Amphiphilic Co-polypeptides Self-Assembled into Spherical Nanoparticles for Dermal Drug Delivery

Poly(L-glutamic acid)-b-poly(N.-acetyl-L-2,4-diaminobutyric acid), P(Glu-b-NADA), amphiphilic block-co-polypeptides with different hydrophobic/hydrophilic ratios were synthesized as drug carriers for dermal delivery. The block-copolypeptides were prepared using ring-opening polymerization (ROP) of gamma-benzyl L-glutamate N-carboxyanhydride and polycondensation of the activated urethane derivative of N-gamma-acetyl-L-2,4-diaminobutyric acid. Structures and conjugations of two blocks were successfully confirmed by H-1 NMR, FTIR, DOSY NMR, GPC, and TGA. The nanocarriers were loaded with 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (m-THPP), a close congener of the approved photosensitizer 5,10,15,20-tetrakis(3hydroxyphenyl)chlorin (m-THPC, temoporfin), and the loading capacity was found to be dependent on the composition of the block-co-polypeptides. Among the synthesized polymers, P(Glu(55)-b-NADA(20)) with moderate hydrophobic content showed the highest drug loading capacity of 4 wt % and self-aggregated into spherical nanoparticles with a size of 180-200 nm, which was confirmed by TEM and DLS. In an in vitro drug release study, P(Glu(55)-b-NADA(20)) could release m-THPP in a controllable manner. Furthermore, the synthesized polymer P(Glu(55)-b-NADA(20)) did not show high toxicity against HaCaT and HeLa cells up to 1000 and 500 mu g mL(-1), respectively, in an in vitro cell viability assay. Finally, it was shown in an ex vivo skin penetration study that the ionic amphiphilic block co-polypeptide enhanced the m-THPP penetration into human skin compared to base cream up to a factor of 12. m-THPP was released from P(Glu(55)-b-NADA(20)) to the viable epidermis while the polymer was deposited in the skin's stratum corneum. Taking advantage of its excellent biodegradability, the low cytotoxcity, and efficient skin penetration, the synthesized block-co-polypeptide has the potential for future topical delivery systems.