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Nanoparticle drug-delivery systems (NP DDS) have proven to be tremendously impactful for delivering therapeutic agents in cancer treatments, vaccinations, gene therapy, and diagnostics, and enabled agents such as RNA therapeutics. However, the exposure of NP DDS to biological milieus leads to the rapid adsorption of proteins and other molecules, forming a proteinaceous corona that obscures NP surface characteristics and controls the biological interactions of the NP DDS. Surface modifications, including poly(ethylene glycol) (PEG) and synthetic zwitterionic polymers, reduce protein adsorption yet lack monomer-scale tunability, have off-target immunological effects, and suffer from targeting-limited steric hindrance, altogether motivating the development of alternative approaches. Peptides can uniquely form many zwitterions and have shown promise in reducing and controlling the NP protein corona as a function of the peptide sequence. However, the impact of zwitterionic peptides (ZIPs) on the drug-delivery properties of polymeric NPs has not been explored. In this work, diverse ZIPs computationally predicted to reduce protein adsorption by assessing peptide–peptide β-strand interaction energies were conjugated to pH-responsive cationic NPs. The resulting ZIP-NP conjugates exhibited up to 88% reduced protein adsorption and a range of siRNA-mediated gene knockdown that correlates with interaction energies. These data suggest that the peptide–peptide interaction energy is a promising design parameter for ZIPs for further model development. ZIP-NP also exhibited sequence-dependent variations in cellular uptake and circulation half-life, indicating that ZIP-NPs are suitable for tuning and improving NP drug-delivery characteristics.
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Influence of particle z‐potential and experimental procedure on protein corona formation and multicomponent aggregation
Abstract Drug delivery systems have renewed attention in recent years to achieve targeted delivery while decreasing toxic side effects. However, there are many factors that prevent optimal administration of drug delivery particles. For instance, protein corona formation and aggregation both decrease the circulation half‐life of drug delivery particles, leading to sequestration to the liver and spleen. Therefore, optimal surface modifications are needed to decrease protein corona formation and avoid aggregation. In this work, polystyrene particles were modified with multi‐arm and linear polyethylene glycol (PEG) to determine their aggregation profiles and protein corona formation. Multi‐arm PEGs were found to aggregate more than linear PEGs, due to the change in zeta potential from unreacted end groups, which may lead to shorter circulation half‐lives. Furthermore, the protein corona formation and composition were studied after different washing procedures, highlighting the importance of studying protein corona formation with undiluted blood plasma.
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- PAR ID:
- 10458657
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- AIChE Journal
- Volume:
- 69
- Issue:
- 12
- ISSN:
- 0001-1541
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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