P-Glycoprotein-Targeted Photothermal Therapy of Drug-Resistant Cancer Cells Using Antibody-Conjugated Carbon Nanotubes

ACS Appl Mater Interfaces. 2018 Oct 3;10(39):33464-33473. doi: 10.1021/acsami.8b11974. Epub 2018 Sep 18.

Abstract

P-Glycoprotein (Pgp)-medicated multidrug resistance (MDR) remains a formidable challenge to cancer therapy. As conventional approaches using small-molecule inhibitors failed in clinical development because of the lack of cancer specificity, we develop Pgp-targeted carbon nanotubes to achieve highly cancer-specific therapy through combining antibody-based cancer targeting and locoregional tumor ablation with photothermal therapy. Through a dense coating with phospholipid-poly(ethylene glycol), we have engineered multiwalled carbon nanotubes (MWCNTs) which show minimum nonspecific cell interactions and maximum intercellular diffusion. After chemically modifying with an anti-Pgp antibody, these MWCNTs showed highly Pgp-specific cellular uptake. Treatment of the targeted MWCNTs caused dramatic cytotoxicity in MDR cancer cells upon photoirradiation, whereas they did not cause any toxicity in the dark or phototoxicity toward normal cells that do not express Pgp. Because of excellent intratumor diffusion and Pgp-specific cellular uptake, the targeted MWCNTs produced strong phototoxicity in tumor spheroids of MDR cancer cells, a 3-D tumor model for studying tumor penetration and therapy. In conclusion, we have developed highly Pgp-specific MWCNTs that may provide an effective therapy for MDR cancers where other approaches have failed.

Keywords: P-glycoprotein; cancer multidrug resistance; cancer targeting; carbon nanotubes; photothermal therapy.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Cell Line
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Mice
  • Nanotubes, Carbon / chemistry*
  • Phospholipids / metabolism
  • Photochemotherapy / methods*
  • Polyethylene Glycols / chemistry
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / pathology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Nanotubes, Carbon
  • Phospholipids
  • Polyethylene Glycols