Targeting tumor and its microenvironment using nanotherapeutics for pancreatic cancer

使用纳米疗法治疗胰腺癌靶向肿瘤及其微环境

基本信息

批准号：
10795441
负责人：
Satyanarayana Rachagani
金额：
$ 38.11万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10795441
关键词：
Address Biodistribution CASP3 gene CASP7 gene Cancer cell line Cell Line Chemosensitization Clinic Clinical Clinical Trials Combined Modality Therapy Complex Cytotoxic agent Data Development Device Designs Devices Diagnosis Diagnostic Diffusion Disease-Free Survival Distant Dose Dose Limiting Down-Regulation Drug Combinations Drug Kinetics Drug resistance Ectopic Expression Electrostatics Encapsulated Endosomes Epithelium Extracellular Matrix Future Genes Goals Growth HIF1A gene Human In Vitro Invaded KPC model MUC4 mucin Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mesenchymal MicroRNAs Modeling Molecular Mus Nanodelivery Neoplasm Metastasis Normal Cell Organ Organoids Pancreatic Intraepithelial Neoplasia Pathogenesis Pathologic Pathway interactions Patients Perfusion Pharmaceutical Preparations Play Prognosis Property Reporting Resistance Role SHH gene Signal Transduction Signaling Molecule Site Survival Rate System Temperature Testing Therapeutic Therapeutic Agents Tissues Toxic effect Treatment Efficacy Up-Regulation Vascular Endothelium Work Xenograft procedure aldehyde dehydrogenase 1 angiogenesis beta catenin c-myc Genes cancer cell cancer stem cell cancer therapy cell motility chemotherapy clinical application cohort copolymer drug release kinetics drug sensitivity efficacious treatment epithelial to mesenchymal transition gemcitabine humanized mouse improved in vivo liposome vector lymph nodes microRNA delivery mouse model nanoscale nanotherapeutic novel novel therapeutics pancreatic cancer cells pancreatic cancer patients pancreatic neoplasm pancreatic stellate cell pre-clinical prognostic restoration self assembly side effect success symptomatic improvement synergism therapeutic evaluation therapeutic target therapy outcome therapy resistant tumor tumor growth tumor progression tumor xenograft

项目摘要

ABSTRACT Pancreatic cancer (PC) is lethal with a five-year survival rate of less than 9.2 % and a median survival of 5-6 months. The limited efficacy of mono-therapies has led to the exploration of combination therapies with limited success because of challenges associated with dose-limiting side effects, drug-associated toxicities, drug resistance, and poor pharmacokinetics. Importantly, these past approaches have not attempted the concurrent targeting of the pancreatic tumor and its stroma and PC stem cells. Our proposed work addresses these challenges by determining functional and clinic-pathological significance of miR-345 as well as developing a dual delivery nanoscale device (DDND) for combined delivery of miR-345 and GEM for the treatment of PC. Our preliminary studies have shown that miR-345 targets several important genes, including sonic hedgehog (Shh), Kras, MUC4 mucin and its downstream targets, genes-associated with cancer stem cells (ALDH1, ESA, Hif1α, and Oct/3/4), and causes up regulation of cleaved caspase-3, -7, and PARP. The Kras, Shh and MUC4-signaling play critical roles in tumor growth and metastasis by promoting epithelial to mesenchymal transition (EMT), PC stem cells, angiogenesis, desmoplasia, which limit the delivery and efficacy of chemotherapy. MiR-345 targeting Kras, Shh and MUC4, which makes miR-345 is an excellent candidate for diagnostic/prognostic and therapeutic targets in PC. We hypothesize that downregulation of miR-345 contributes to PC pathogenesis by upregulation of Kras, SHH, and MUC4; Its restoration, combination with GEM through the DDND, enhances GEM sensitivity in PC through modulation of SHH/Kras/MUC4 pathways, resulting in inhibition of desmoplasia, pancreatic stellate cells, and PC stem cells leading to an improved therapeutic outcome of GEM in PC through improving its tumor perfusion. The DDND is based on temperature and pH responsive pentablock copolymers electrostatically complexed with miR-345 and subsequently self-assembled with GEM encapsulated layers. The DDND design allows effective co-incorporation of miRNA/GEM combination; facilitates cellular entry; enhances stability compared to liposomal carriers; provides miRNA protection; allows targeting by selectively facilitating endosomal escape in cancer cells as opposed to normal cells by exploiting intracellular pH differences; and allows dose- sparing of the cytotoxic drugs. Aim 1 will focus to determine functional role and clinico-pathological significance of miR-345/Shh/Kras/MUC4 axis in highly aggressive and metastatic PC. Aim 2 will focus on the development of DDND loaded miR-345/GEM as a novel therapeutic agent against lethal PC by evaluating their therapeutic efficacy in vitro. In the final Aim 3, we will evaluate therapeutic efficacy of DDND loaded miR-345/GEM alone or in combination in mouse models. Altogether, the proposed work decipher the clinic-pathological significance of miR-345 and expected to significantly advance the goal of combining GEM and miR-345 delivery for treatment of PC patients, enhance understanding of the synergistic mechanisms involved, and will provide a novel DDND design for delivery of other therapeutics as well in the future.

抽象的胰腺癌 (PC) 具有致命性，五年生存率低于 9.2%，中位生存期为 5-6 单一疗法的有限疗效导致了对有限的联合疗法的探索。成功是因为与剂量限制副作用、药物相关毒性、药物相关的挑战相关重要的是，这些过去的方法没有尝试同时进行。我们提出的针对胰腺肿瘤及其间质和 PC 干细胞的工作解决了这些问题。通过确定 miR-345 的功能和临床病理意义以及开发双重挑战用于联合递送 miR-345 和 GEM 来治疗 PC 的纳米级递送装置 (DDND)。初步研究表明，miR-345靶向几个重要基因，包括音猬因子（Shh）、 Kras、MUC4 粘蛋白及其下游靶标、与癌症干细胞相关的基因（ALDH1、ESA、Hif1α、和 Oct/3/4），并导致 cleaved caspase-3、-7 和 PARP 的调节上调。通过促进上皮间质转化 (EMT)、PC 在肿瘤生长和转移中发挥关键作用干细胞、血管生成、结缔组织增生，这些限制了 MiR-345 靶向化疗的递送和疗效。 Kras、Shh 和 MUC4，这使得 miR-345 成为诊断/预后和治疗的优秀候选者我们发现 miR-345 的下调通过上调促进 PC 发病机制。 Kras、SHH 和 MUC4 的修复，通过 DDND 与 GEM 结合，增强 GEM 灵敏度在 PC 中，通过调节 SHH/Kras/MUC4 通路，抑制结缔组织增生、胰星状细胞细胞和 PC 干细胞通过改善 PC 的肿瘤来改善 GEM 的治疗效果 DDND 基于静电响应的温度和 pH 值五嵌段共聚物。与 miR-345 复合，随后与 GEM 封装层自组装。允许 miRNA/GEM 组合有效共掺入，促进细胞进入，增强稳定性；与脂质体载体相比；提供 miRNA 保护；允许通过选择性促进内体进行靶向；通过利用相反的细胞内 pH 差异，癌细胞与正常细胞一样逃逸，并允许剂量调节；目标 1 将重点确定功能作用和临床病理意义。 Aim 2将重点开发miR-345/Shh/Kras/MUC4轴在高侵袭性和转移性PC中的作用。 DDND 负载 miR-345/GEM 作为对抗致命性 PC 的新型治疗剂在最终目标 3 中，我们将评估单独或负载 miR-345/GEM 的 DDND 的治疗效果。总而言之，所提出的工作破译了小鼠模型的临床病理意义。 miR-345 有望显着推进 GEM 和 miR-345 联合递送治疗的目标 PC 患者的研究，增强对所涉及协同机制的理解，并将提供一种新的 DDND 设计用于将来提供其他疗法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Red Cabbage Juice-Mediated Gut Microbiota Modulation Improves Intestinal Epithelial Homeostasis and Ameliorates Colitis.

DOI：
10.3390/ijms25010539
发表时间：
2023-12-30
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Wilson, Emily Jean;Natesh, Nagabhishek Sirpu;Ghadermazi, Parsa;Pothuraju, Ramesh;Prajapati, Dipakkumar R.;Pandey, Sanjit;Kaifi, Jussuf T.;Dodam, John R.;Bryan, Jeffrey N.;Lorson, Christian L.;Watrelot, Aude A.;Foster, Jason M.;Mansell, Thomas J.;Chan, Siu Hung Joshua;Batra, Surinder K.;Subbiah, Jeyamkondan;Rachagani, Satyanarayana
通讯作者：
Rachagani, Satyanarayana

Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β.

DOI：
10.3390/cancers13133105
发表时间：
2021-06-22
期刊：
Cancers
影响因子：
5.2
作者：
Kaushal JB;Bhatia R;Kanchan RK;Raut P;Mallapragada S;Ly QP;Batra SK;Rachagani S
通讯作者：
Rachagani S

Gut microbiota: a non-target victim of pesticide-induced toxicity.

DOI：
10.1080/19490976.2023.2187578
发表时间：
2023-01
期刊：
Gut microbes
影响因子：
12.2
作者：
通讯作者：

Synthesis and Optimization of Next-Generation Low-Molecular-Weight Pentablock Copolymer Nanoadjuvants.

DOI：
10.3390/vaccines11101572
发表时间：
2023-10-09
期刊：
Vaccines
影响因子：
7.8
作者：
Siddoway AC;White BM;Narasimhan B;Mallapragada SK
通讯作者：
Mallapragada SK

Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers.

DOI：
10.3390/pharmaceutics13121987
发表时间：
2021-11-23
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Natesh NS;White BM;Bennett MMC;Uz M;Kalari Kandy RR;Batra SK;Mallapragada SK;Rachagani S
通讯作者：
Rachagani S