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.

On the intracellular release mechanism of hydrophobic cargo and its relation to the biodegradation behavior of mesoporous silica nanocarriers

“…(Mamaeva et al, 2011) Furthermore, the drug-loaded particles have exhibited higher therapeutic efficacy than corresponding amounts of free drug. (Desai et al, 2016;Mamaeva et al, 2011) In our abovementioned studies, we have been able to indirectly establish that no premature leakage of drug takes place and that the drug is primarily intracellularly released. Though this is the optimal scenario from an in vivo drug delivery point of view for intracellular drug targets, knowledge around fundamental mechanisms related to drug release is still lacking.…”

“…The preparation of amino-functionalized mesoporous silica nanoparticles (MSNs) was carried out according to protocols described in previous publications (Desai et al, 2016;Nakamura et al, 2007;Rosenholm et al, 2009a) In a typical synthesis, co-condensation of 3-aminopropyltrimethtoxysilane (APTMS; Sigma-Aldrich) (10 mol-%), together with tetramethoxy orthosilicate (TMOS; ≥98%, Fluka), was performed by first mixing the silicasources and then adding them to an alkaline (sodium hydroxide solution; ≥98%, SigmaAldrich) water/methanol solution, containing hexadecyltrimethylammonium chloride (CTACl; 25 wt% in water; Sigma-Aldrich) as a structure-directing agent. The sol was stirred over night at room temperature (RT), after which the particles were separated by centrifugation and extracted three times with acidic (hydrochloric acid, HCl; 37-38%, Bruker) ethanol and dried under vacuum at RT.…”

“…Our nanocarrier system has already previously been comprehensively evaluated for cytotoxicity, proven non-cytotoxic and biocompatible, (Desai et al, 2016;Mamaeva et al, 2011;Rosenholm et al, 2009a;Senthilkumar et al, 2015;Wittig et al, 2014) and was thus A C C E P T E D M A N U S C R I P T…”

“…surface polymerization of aziridine (98%, Menadiona, Spain) (Desai et al, 2016). In a typical conjugation procedure 100 mg particles were suspended in anhydrous toluene (purity 99.8%, Sigma-Aldrich) and kept under inert atmosphere.…”

Folate-mediated chemotherapy and diagnostics: An updated review and outlook

“…As another example, mesoporous silica NPs (MSNs) functionalized with PEG, PEI, and FA were developed for colon cancer and inflammation drug delivery via enteric administration [60]. In an 18 FVB/N mouse model, the number of intestinal goblet cell differentiation in the colon of mice given γ-secretase inhibitor (DAPT)/FA-PEG-PEI-MSNs were significantly higher than DAPT alone, DAPT/FA-PEI-MSNs, and FA-PEG-PEI-MSNs after gavage.…”