Strongly amphiphilic photosensitizers are not substrates of the cancer stem cell marker ABCG2 and provides specific and efficient light-triggered drug delivery of an EGFR-targeted cytotoxic drug

J Control Release. 2012 Apr 30;159(2):197-203. doi: 10.1016/j.jconrel.2012.02.003. Epub 2012 Feb 10.


A wide range of anti-cancer drugs are substrates of the ATP-binding cassette transporter ABCG2/CD338/BCRP/MXR, which is thought to play an important role in multi-drug resistance (MDR) and protection of cancer stem cells (CSC) against chemotherapeutics and photodynamic therapy (PDT). Hence, it is of importance to develop drugs that are not substrates of ABCG2. The aim of this study was to elucidate if photosensitizers utilized for the endo-lysosomal release drug delivery method photochemical internalization (PCI) are substrates for ABCG2. The breast carcinoma cell line MA11, with a Hoechst 33342 side population of >50% was used as an ABCG2high model. The photosensitizer Pheophorbide A (PhA) and Hoechst 33342 were used as positive control substrates of ABCG2. ABCG2-inhibition by fumitremorgin C (FTC) did neither induce an increased accumulation of three different PCI-photosensitizers (di-sulfonated meso-tetraphenylporphine (TPPS(2a)), di-sulfonated meso-tetraphenylchlorin (TPCS(2a)) and di-sulfonated aluminium phtalocyanine (AlPcS(2a))) nor enhanced the photosensitization (P=0.65 for TPCS(2a)-PDT) of these PCI-based photosensitizers in the MA11 cells. The same results were also obtained with TPPS(2a) in the malignant glioma cell line U87 having a SP of ~0.1%. In contrast, both uptake and PDT-induced cytotoxicity was strongly enhanced for PhA when combined with FTC (P<0.001)). Specific and efficient light-controlled killing of EGFR+/ABCG2+ MA11 cells was obtained by PCI of the targeting toxin EGF-saporin. The novel data obtained in this study demonstrates that strongly amphiphilic photosensitizers used for PCI-based drug delivery are not substrates of ABCG2. This important findings warrant further development of the PCI technology as a strategy for efficient and site-specific eradication of MDR cells and CSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Drug Carriers / chemistry
  • Drug Carriers / pharmacology*
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Multiple / radiation effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / radiation effects
  • Endocytosis / drug effects
  • Endocytosis / radiation effects
  • ErbB Receptors / metabolism*
  • Flow Cytometry
  • Humans
  • Light*
  • Microscopy, Fluorescence
  • Molecular Structure
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / metabolism*
  • Photosensitizing Agents / chemistry
  • Photosensitizing Agents / pharmacology*
  • Porphyrins / chemistry
  • Porphyrins / pharmacology
  • Substrate Specificity
  • Surface-Active Agents / chemistry
  • Surface-Active Agents / pharmacology*


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Drug Carriers
  • Neoplasm Proteins
  • Photosensitizing Agents
  • Porphyrins
  • Surface-Active Agents
  • di(4-sulfonatophenyl)diphenylporphine
  • meso-tetraphenyl chlorin disulphonate
  • EGFR protein, human
  • ErbB Receptors