Enhanced oral bioavailability of insulin using PLGA nanoparticles co-modified with cell-penetrating peptides and Engrailed secretion peptide (Sec)

Drug Deliv. 2016 Jul;23(6):1980-91. doi: 10.3109/10717544.2015.1043472. Epub 2015 Jul 16.

Abstract

Biodegradable polymer nanoparticle drug carriers are an attractive strategy for oral delivery of peptide and protein drugs. However, their ability to cross the intestinal epithelium membrane is largely limited. Therefore, in the present study, cell-penetrating peptides (R8, Tat, penetratin) and a secretion peptide (Sec) with N-terminal stearylation were introduced to modify nanoparticles (NPs) on the surface to improve oral bioavailability of peptide and protein drugs. In vitro studies conducted in Caco-2 cells showed the value of the apparent permeability coefficient (Papp) of the nanoparticles co-modified with Sec and penetratin (Sec-Pen-NPs) was about two-times greater than that of the nanoparticles modified with only penetratin (Pen-NPs), while the increase of transcellular transport of nanoparticles modified together with Sec and R8 (Sec-R8-NPs), or Sec and Tat (Sec-Tat-NPs), was not significant compared with nanoparticles modified with only R8 (R8-NPs) or Tat (Tat-NPs). Using insulin as the model drug, in vivo studies performed on rats indicated that compared to Pen-NPs, the relative bioavailability of insulin for Sec-Pen-NPs was 1.71-times increased after ileal segments administration, and stronger hypoglycemic effects was also observed. Therefore, the nanoparticles co-modified with penetratin and Sec could act as attractive carriers for oral delivery of insulin.

Keywords: Cell-penetrating peptides; Engrailed secretion peptide (Sec); nanoparticles; oral administration; peptide and protein drugs.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Caco-2 Cells
  • Cell-Penetrating Peptides / administration & dosage*
  • Cell-Penetrating Peptides / chemistry
  • Drug Carriers / chemistry*
  • Drug Carriers / metabolism
  • Humans
  • Insulin / administration & dosage*
  • Insulin / chemistry
  • Lactic Acid / chemistry*
  • Nanoparticles / chemistry*
  • Permeability
  • Polyglycolic Acid / chemistry*
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Rats

Substances

  • Cell-Penetrating Peptides
  • Drug Carriers
  • Insulin
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid