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Mucosal delivery across the gastrointestinal (GI) tract, airways, and buccal epithelia is an attractive mode of therapeutic administration, but the challenge is to overcome the mucus and epithelial barriers. Here, we present degradable star polypept­(o)­ides capable of permeating both barriers as a promising biomaterial platform for mucosal delivery. Star polypept­(o)­ides were obtained by the initiation of benzyl-l-glutamate N-carboxyanhydride (NCA) from an 8-arm poly­(propyleneimine) (PPI) dendrimer, with subsequent chain extension with sarcosine NCA. The hydrophobic poly­(benzyl-l-glutamate) (PBLG) block length was maintained at 20 monomers, while the length of the hydrophilic poly­(sarcosine) (PSar) block ranged from 20–640 monomers to produce star polypept­(o)­ides with increasing hydrophilic: hydrophobic ratios. Transmission electron microscopy (TEM) images revealed elongated particles of ∼120 nm length, while dynamic light scattering (DLS) provided evidence of a decrease in the size of polymer aggregates in water with increasing poly­(sarcosine) block length, with the smallest size obtained for the star PBLG20-b-PSar640. Fluorescein isothiocyanate (FITC)-conjugated PBLG20-b-PSar640 permeated artificial mucus and isolated rat mucus, as well as rat intestinal jejunal tissue mounted in Franz diffusion chambers. An apparent permeability coefficient (P app) of 15.4 ± 3.1 ×10–6 cm/s for FITC-PBLG20-b-PSar640 was calculated from the transepithelial flux obtained with the apical-side addition of 7.5 mg polypept­(o)­ide to jejunal tissue over 2 h. This P app could not be accounted for by flux of unconjugated FITC. Resistance to trypsin demonstrated the stability of FITC-labeled polypept­(o)­ide over 2 h, but enzymatic degradation at the mucus-epithelial interface or during flux could not be ruled out as contributing to the P app. The absence of any histological damage to the jejunal tissue during the 2 h exposure suggests that the flux was not associated with overt toxicity.

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