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Silvia Acosta-Gutiérrez1,1,2, Diana Matias1,1, Milagros Avila-Olias3

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This study shows how promiscuous ligand interactions can create targeted drug delivery systems. Poly(2-(methacryloyloxy)ethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes effectively target monocytes in vivo.

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Area of Science:

  • Biomaterials Science
  • Nanotechnology
  • Cell Biology

Background:

  • Phenotypic targeting demands drug delivery systems that can differentiate cells based on specific receptor combinations.
  • Multiplexed-multivalent carriers with multiple ligands are typically used for achieving such selectivity.
  • Leveraging single ligand promiscuity offers an alternative strategy for phenotypic targeting.

Purpose of the Study:

  • To demonstrate the use of promiscuous single ligand interactions for phenotypic targeting.
  • To investigate the cellular uptake of poly(2-(methacryloyloxy)ethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes based on cell receptor expression.
  • To develop and validate a theoretical model for polymersome-cell association, including glycocalyx interactions.

Main Methods:

  • Utilized poly(2-(methacryloyloxy)ethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes.
  • Employed all-atom molecular modeling to study polymersome insertion at the single chain/receptor level.
  • Developed a statistical mechanics-based model for polymersome-cell association.
  • Validated the model through experimental studies.
  • Investigated in vivo targeting of monocytes.

Main Results:

  • Cellular uptake of PMPC-PDPA polymersomes varied based on cell receptor expression.
  • The theoretical model accurately predicted polymersome-cell association, highlighting the role of the glycocalyx.
  • Binding energy was found to be a nonlinear function of polymersome radius and degree of polymerization.
  • PMPC-PDPA polymersomes demonstrated successful in vivo targeting of monocytes through promiscuous interactions with SRB1, CD36, and CD81 receptors.

Conclusions:

  • Promiscuous ligand interactions can be effectively utilized to engineer multiplexed-multivalent carriers for phenotypic targeting.
  • The developed theoretical model provides insights into polymersome-cell interactions and can guide the design of targeted delivery systems.
  • PMPC-PDPA polymersomes represent a promising platform for in vivo monocyte targeting.