P-glycoprotein targeted and near-infrared light-guided depletion of chemoresistant tumors

J Control Release. 2018 Sep 28;286:289-300. doi: 10.1016/j.jconrel.2018.08.005. Epub 2018 Aug 4.

Abstract

Drug resistance remains a formidable challenge to cancer therapy. P-glycoprotein (Pgp) contributes to multidrug resistance in numerous cancers by preventing accumulation of anticancer drugs in cancer cells. Strategies to overcome this resistance have been vigorously sought for over 3 decades, yet clinical solutions do not exist. The main reason for the failure is lack of cancer specificity of small-molecule Pgp inhibitors, thus causing severe toxicity in normal tissues. In this study, Pgp-targeted photodynamic therapy (PDT) was developed to achieve superior cancer specificity through antibody targeting plus locoregional light activation. Thus, a Pgp monoclonal antibody was chemically modified with IR700, a porphyrin photosensitizer. In vitro studies showed that the antibody-photosensitizer conjugates specifically bind to Pgp-expressing drug resistant cancer cells, and caused dramatic cytotoxicity upon irradiation with a near infrared light. We then tested our Pgp-targeted approach in mouse xenograft models of chemoresistant ovarian cancer and head and neck cancer. In both models, targeted PDT produced rapid tumor shrinkage, and significantly prolonged survival of tumor-bearing mice. We conclude that our targeted PDT approach produces molecularly targeted and spatially selective ablation of chemoresistant tumors, and thereby provides an effective approach to overcome Pgp-mediated multidrug resistance in cancer, where conventional approaches have failed.

Keywords: Antibody conjugates; Cancer multidrug resistance; Cancer targeted therapy; P-glycoprotein; Photodynamic therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Cell Line, Tumor
  • Drug Delivery Systems / methods*
  • Female
  • Humans
  • Immunoconjugates / administration & dosage*
  • Immunoconjugates / chemistry
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / therapeutic use
  • Infrared Rays
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Photochemotherapy / methods
  • Photosensitizing Agents / administration & dosage*
  • Photosensitizing Agents / chemistry
  • Photosensitizing Agents / pharmacokinetics
  • Photosensitizing Agents / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunoconjugates
  • Photosensitizing Agents