A Targeted Nanomedicine Prototype Against Enzalutamide-resistant Prostate Cancer

摘要 8%的前列腺癌患者会发展为致命的转移性疾病。发展 对雄激素剥夺疗法产生抵抗，并最终对最后一线化疗药物产生抵抗，例如 恩杂鲁胺（ENZ）可导致致命的转移性前列腺癌。虽然有兴趣确定肿瘤特异性 分子签名，被称为精确医学，正在获得普遍的青睐，它需要识别 生理上可接近的目标通过转移分子肿瘤靶点的功能， 癌症药物，肿瘤生长的速度预计将下降;然而，这并不考虑到， 获得性耐药机制依赖于全身药物稳定性、溶解度或毒性。 稳定难溶性和/或高毒性药物并潜在地克服耐药性的一种方法是 将药物封装在纳米颗粒（NPs）中，以防止其降解并延长其循环时间。 此外，通过添加肿瘤特异性靶向，可以改善负载的NP在肿瘤部位的积累。 诱导NP内吞作用的部分，从而提高治疗指数，同时最小化侧支 损害健康细胞。前列腺肿瘤特异性生物标志物，78 kDa葡萄糖调节蛋白（GRP 78）， 由Pasqualini和Arap团队通过筛选前列腺癌患者血清中的抗体鉴定。 GRP 78是疾病进展的生物标志物，对我们提出的研究至关重要，我们最近发现， 具有最佳体内肿瘤靶向的人重组抗GRP 78抗体。在这份提案中，我们的目标是 是产生针对ENZ抗性前列腺癌的GRP 78靶向NP。我们将采用新颖的模块化 Brinker团队开发的“protocell”平台。原细胞由多孔二氧化硅核心组成，其可以是 被设计成容纳各种和组合的货物，包封在支持的脂质双层内， 保护和保留所述货物，并提供生物相容性表面用于缀合至靶向和/或 贩运配体。Brinker团队展示了靶向的第一代原始细胞的特殊稳定性 在体内与单个循环白血病细胞特异性结合和货物递送。而不是交付 在蛋白质水平上发挥作用的化疗药物，我们建议将小干扰RNA（siRNA） 针对长的非编码RNA，PCA 3。我们发现，干扰PCA 3抑制生长， 人前列腺异种移植物。在Cristini团队进行的预测建模的指导下， GRP 78靶向的原始细胞将被设计成包装PCA 3 siRNA以选择性地结合表达GRP 78的细胞。 前列腺癌细胞，并在细胞内递送PCA 3 siRNA以抑制肿瘤生长。我们的项目是首次- 实地研究，激发我们目前的专业知识和技术相结合。双前列腺肿瘤“中心” 这些下一代NP原型平台的特征增加了它们的特异性和有效性，并克服了 常规标准治疗药物的局限性，特别是在获得性耐药性的情况下。

ABSTRACT Eight percent of patients diagnosed with prostate cancer progress to lethal metastatic disease. Development of resistance to androgen-deprivation therapy and eventually, to last line chemotherapeutics such as enzalutamide (ENZ), contribute to lethal, metastatic prostate cancer. While interest to identify tumor-specific molecular signatures, termed precision medicine, is gaining popular favor, it requires identification of physiologically accessible targets. By diverting the function of a molecular tumor target by conventional anti- cancer drugs, rates of tumor growth are expected to decrease; however, this does not take into account acquired drug resistance mechanisms which are dependent on systemic drug stability, solubility or toxicity. One method to stabilize poorly soluble and/or highly toxic drugs, and potentially overcome resistance, is to encapsulate drugs in nanoparticles (NPs) to prevent their degradation and enhance their circulation time. Moreover, accumulation of loaded NPs at the tumor site can be improved by adding tumor-specific targeting moieties that induce NP endocytosis, thereby improving the therapeutic index while minimizing collateral damage to healthy cells. A prostate tumor-specific biomarker, the 78 kDa glucose-regulated protein (GRP78), was identified by the Pasqualini and Arap team by screening antibodies from prostate cancer patient sera. GRP78 is a biomarker of disease progression and, crucial to our proposed research, we recently identified human recombinant anti-GRP78 antibodies with optimal in vivo tumor targeting. In this proposal, our objective is to generate GRP78-targeted NPs against ENZ-resistant prostate cancer. We will employ the novel, modular “protocell” platform developed by the Brinker team. Protocells consist of a porous silica core, which can be engineered to accommodate varied and combination cargos, encapsulated within a supported lipid bilayer that protects and retains the cargo, and provides a biocompatible surface for conjugation to targeting and/or trafficking ligands. The Brinker team demonstrated exceptional stability of targeted, first-generation protocells in vivo with specific binding and cargo delivery to individual circulating leukemia cells. Instead of delivering chemotherapeutic drugs that work at the protein level, we propose to deliver small interfering RNAs (siRNAs) directed against the long non-coding RNA, PCA3. We showed that interfering with PCA3 inhibits growth of human prostate xenografts. Guided by predictive modeling conducted by the Cristini team, our modular GRP78-targeted protocells will be designed to package PCA3 siRNAs to selectively bind to GRP78-expressing prostate cancer cells, and deliver PCA3 siRNAs intracellularly to inhibit tumor growth. Our project is a first-in- field study that galvanizes our current combined expertise and technology. The dual prostate tumor “centric” feature of these next generation NP prototype platforms increases their specificity and efficacy, and overcomes the limitation of conventional standard-of-care drugs, particularly in the case of acquired drug resistance.