Details

Autor(en) / Beteiligte

• Chu, David S.H.
• Johnson, Russell N.
• Pun, Suzie H.

Titel

Cathepsin B-sensitive polymers for compartment-specific degradation and nucleic acid release

Ist Teil von

• Journal of controlled release, 2012-02, Vol.157 (3), p.445-454

Ort / Verlag

Kidlington: Elsevier B.V

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Degradable cationic polymers are desirable for in vivo nucleic acid delivery because they offer significantly decreased toxicity over non-degradable counterparts. Peptide linkers provide chemical stability and high specificity for particular endopeptidases but have not been extensively studied for nucleic acid delivery applications. In this work, enzymatically degradable peptide-HPMA copolymers were synthesized by RAFT polymerization of HPMA with methacrylamido-terminated peptide macromonomers, resulting in polymers with low polydispersity and near quantitative incorporation of peptides. Three peptide-HPMA copolymers were evaluated: (i) pHCathK10, containing peptides composed of the linker phe-lys-phe-leu (FKFL), a substrate of the endosomal/lysosomal endopeptidase cathepsin B, connected to oligo-(l)-lysine for nucleic acid binding, (ii) pHCath(d)K10, containing the FKFL linker with oligo-(d)-lysine, and (iii) pH(d)Cath(d)K10, containing all (d) amino acids. Cathepsin B degraded copolymers pHCathK10 and pHCath(d)K10 within 1h while no degradation of pH(d)Cath(d)K10 was observed. Polyplexes formed with pHCathK10 copolymers show DNA release by 4h of treatment with cathepsin B; comparatively, polyplexes formed with pHCath(d)K10 and pH(d)Cath(d)K10 show no DNA release within 8h. Transfection efficiency in HeLa and NIH/3T3 cells were comparable between the copolymers but pHCathK10 was less toxic. This work demonstrates the successful application of peptide linkers for degradable cationic polymers and DNA release. [Display omitted]