? Neuroblastoma is the most common extracranial tumor in childhood, with poor clinical outcomes for high-risk patients using systemic, multi-drug chemotherapy followed by surgical resection. There is a strong clinical need for new approaches to chemotherapy administration due to poor outcomes and secondary organ toxicities with long-term negative consequences particularly in children. The goal of this proposal is to develop focal drug delivery systems that can be applied within the tumor or over a post-resection tumor bed. The hypothesis is that local delivery coupled with sustained drug release using silk protein-based biomaterial sponges and films (implantable) or gels (injectable) will provide new therapeutic strategies for high-risk neuroblastoma patients while reducing systemic side effects. We will build upon our extensive prior experience and success using silk biomaterials for sustained drug release to optimize local tumor treatment while minimizing the impact on healthy tissue. This will include targeting tumor drug concentration to match or exceed clinical blood levels on a sustained basis, as well as exploiting directional diffusion to further improve targeting to the tumor site versus healthy tissue. The focus will be on delivering cytotoxic chemotherapeutic agents (doxorubicin, vincristine, etoposide-4'-phosphate, cisplatin) in both single and dual drug-loaded delivery systems using silk biomaterials. These silk delivery systems will be assessed in vitro for impact on neuroblastoma cell lines and in vivo using an orthotopic tumor models generated from neuroblastoma cell lines and patient-derived xenografts. Drug release kinetics and toxicity will be assessed in the animal models to assess the impact of local drug release on tumor growth as well as pharmacokinetics and toxicity in tissue compartments. All studies are supported by extensive preliminary data and represent a collaborative team consisting of a bioengineer (Kaplan) with expertise with the biomaterials and drug delivery and a physician (Chiu) who focuses on neuroblastoma treatments.

Public Health Relevance

- Pediatric surgeons treating high-risk neuroblastoma patients with locally unresectable tumors are faced with a limited repertoire of treatment options; thus the prognosis for 50% of those children remains poor. This research will develop novel treatment options for pediatric surgeons using focal therapy to deliver chemotherapy directly to the tumor site. This approach has not only the potential to revolutionize neuroblastoma care, but also provide the cancer community with a new platform technology to deliver therapeutics drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094218-02
Application #
9415441
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fountain, Jane W
Project Start
2017-02-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Tufts University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155
Coburn, Jeannine M; Harris, Jamie; Cunningham, Rachel et al. (2017) Manipulation of variables in local controlled release vincristine treatment in neuroblastoma. J Pediatr Surg 52:2061-2065
Harris, Jamie; Herrero-Garcia, Erika; Russo, Angela et al. (2017) Silencing Intersectin 1 Slows Orthotopic Neuroblastoma Growth in Mice. J Pediatr Hematol Oncol 39:e413-e418