title: Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma.
abstract: Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB patients have advanced stage disease with poor prognosis, so more effective, less toxic therapy is needed. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. We formulated ultrasmall-sized (<100 nm) biodegradable poly(lactide)-poly(ethylene glycol) based nanoparticles (NPs) containing SN38 conjugated to tocopherol succinate (SN38-TS). Alternative dosing schedules of SN38-TS NPs were compared to irinotecan. Comparison of SN38-TS NPs (2 doses) with irinotecan (20 doses) showed equivalent efficacy but no cures. Comparison of SN38-TS NPs (8, 8, and 16 doses, respectively) to irinotecan (40 doses) showed that all SN38-TS NP regimens were far superior to irinotecan, and "cures" were obtained in all NP arms. SN38-TS NP delivery resulted in 200× the amount of SN38 in NB tumors at 4 hr post-treatment, compared to SN38 detected for the irinotecan arm; no toxicity was seen with NPs. We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity.
authors: Division of Oncology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
authors: Radhika
authors: R
authors: Iyer
authors: Division of Oncology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
authors: Jamie L
authors: JL
authors: Croucher
authors: Division of Cardiology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Michael
authors: M
authors: Chorny
authors: Division of Oncology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
authors: Jennifer L
authors: JL
authors: Mangino
authors: Division of Cardiology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Ivan S
authors: IS
authors: Alferiev
authors: Division of Cardiology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Robert J
authors: RJ
authors: Levy
authors: Division of Oncology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
authors: Venkatadri
authors: V
authors: Kolla
authors: Division of Oncology, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: Brodeur@email.chop.edu.
authors: Garrett M
authors: GM
authors: Brodeur
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin
keywords: Irinotecan; Nanoparticles; Neuroblastoma; SN38; Tocopherol succinate