors report no conflicts of interest in this work.