On-demand releasing nano-VCR for effective neuroblastoma therapy

 描述（由申请人提供）：高危神经母细胞瘤的治疗仍然是儿科肿瘤学家面临的最大挑战之一。长春新碱（VCR）是有效的治疗 神经母细胞瘤然而，由于VCR的神经毒性作用、不利的药代动力学以及药物暴露和靶组织递送不良，VCR的临床疗效有限。Marqibo（r）是第一种可改善VCR药代动力学和毒性特征的VCR脂质体制剂。然而，Marqibo（r）缺乏聚乙二醇化和相对较大的尺寸（约150 nm）可能导致生物分布不利和肿瘤渗透较浅。Marqibo（r）仅在临床上用于治疗一种非常罕见的白血病，称为费城染色体阴性（Ph-）急性淋巴细胞白血病（ALL）。尚未确定Marqibo（r）在儿科患者中的安全性和有效性。据报道，较小的纳米颗粒如30 nm胶束可以穿透渗透性差的肿瘤，以获得更好的抗肿瘤效果。本提案中开发的具有较小尺寸（约16 nm）和按需药物释放特性的智能VCR负载胶束纳米颗粒（纳米VCR）可能对神经母细胞瘤提供更好的疗效和毒性特征，因此具有巨大的商业潜力，从而产生可销售的用于治疗神经母细胞瘤的VCR纳米制剂。该I期SBIR提案的总体目标是在临床前动物模型中开发针对神经母细胞瘤的高效且毒性较低的VCR胶束制剂，为II期研究的可行性提供验证，最终将导致向FDA提交IND申请。我们的假设是：（一） VCR的较小交联胶束制剂（ii）微调纳米VCR的二硫化物交联水平将使循环期间的过早药物释放最小化，但允许在肿瘤部位或肿瘤细胞中的即时药物释放，因此将大大改善疗效和毒性特征;和（iii）N-乙酰半胱氨酸，当给药后24小时给予动物时， 纳米VCR的初始给药将进一步提高其治疗指数。Nano-VCR将进一步用高效配体修饰，以增强其靶向神经母细胞瘤新血管中过表达的α v β 3整联蛋白的能力。在本研究中，这些假设将在小鼠神经母细胞瘤模型中得到验证。该项目解决了神经母细胞瘤治疗中的一个关键问题，以减少药物毒性和提高药物疗效。通过设计具有明确结构的末端树枝状聚合物来设计纳米载体的最新技术水平代表了纳米医学在多功能、精细可调和高度可再现的结构和性质方面的前沿发展。使用具有微调稳定性和按需药物释放特性的可逆交联胶束递送VCR以对抗神经母细胞瘤是高度创新的。这是一种很好的方法来防止药物在循环过程中过早释放，并将高浓度的药物输送到肿瘤部位。本研究有望为神经母细胞瘤的治疗开辟新的途径。

 DESCRIPTION (provided by applicant): Treatment of high-risk neuroblastoma remains one of the greatest challenges for pediatric oncologists. Vincristine (VCR) is effective for the treatment of neuroblastoma. The clinical efficacy of VCR is limited, however, due to its neurotoxic effect, unfavorable pharmacokinetics, and poor drug exposure and delivery to target tissues. Marqibo(r) is the first liposomal formulation of VCR that could improve the pharmacokinetics and toxicity profiles of VCR. However, the lack of pegylation and relatively large size (~150 nm) of Marqibo(r) may result in unfavorable biodistribution and less deeper tumor penetration. Marqibo(r) is only used in clinic to treat adults with a very rare type of leukemia called Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL). The safety and effectiveness of Marqibo(r) in pediatric patients have not been established. It has been reported that smaller nanoparticles such as 30 nm micelles could penetrate poorly permeable tumors for a better anti-tumor effect. The smart VCR loaded micellar nanoparticles (nano-VCR) with smaller size (~16 nm) and on-demand drug releasing properties to be developed in this proposal may offer better efficacy and toxicity profile against neuroblastoma, therefore have great commercial potentials to lead to a marketable VCR-nanoformulation for the treatment of neuroblastoma. The overall goal of this Phase I SBIR proposal is to develop highly effective and less toxic micellar formulation of VCR against neuroblastoma in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to FDA. Our hypotheses are: (i) The smaller crosslinked micelle formulation of VCR (nano-VCR), compared to its free form are more efficacious and less toxic against neuroblastoma; (ii) Fine tuning the level of disulfide crosslinking of nano-VCR will minimize the premature drug release during circulation but allow instant drug release at tumor sites or in tumor cells, therefore will greatly improve the efficacy and toxicity profile; and (iii) N-acetyl cysteine, when administered to the animal 24 hrs after the initial administration of nano-VCR, will further improve its therapeutic index. Nano-VCR will be further decorated with a highly potent ligand to enhance their targeting capability to avß3 integrin overexpressed in neovasculatures of neuroblastoma. In this proposal, these hypotheses will be tested in murine neuroblastoma tumor model. The project addresses a critical issue in neuroblastoma therapy to reduce drug toxicity and increase drug efficacy. State of the art design of the nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of multiple functions, fine-tunable and highly reproducible structure and properties. The use of reversibly crosslinked micelles with fine-tuned stability and on-demand drug releasing property to delivery VCR against neuroblastoma is highly innovative. It's an excellent approach to prevent pre-mature drug release during circulation and deliver high concentrations of drug to tumor site. It is expected that this research will lead to new approach for neuroblastoma therapy.