Hydrophobic drugs are problematic to deliver. We have previously shown that poly(ethylenimine) (PEI) amphiphile nanoparticles facilitate the oral absorption of the model drug cyclosporine A (CsA). We hypothesised that polymer molecular features (molecular weight, a branched or linear polymer architecture, polymer hydrophobicity) would drive this oral absorption enhancement. To test this hypothesis, we synthesised five linear PEI amphiphiles (Mn ~ 1.3 kDa or 13 kDa) and two branched PEI amphiphiles (Mn ~ 4 kDa or 10 kDa) by cetylation of PEI, followed by methylation to give N-cetyl, N-methyl, N,N-dimethyl, N,N,N-trimethyl poly(ethylenimines). Polymer aggregation, CsAencapsulation, polymer in vitro cytotoxicity and polymer enabled oral drug absorption were all studied. The polymers aggregated in aqueous media, with critical micellar concentrations (CMCs) ranging from 0.2 – 0.9 mg mL-1. The polymer CMCs, CsA encapsulation (up to 0.36 g CsA per g of PEI amphiphile) within the 60 – 200 nm nanoparticles and rat oral drug absorption after a 7.5 mg kg-1 dose of CsA, polymer nanoparticles (polymer, drug weight ratio – 5: 1) all increased with polymer hydrophobicity, although these parameters were not affected by polymer molecular weight or polymer branching. Release of CsA from a tablet dosage form was enhanced in the presence of the more hydrophilic branched polymer, however, as the more hydrophobic polymers endowed the tablets with longer disintegration times. Cell cytotoxicity (A431 cells and rat erythrocytes) was similar for all polymers (A431 IC50 = 10 – 50 μg mL-1 and 50% haemolysis = 30 – 55 μg mL-1).We conclude that the most important parameter controlling amphiphilic polymer nanoparticle enabled oral drug absorption is the hydrophobicity of the polymer amphiphile.
Keywords: Bioavailability, cyclosporine A, nanomedicines, nanoparticles, oral absorption, poly(ethylenimine).