Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment

这项提议的目标是使用自组装纳米材料来改善结肠癌的系统治疗。 它可以传递有效的抗癌miRNA，然后在癌细胞中降解为活性小分子调节剂 多胺代谢失调的原因。尽管有巨大的治疗潜力，miRNA的临床翻译 面临着尚未解决的重大药物输送挑战。由于涉及到多个突变 肿瘤发生和肿瘤进展，miRNAs与多胺代谢调节剂的结合 巨大的治疗潜力。多胺代谢是许多癌基因下游的事实， 肿瘤抑制通路使其成为miRNA联合治疗方法的合理靶点。我们的 目的是开发多胺前体药物(PAPs)，它可以调节失调的多胺代谢，并 包裹并系统地递送抗癌药物miR-34a。假设是自焚的帕普斯基于 多胺代谢调节剂将miR-34a输送到肿瘤，这将导致增强 肿瘤多胺生物合成下调与多胺分解代谢上调的联合作用 以及由于miR-34a而恢复重要的细胞生长和死亡调节功能。我们将完成 目标：(1)优化肿瘤穿透性Pap/miR-34a的处方 传递miRNA并调节多胺代谢的纳米颗粒。基于鼓励体内抗癌活性 在我们的初步研究中，我们假设用肿瘤穿透性IRGD多肽和 具有稳定的超疏水氟化部分将导致有效的全身给药。(2)我们会 确定Pap/miR-34a纳米粒的体外作用机制。我们的结果表明，PAPS是有效的 在抑制肿瘤细胞生长和诱导细胞凋亡方面，但其确切的作用机制 纳米粒子及其与其细胞内运输、分解和多胺类似物释放速率的关系是 未知。我们将确定作用机制，并确定哪些组合策略是最 有效产生较强的抗肿瘤作用。(3)我们将测试这些颗粒对结肠癌的体内疗效 使用人肿瘤异种移植和同基因免疫活性肿瘤模型。我们将全面开展 在与人类疾病相关的模型中评价Pap/miR-34a的抗癌活性和生存优势。 抗肿瘤免疫原性对疗效的贡献也将被研究，因为已知的作用 多胺类似物对增强抗肿瘤免疫反应的作用。我们预测我们将能够做好准备 纳米颗粒具有更好的抗癌活性和更长的寿命。建议的综合方法是创新的。 由于Pap聚合物作为多胺代谢调节剂和miRNA的双重功能设计 承运人。这项研究意义重大，因为它将解决开发药物/核酸的主要障碍。 纳米技术用于癌症的系统治疗，并建立一个广泛适用和通用的平台 以多胺代谢为靶点的组合给药系统，作为改进抗癌治疗的一种方式。

The goal of this proposal is to improve systemic therapies of colon cancer using self-assembled nanomaterials that can deliver potent anticancer miRNA and then degrade in cancer cells to active small molecule modulators of dysregulated polyamine metabolism. Despite tremendous therapeutic potential, clinical translation of miRNA faces major unsolved pharmaceutical delivery challenges. Due to the involvement of multiple mutations in tumorigenesis and tumor progression, combination of miRNAs with modulators of polyamine metabolism has significant therapeutic potential. The fact that polyamine metabolism is downstream from many oncogenes and tumor suppressor pathways make it a logical target for such combination miRNA therapy approaches. Our objective is to develop polyamine prodrugs (PaPs) that can modulate dysregulated polyamine metabolism and encapsulate and systemically deliver anticancer miR-34a. The hypothesis is that self-immolative PaPs based on modulators of polyamine metabolism will deliver miR-34a to the tumors, which will result in enhanced combination effect due to the downregulation of tumor polyamine biosynthesis and upregulation of polyamine catabolism and restoration of important cell growth and death-regulatory functions due to miR-34a. We will accomplish the objectives in three specific aims: (1) we will optimize formulation of tumor-penetrating PaP/miR-34a nanoparticles that deliver miRNA and modulate polyamine metabolism. Based on encouraging anticancer in vivo activity in our preliminary studies, we hypothesize that particle modification with tumor-penetrating iRGD peptide and with stabilizing superhydrophobic fluorinated moieties will result in efficient systemic delivery. (2) we will determine the mechanism of action of PaP/miR-34a nanoparticles in vitro. Our results indicate that PaPs are effective in reducing tumor cell growth and induction of apoptosis, but the precise mechanism of action of the nanoparticles and how it relates to their intracellular trafficking, disassembly and rate of polyamine analog release is unknown. We will ascertain the mechanisms of action and determine which composition strategies are most effective in producing strong antitumor effect. (3) we will test the in vivo efficacy of the particles in colon cancer using human tumor xenografts and syngeneic immune competent tumor models. We will conduct comprehensive evaluation of anticancer activity and survival advantage of PaP/miR-34a in models relevant for human disease. Contribution of the antitumor immunogenicity to the efficacy will be also studied due to known effects of polyamine analogs on increasing the antitumor immune response. We predict that we will be able to prepare nanoparticles with improved anticancer activity and prolonged survival. The proposed integrative approach is innovative because of the dual-function design of the PaP polymers as modulators of polyamine metabolism and miRNA carriers. The research is significant because it will address major barriers in developing drug/nucleic acid nanotechnology for systemic treatment of cancer and establish a widely applicable and versatile platform for combination delivery systems that target polyamine metabolism as a way of improving anticancer therapies.