title: Immunoliposomal delivery of doxorubicin can overcome multidrug resistance mechanisms in EGFR-overexpressing tumor cells.
abstract: Immunoliposomes (ILs) can be constructed to target the epidermal growth factor receptor (EGFR) to provide efficient intracellular drug delivery in tumor cells. We hypothesized that this approach might be able to overcome drug resistance mechanisms, which remain an important obstacle to better outcomes in cancer therapy. ILs were evaluated in vitro and in vivo against EGFR-overexpressing pairs of human cancer cells (HT-29 and MDA-MB-231) that either lack or feature the multidrug resistance (mdr) phenotype. In multidrug-resistant cell lines, ILs loaded with doxorubicin (DOX) produced 19-216-fold greater cytotoxicity than free DOX, whereas in nonresistant cells, immunoliposomal cytotoxicity of DOX was comparable with that of the free drug. In intracellular distribution studies, free DOX was efficiently pumped out of the multidrug-resistant tumor cells, whereas immunoliposomal DOX leads to 3.5-8 times higher accumulation of DOX in the cytoplasm and 3.5-4.9 times in the nuclei compared with the free drug. Finally, in vivo studies in the MDA-MB-231 Vb100 xenograft model confirmed the ability of anti-EGFR ILs-DOX to efficiently target multidrug-resistant cells and showed impressive antitumor effects, clearly superior to all other treatments. In conclusion, ILs provide efficient and targeted drug delivery to EGFR-overexpressing tumor cells and are capable of completely reversing the multidrug-resistant phenotype of human cancer cells.
authors.affiliation: Division of Oncology, University Hospital of Basel, Basel, Switzerland. christoph.mamot@ksa.ch
authors.forename: Christoph
authors.initials: C
authors.lastname: Mamot
authors.forename: Reto
authors.initials: R
authors.lastname: Ritschard
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.forename: Willy
authors.initials: W
authors.lastname: Küng
authors.forename: Jan
authors.initials: J
authors.lastname: Schuller
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Rochlitz
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin; D066246:ErbB Receptors