Proapoptotic Peptide Brush Polymer Nanoparticles via Photoinitiated Polymerization‐Induced Self‐Assembly

• Published in: Angewandte Chemie International Edition 2020-10, Vol.59 (43), p.19136-19142
• Main Authors: Sun, Hao, Cao, Wei, Zang, Nanzhi, Clemons, Tristan D., Scheutz, Georg M., Hu, Ziying, Thompson, Matthew P., Liang, Yifei, Vratsanos, Maria, Zhou, Xuhao, Choi, Wonmin, Sumerlin, Brent S., Stupp, Samuel I., Gianneschi, Nathan C.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Apoptosis; Assembly; Cell Survival - drug effects; Chemical synthesis; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Light; Micelles; Nanoparticles; Nanoparticles - chemistry; peptide delivery; Peptides; Peptides - chemistry; peptide–polymer conjugates; Polymerization; Polymers; Polymers - chemistry; Proteolysis; scaled synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202006385

Herein, we report the photoinitiated polymerization‐induced self‐assembly (photo‐PISA) of spherical micelles consisting of proapoptotic peptide–polymer amphiphiles. The one‐pot synthetic approach yielded micellar nanoparticles at high concentrations and at scale (150 mg mL−1) with tunable peptide loadings up to 48 wt. %. The size of the micellar nanoparticles was tuned by varying the lengths of hydrophobic and hydrophilic building blocks. Critically, the peptide‐functionalized nanoparticles imbued the proapoptotic “KLA” peptides (amino acid sequence: KLAKLAKKLAKLAK) with two key properties otherwise not inherent to the sequence: 1) proteolytic resistance compared to the oligopeptide alone; 2) significantly enhanced cell uptake by multivalent display of KLA peptide brushes. The result was demonstrated improved apoptosis efficiency in HeLa cells. These results highlight the potential of photo‐PISA in the large‐scale synthesis of functional, proteolytically resistant peptide–polymer conjugates for intracellular delivery. Polymerization‐induced self‐assembly enables the at scale synthesis of nanoparticles with a high‐density display of peptide, tunable particle size, and tunable peptide loadings. The resulting peptide brush polymer nanoparticles exhibit enhanced stability, and cell uptake efficiency and efficacy in comparison with their peptide analogues, highlighting the potential of these peptide–polymer amphiphiles as peptide delivery systems.