title: Benefit of anti-HER2-coated paclitaxel-loaded immuno-nanoparticles in the treatment of disseminated ovarian cancer: Therapeutic efficacy and biodistribution in mice.
abstract: The benefit of polymeric immuno-nanoparticles (NPs-Tx-HER), consisting of paclitaxel (Tx)-loaded nanoparticles coated with anti-HER2 monoclonal antibodies (Herceptin, trastuzumab), in cancer treatment was assessed in a disseminated xenograft ovarian cancer model induced by intraperitoneal inoculation of SKOV-3 cells overexpressing HER2 antigens. The study was focused on the evaluation of therapeutic efficacy and biodistribution of NPs-Tx-HER compared to other Tx formulations. The therapeutic efficacy was determined by two methods: bioluminescence imaging and survival rate. The treatment regimen consisted in an initial dose of 20mg/kg Tx administered as 10mg/kg intravenously (IV) and 10mg/kg intraperitonealy (IP), followed by five alternative IP and IV injections of 10mg/kg Tx every 3 days. The bioluminescence study has clearly shown the superior anti-tumor activity of NPs-Tx-HER compared to free Tx. As a confirmation of these results, a significantly longer survival of mice was observed for NPs-Tx-HER treatment compared to free Tx, Tx-loaded nanoparticles coated with an irrelevant mAb (Mabthera, rituximab) or Herceptin alone, indicating the potential of immuno-nanoparticles in cancer treatment. The biodistribution pattern of Tx was assessed on healthy and tumor bearing mice after IV or IP administration. An equivalent biodistribution profile was observed in healthy mice for Tx encapsulated either in uncoated nanoparticles (NPs-Tx) or in NPs-Tx-HER. No significant difference in Tx biodistribution was observed after IV or IP injection, except for a lower accumulation in the lungs when NPs were administered by IP. Encapsulated Tx accumulated in the organs of the reticulo-endothelial system (RES) such as the liver and spleen, whereas free Tx had a non-specific distribution in all tested organs. Compared to free Tx, the single dose injection (IV or IP) of encapsulated Tx in mice bearing tumors induced a higher tumor accumulation. However, no difference in overall tumor accumulation between NPs-Tx-HER and NPs-Tx was observed. In conclusion, the encapsulation of Tx into NPs-Tx-HER immuno-nanoparticles resulted in an improved efficacy of drug in the treatment of disseminated ovarian cancer overexpressing HER2 receptors.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Cirstoiu-Hapca
authors.forename: F
authors.initials: F
authors.lastname: Buchegger
authors.forename: N
authors.initials: N
authors.lastname: Lange
authors.forename: L
authors.initials: L
authors.lastname: Bossy
authors.forename: R
authors.initials: R
authors.lastname: Gurny
authors.forename: F
authors.initials: F
authors.lastname: Delie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D014018:Tissue Distribution; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab