title: Implantable chemotherapy-loaded silk protein materials for neuroblastoma treatment.
abstract: Neuroblastoma is the most common extracranial childhood solid tumor. Treatment of high risk tumors require intense multicycle chemotherapies, resulting in short- and long-term toxicities. Here, we present treatment of an orthotopic neuroblastoma mouse model, with silk fibroin materials loaded with vincristine, doxorubicin or the combination as a intratumoral, sustained release system. The materials, loaded with vincristine with or without doxorubicin, significantly decreased neuroblastoma tumor growth compared to materials loaded without drug or doxorubicin only as well as intravenous (IV) drug treatment. The intratumoral drug concentration was significantly higher with intratumoral delivery versus IV. Furthermore, intratumor delivery decreased the maximum plasma concentration compared to IV delivery, reducing systemic exposure and possibly reduing long-term side effects of chemotherapy exposure. Histopathologically, tumors with remission periods >25 days before recurrence transformed from a "small-round-blue cell" (SBRC) to predominantly "large cell" neuroblastoma (LCN) histopathology, a more aggressive tumor subtype with unfavorable clinical outcomes. These results show that intratumoral chemotherapy delivery may be a treatment strategy for pediatric neuroblastoma, potentially translatable to other focal tumors types. Furthermore, this treatment modality allows for a clinically relevant mouse model of tumor transformation that may be used for studying the phenotypical tumor recurrence and developing more effective treatment strategies for recurrent tumors.
authors: Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA.
authors: Jeannine
authors: J
authors: Coburn
authors: Department of Surgery, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL.
authors: Jamie
authors: J
authors: Harris
authors: Department of Pharmacology, Toxicology Research Laboratory, 808 S Wood Street, Chicago, IL.
authors: Alexander D
authors: AD
authors: Zakharov
authors: Department of Surgery, Rush University, 1653 W. Congress Parkway, Chicago, IL.
authors: Jennifer
authors: J
authors: Poirier
authors: Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S. Wood Street, Chicago, IL.
authors: Naohiko
authors: N
authors: Ikegaki
authors: Department of Pathology, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL.
authors: Andre
authors: A
authors: Kajdacsy-Balla
authors: Department of Pathology, Tufts Medical Center, 800 Washington Street, Boston, MA.
authors: Monika
authors: M
authors: Pilichowska
authors: Department of Pharmacology, Toxicology Research Laboratory, 808 S Wood Street, Chicago, IL.
authors: Alexander V
authors: AV
authors: Lyubimov
authors: Department of Pathology, Children's Hospital of Los Angeles, 4650 Sunset Blvd, Los Angeles, CA.
authors: Hiroyuki
authors: H
authors: Shimada
authors: Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA.
authors: David L
authors: DL
authors: Kaplan
authors: Department of Surgery, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL.
authors: Bill
authors: B
authors: Chiu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods; D005349:Fibroins / Q000008:administration & dosage*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009447:Neuroblastoma / Q000188:drug therapy*; D047011:Silk / Q000008:administration & dosage*; D014750:Vincristine / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D047011:Silk; D014750:Vincristine; D004317:Doxorubicin; D005349:Fibroins
keywords: chemotherapy; neuroblastoma; orthotopic animal model; silk materials; sustained-release; tumor recurrence