| Autor: |
Smith SA; Department of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia., Rossi Herling B; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3010, Australia., Zhang C; Department of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia., Beach MA; Department of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia., Teo SLY; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3010, Australia., Gillies ER; Department of Chemistry and Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Ontario N6A 5B7, Canada., Johnston APR; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3010, Australia., Such GK; Department of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia. |
| Abstrakt: |
Polymer nanoparticles have generated significant interest as delivery systems for therapeutic cargo. Self-immolative polymers (SIPs) are an interesting category of materials for delivery applications, as the characteristic property of end-to-end depolymerization allows for the disintegration of the delivery system, facilitating a more effective release of the cargo and clearance from the body after use. In this work, nanoparticles based on a pH-responsive polymer poly(ethylene glycol)- b -(2-diisopropyl)amino ethyl methacrylate) and a self-immolative polymer poly[ N , N -(diisopropylamino)ethyl glyoxylamide- r - N , N -(dibutylamino)ethyl glyoxylamide] (P(DPAEGAm- r -DBAEGAm)) were developed. Four particles were synthesized based on P(DPAEGAm- r -DBAEGAm) polymers with varied diisopropylamino to dibutylamino ratios of 4:1, 2:1, 2:3, and 0:1, termed 4:1, 2:1, 2:3, and 0:1 PGAm particles. The pH of particle disassembly was tuned from pH 7.0 to pH 5.0 by adjusting the ratio of diisopropylamino to dibutylamino substituents on the pendant tertiary amine. The P(DPAEGAm- r -DBAEGAm) polymers were observed to depolymerize (60-80%) below the particle disassembly pH after ∼2 h, compared to <10% at pH 7.4 and maintained reasonable stability at pH 7.4 (20-50% depolymerization) after 1 week. While all particles exhibited the ability to load a peptide cargo, only the 4:1 PGAm particles had higher endosomal escape efficiency (∼4%) compared to the 2:3 or 0:1 PGAm particles (<1%). The 4:1 PGAm particle is a promising candidate for further optimization as an intracellular drug delivery system with rapid and precisely controlled degradation. |
