Nanospheres as Vehicles for Treatment of Neuroblastoma

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DESCRIPTION (provided by applicant): Neuroblastoma, the most common solid tumor of children, arises from a block of differentiation and a resultant continuation of the proliferative state. Neuroblastomas often spontaneously revert by undergoing partial differentiation, which leads to their ultimate degeneration. A useful therapeutic approach for clinical neuroblastoma may therefore encompass strategies to force differentiation. In our ongoing studies we have developed an anti-oxidant synergistic formulation ("ASF"), comprised of alpha-tocopherol (vitamin E), sodium pyruvate and phosphatidyl choline, that supports axonal elaboration in cultured neurons. We demonstrate herein that ASF prevents neuroblastoma proliferation and promotes their differentiation in culture, even in the presence of serum (which otherwise induces rapid neuroblastoma proliferation), This holds the promise that ASF, with proper administration, may foster differentiation (and therefore ultimate degeneration) of neuroblastoma in situ and may therefore represent a novel approach towards suppression of clinical neuroblastoma. However, ASF was unable to prevent continued increase in size of tumors generated following injection of neuroblastoma into nude mice, despite injection directly into the tumor. Since ASF is effective on these cells in culture in the presence of serum, one likely interpretation is that we were unable to maintain a sufficient concentration of ASF at the tumor site. To accomplish this, we propose administration of ASF within our novel non-toxic nanospheres, which foster intracellular delivery of their contents Encapsulation within nanospheres dramatically improves the efficacy of known anti-cancer drugs, as well as that of ASF, in culture. We propose to determine the efficacy of nanosphere-mediated delivery of ASF and known anti-cancer agents on neuroblastoma tumors in nude mice by injection into the tumor site, transdermal application (our data indicate that our nanospheres foster transdermal delivery of their contents), inclusion within their diet (our data indicate that dietary administration of ASF is physiologically effective), and combinations of these methods. Controls will include injection and transdermal application at sites distal to the tumor, administration of non-encapsulated compounds, and administration of "empty" nanospheres. Resulting data will indicate whether or not nanospheres represent useful delivery agents for cancer therapy.