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pH-Dependent Cellular Internalization of Paramagnetic Nanoparticle.

Branislava Janic1, Mohammed Pi Bhuiyan2, James R Ewing2

  • 1Radiation Oncology, Henry Ford Hospital, Detroit, MI 48202, United States.

ACS Sensors
|January 10, 2017
PubMed
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Researchers developed pH-sensitive nanoparticles for targeted drug delivery. These nanoparticles, utilizing pH Low Insertion Peptide (pHLIP), bind to cancer cell membranes in acidic tumor environments, enhancing cellular uptake.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Oncology

Background:

  • Extracellular acidosis is a key characteristic of the tumor microenvironment in malignant tumors.
  • This acidic environment presents an opportunity for targeted drug and imaging agent delivery.
  • Developing pH-sensitive materials is crucial for exploiting this tumor-specific feature.

Purpose of the Study:

  • To engineer a pH-sensitive paramagnetic nanoparticle for targeted delivery.
  • To leverage the pH-selective properties of pHLIP (pH Low Insertion Peptide) for enhanced cellular uptake in acidic conditions.
  • To investigate the binding, fusion, and intracellular trafficking of the developed nanoparticle.

Main Methods:

  • Incorporation of GdDOTA-4AmP MRI contrast agent and pHLIP into a G5-PAMAM dendrimer.
Keywords:
Cell internalizationMRIintracellular traffickingpH sensing probeparamagnetic nanoparticle

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  • Synthesis of a pH-sensitive paramagnetic nanoparticle (NP).
  • Evaluation of NP binding, membrane fusion, and cellular uptake at varying pH levels (acidic vs. physiological).
  • Analysis of intracellular trafficking pathways using microscopy.

    • Main Results:

    • The pHLIP-conjugated Gd44-G5 nanoparticle demonstrated pH-selective binding and fusion with cell membranes, occurring only under acidic conditions.
    • Cellular uptake of the nanoparticle was significantly promoted at low pH compared to normal physiological pH.
    • Intracellular trafficking studies indicated that the nanoparticles followed endosomal/lysosomal pathways.

    Conclusions:

    • The developed pH-sensitive paramagnetic nanoparticle effectively targets and enters cells in acidic environments characteristic of tumors.
    • The pH-selective insertion of pHLIP is key to the nanoparticle's targeted cellular interaction.
    • These findings support the potential of this nanoparticle for targeted drug delivery and imaging in cancer therapy.