Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment

该提案的目标是使用自组装纳米材料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， 多胺代谢失调尽管有巨大的治疗潜力， 面临着重大的未解决的药物输送挑战。由于涉及多个突变， 肿瘤发生和肿瘤进展，miRNA与多胺代谢调节剂的组合， 显著的治疗潜力。多胺代谢是许多癌基因的下游， 肿瘤抑制途径使其成为这种组合miRNA治疗方法的逻辑靶点。我们 目的是开发能够调节多胺代谢失调的多胺前药（PaPs）， 包封并全身递送抗癌miR-34a。假设是，自我毁灭的PaPs基于 多胺代谢的调节剂将miR-34a递送至肿瘤，这将导致增强的肿瘤细胞增殖。 由于肿瘤多胺生物合成的下调和多胺催化剂的上调的组合效应 以及恢复由miR-34a引起的重要的细胞生长和死亡调节功能。我们将实现 我们的目标有三个：（1）优化肿瘤穿透PaP/miR-34a的制剂， 这些纳米颗粒递送miRNA并调节多胺代谢。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iRGD肽修饰颗粒， 与稳定的超疏水性氟化部分一起将导致有效的全身递送。(2)我们将 确定PaP/miR-34a纳米颗粒的体外作用机制。我们的研究结果表明，PAP是有效的 在减少肿瘤细胞生长和诱导凋亡方面， 纳米颗粒以及它如何与它们的细胞内运输、分解和多胺类似物释放速率相关， 未知我们将确定作用机制，并确定哪些组合策略是最重要的。 具有较强的抗肿瘤作用。(3)我们将测试这些微粒在结肠癌中的体内功效 使用人肿瘤异种移植物和同源免疫活性肿瘤模型。我们将进行全面的 在与人类疾病相关的模型中评估PaP/miR-34a的抗癌活性和存活优势。 由于已知的抗肿瘤免疫原性效应，还将研究抗肿瘤免疫原性对疗效的贡献。 多胺类似物对增加抗肿瘤免疫应答的作用。我们预测我们将能够准备 纳米颗粒具有改善的抗癌活性和延长的生存期。所提出的综合办法是创新的 由于PaP聚合物作为多胺代谢和miRNA调节剂的双重功能设计， 载波这项研究意义重大，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的和通用的平台， 靶向多胺代谢的组合递送系统作为改善抗癌疗法的方式。

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.