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A Single-Molecule View at Nanoparticle Targeting Selectivity: Correlating Ligand Functionality and Cell Receptor

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Quantifying antibody-functionalized nanoparticles (NPs) and cell receptors at the single-molecule level using dSTORM microscopy enhances nanomedicine design. This approach maps NP functionality for improved targeting selectivity in cancer therapy.

Keywords:
active targetingdSTORMheterogeneitynanomedicinenanoparticle functionalitysuper-resolution microscopy

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Area of Science:

  • Nanotechnology
  • Biomedical Engineering
  • Molecular Imaging

Background:

  • Antibody-functionalized nanoparticles (NPs) are crucial for targeted drug delivery, but their efficacy depends on molecular interactions.
  • Accurate quantification of surface antibodies on NPs and cell receptors is essential for rational nanomedicine design.
  • Existing techniques lack the nanometric resolution needed for precise single-molecule counting in NP targeting.

Purpose of the Study:

  • To develop a method for quantifying functional antibodies on NPs and epidermal growth factor receptors (EGFRs) on cancer cells at the single-molecule level.
  • To investigate the relationship between NP functionality, receptor density, and cellular uptake for improved targeting selectivity.
  • To provide a molecular understanding of NP targeting to guide the rational design of selective nanomedicines.

Main Methods:

  • Developed a labeling approach for quantifying functional cetuximab antibodies on NPs and EGFRs on breast cancer cells.
  • Utilized direct stochastic optical reconstruction microscopy (dSTORM) for single-molecule resolution imaging and quantification.
  • Employed a geometrical model to predict the accessible fraction of antibody-conjugated NPs and correlated NP uptake with molecular parameters.

Main Results:

  • Successfully quantified individual functional antibodies on NPs and EGFRs on cancer cells with nanometric resolution using dSTORM.
  • Demonstrated that the total number of antibodies on NPs exceeds the accessible number for targeting.
  • Identified optimal regimes for high cell uptake selectivity by correlating NP functionality, receptor density, and NP uptake.

Conclusions:

  • Single-molecule mapping of NP functionality using dSTORM provides critical molecular insights into nanoparticle targeting.
  • This approach aids in the rational design of more selective and effective nanomedicines for cancer therapy.
  • Understanding the interplay between NP ligands and cell receptors at the nanoscale is key to optimizing targeted delivery.