title: Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy.
abstract: Nanomedicine-based strategies have the potential to improve therapeutic performance of a wide range of anticancer agents. However, the successful implementation of nanoparticulate delivery systems requires the development of adequately sized nanocarriers delivering their therapeutic cargo to the target in a protected, pharmacologically active form. The present studies focused on a novel nanocarrier-based formulation strategy for SN-38, a topoisomerase I inhibitor with proven anticancer potential, whose clinical application is compromised by toxicity, poor stability and incompatibility with conventional delivery vehicles. SN-38 encapsulated in biodegradable sub-100 nm sized nanoparticles (NP) in the form of its rapidly activatable prodrug derivative with tocopherol succinate potently inhibited the growth of neuroblastoma cells in a dose- and exposure time-dependent manner, exhibiting a delayed response pattern distinct from that of free SN-38. In a xenograft model of neuroblastoma, prodrug-loaded NP caused rapid regression of established large tumors, significantly delayed tumor regrowth after treatment cessation and markedly extended animal survival. The NP formulation strategy enabled by a reversible chemical modification of the drug molecule offers a viable means for SN-38 delivery achieving sustained intratumoral drug levels and contributing to the potency and extended duration of antitumor activity, both prerequisites for effective treatment of neuroblastoma and other cancers.
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Alferiev
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Iyer
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Croucher
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Adamo
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Kehan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Mangino
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Venkatadri
authors.initials: V
authors.lastname: Kolla
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Ilia
authors.initials: I
authors.lastname: Fishbein
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Brodeur
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Levy
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. Electronic address: chorny@email.chop.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Chorny
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D006801:Humans; D000077146:Irinotecan; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010316:Particle Size; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D024502:alpha-Tocopherol / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D011355:Prodrugs; D000077146:Irinotecan; D024502:alpha-Tocopherol; D002166:Camptothecin
keywords: Drug delivery; Nanoparticle; Neuroblastoma; Prodrug; Topoisomerase I inhibitor