Nanospheres as Vehicles for Treatment of Neuroblastoma

描述（由申请人提供）：神经母细胞瘤是儿童最常见的实体瘤，源于分化阻滞和增殖状态的持续。 神经母细胞瘤通常通过部分分化自发地恢复，这导致其最终变性。因此，临床神经母细胞瘤的一种有用的治疗方法可能包括强制分化的策略。 在我们正在进行的研究中，我们已经开发了一种抗氧化协同制剂（“ASF”），其由α-生育酚（维生素E）、丙酮酸钠和磷脂酰胆碱组成，其支持培养的神经元中的轴突加工。 我们在本文中证明，ASF防止神经母细胞瘤增殖并促进其在培养物中的分化，即使在血清（其否则诱导快速神经母细胞瘤增殖）存在下也是如此。这保证了ASF在适当施用的情况下可以原位促进神经母细胞瘤的分化（并因此最终变性），因此可以代表抑制临床神经母细胞瘤的新方法。然而，ASF不能阻止将神经母细胞瘤注射到裸鼠体内后产生的肿瘤尺寸的持续增加，尽管直接注射到肿瘤中。由于ASF在血清存在下对培养物中的这些细胞有效，一种可能的解释是我们无法在肿瘤部位维持足够浓度的ASF。 为了实现这一点，我们建议在我们的新型无毒纳米球内施用ASF，其促进其内容物的细胞内递送 纳米球内的封装显著提高了已知抗癌药物以及ASF在培养中的功效。 我们建议通过注射到肿瘤部位、透皮应用（我们的数据表明，我们的纳米球促进其内容物的透皮递送）、包含在其饮食中（我们的数据表明，ASF的饮食给药在生理上有效）以及这些方法的组合来确定纳米球介导的ASF和已知抗癌剂递送对裸鼠神经母细胞瘤肿瘤的功效。 对照将包括在肿瘤远端部位的注射和经皮施用、施用未包封的化合物和施用“空”纳米球。 所得数据将表明纳米球是否代表用于癌症治疗的有用递送剂。

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.