Joshua Seaberg, Nicholas H. Flynn, Amanda Cai
May 4, 2020
Citations
0
Influential Citations
5
Citations
Quality indicators
Journal
Biotechnology and Bioengineering
Abstract
Therapeutic proteins are utilized in a variety of clinical applications, but side effects and rapid in vivo clearance still present hurdles. An approach that addresses both drawbacks is protein encapsulation within in a polymeric nanoparticle, which is effective but introduces the additional challenge of destabilizing the nanoparticle shell in clinically relevant locations. This study examined the effects of crosslinking self‐assembled poly(l‐lysine)‐grafted‐poly(ethylene glycol) nanoparticles with redox‐responsive 3,3′‐dithiobis(sulfosuccinimidyl propionate) (DTSSP) to achieve nanoparticle destabilization in a reductive environment. The polymer‐protein nanoparticles (DTSSP NPs) were formed through electrostatic self‐assembly and crosslinked with DTSSP, which contains a glutathione‐reducible disulfide. As glutathione is upregulated in various cancers, DTSSP NPs could display destabilization within cancer cells. A library of DTSSP NPs was formed with varying copolymer to protein (C:P) and crosslinker to protein (X:P) mass ratios and characterized by size and encapsulation efficiency. DTSSP NPs with a 7:1 C:P ratio and 2:1 X:P ratio were further characterized by stability in the presence proteases and reducing agents. DTSSP NPs fully encapsulated the model protein and displayed 81% protein release when incubated with 5 mM dithiothreitol for 12 hr. This study contributes to understanding stimulus‐responsive crosslinking of polymeric nanoparticles and could be foundational to clinical administration of therapeutic proteins.