ABSTRACT
The intestinal epithelial and mucus barriers on the gastrointestinal tract limit the bioavailability of oral protein or peptide drugs. Therefore, efficient mucus permeability and cellular internalization are required properties for oral delivery systems. To overcome these two obstacles, porous silicon nanoparticles were modified with poly (pyridyl disulfide ethylene phosphate/sulfobetaine) polymers to make P(PyEP-g-SBm)n-AmPSiNPs (m = 0.1, 0.2, 0.3 and n = 10, 20, 30) nanoparticles (NPs). The insulin-loaded P(PyEP-g-SB)-AmPSiNPs showed favorable stability and good biocompatibility in vitro. The zwitterionic dodecyl sulfobetaine (SB) coated nanoparticles improved the mucus permeability. P(PyEP-g-SBm)20 with the optimal conjugated ratio (m = 0.3) of SB units was determined by evaluating the mucus diffusion rate of NPs. The cellular uptake of P(PyEP-g-SB0.3)n-AmPSiNPs (n = 10, 20, 30) was much higher than AmPSiNPs in the presence of inhibitors (N-acetylcysteine solution and sodium chlorate) (p < 0.01) due to the enhanced charge shielding effect of P(PyEP-g-SB) modification. The P(PyEP-g-SB0.3)20-AmPSiNPs showed about 1.4-1.7 fold increase in the apparent permeability of insulin across Caco-2/HT-29-MTX cell monolayers, compared to AmPSiNPs (p < 0.01). Finally, the in vivo study showed that insulin-loaded P(PyEP-g-SB0.3)20-AmPSiNPs generated 20% reduction of the blood glucose level with an 2-fold increase in oral bioavailability. These suggested that zwitterionic polyphosphoester modified porous silicon nanoparticles, which were of enhanced mucus permeability and cellular internalization, represent a promising carrier for oral delivery of peptide and protein.
Subject(s)
Insulin , Nanoparticles , Administration, Oral , Caco-2 Cells , Drug Carriers , Humans , Porosity , SiliconABSTRACT
BACKGROUND: Glioma is a common brain tumor with a high mortality rate. A small population of cells expressing stem-like cell markers in glioma contributes to drug resistance and tumor recurrence. METHODS: Porous silicon nanoparticles (PSi NPs) as photothermal therapy (PTT) agents loaded with TMZ (TMZ/PSi NPs), was combined with hyperbaric oxygen (HBO) therapy in vitro and in vivo. To further investigate underlying mechanism, we detected the expression of stem-like cell markers and hypoxia related molecules in vitro and in vivo after treatment of TMZ/PSi NPs in combination with PTT and HBO. RESULTS: NCH-421K and C6 cells were more sensitive to the combination treatment. Moreover, the expression of stem-like cell markers and hypoxia related molecules were decreased after combination treatment. The in vivo results were in line with in vitro. The combination treatment presents significant antitumor effects in mice bearing C6 tumor compared with the treatment of TMZ, PTT or TMZ/PSi NPs only. CONCLUSION: These results suggested the TMZ/PSi NPs combined with HBO and PTT could be a potential therapeutic strategy for glioma.
