Suppressing Radiotherapy-Induced Metastasis in Aggressive Breast Cancers via 'On-Demand' siRNA Delivery from Responsive Polymer Nanoparticles

通过响应性聚合物纳米颗粒的“按需”siRNA 传递抑制放射治疗引起的侵袭性乳腺癌转移

• 批准号: 9754479
• 负责人: Millicent O Sullivan
• 金额: $ 19.71万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754479
• 关键词: Address; Antidotes; Behavior; Breast Cancer Cell; Breast Cancer Treatment; Breast cancer metastasis; Caliber; Cancer Biology; Cells; Charge; Chemicals; Chemotactic Factors; Cleaved cell; Clinical; Cutaneous; Dermal; Dermis; Diffuse; Disease; Disseminated Malignant Neoplasm; Dose; Embolism; Encapsulated; Environment; Ethanol; Exhibits; Family suidae; Fibroblasts; Formulation; Fostering; Gamma Rays; Gene Expression; Gene Expression Regulation; Gene Silencing; Growth; Human; In Vitro; Kinetics; Letters; Light; Lipids; Literature; Liver; Lymphatic; Lymphovascular; Malignant Neoplasms; Metastatic Skin Cancer; Modification; Neoplasm Metastasis; Organ; Outcome; Patients; Penetration; Peptides; Permeability; Phenotype; Polymers; Property; Quality of life; Radiation; Radiation induced damage; Radiation therapy; Recipe; Regimen; Scheme; Series; Serum; Side; Signal Transduction; Skin; Small Interfering RNA; Stimulus; Sunlight; Technology; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Work; Xenograft Model; aqueous; base; cell behavior; cell motility; cohesion; cytokine; design; epithelial to mesenchymal transition; extreme temperature; in vivo; inflammatory breast cancer; irradiation; lung small cell carcinoma; malignant breast neoplasm; melanoma; mouse model; nanocarrier; nanoparticle; nucleic acid delivery; particle; pathogen; pre-clinical; radiation effect; response; side effect; skin disorder; spatiotemporal; standard of care; technology development; therapeutic target; tumor

PROJECT SUMMARY. Skin is the most susceptible organ to radiation damage. For example, γ-radiation, commonly used in radiotherapies, induces stromal expression of cytokines such as TGFβ, a powerful chemoattractant that can stimulate skin metastasis. Unfortunately, the inability to treat radiation-induced phenotypic changes has made cutaneous metastasis a deadly phenomenon that is correlated with extremely poor quality of life in inflammatory breast cancer (IBC) and other lethal diseases. We seek to develop topical siRNA delivery agents that can penetrate skin and normalize radiation-triggered maladaptive signaling by releasing siRNA ‘antidotes’ when radiation is applied. These nanocarriers would represent a powerful platform technology with broad relevance in a wide array of skin-based radiation disorders. siRNA offers enormous potential as a therapeutic, yet its delivery to organs other than the liver poses a technological challenge. We propose to address this issue in skin by fusing two nascent delivery schemes with cutting-edge and complementary properties: (i) peptide and solution modifications that facilitate nanocarrier transit into dermal stroma; and (ii) stimulus-responsive polymers [mPEG-P(APNBMA)], designed in our labs, that encapsulate siRNA into nanocarriers with highly tunable properties and a versatile chemical transition that we previously explored using light. Light triggers cleavage of o-nitrobenzyl (o-NB) moieties in the P(APNBMA) side chains, leading to polymer charge reversal and stimulus-responsive gene silencing. We have compelling new evidence that the o-NB bonds in mPEG-P(APNBMA) also cleave in response to mild γ-radiation. Herein, we will exploit this surprising cleavage phenomenon in skin, to determine whether topical mPEG- P(APNBMA) nanocarriers release siRNA in response to γ-radiation and thereby halt IBC skin metastasis. Aim 1 will develop topical formulations of siRNA nanocarriers with both of the desired properties: transcutaneous penetration into dermis, and γ-radiation-triggered siRNA release in skin fibroblasts. It also will provide quantitative information regarding siRNA nanocarrier distribution and radiation-triggered gene silencing kinetics in skin. Aim 2 will evaluate two governing hypotheses in IBC metastasis: (i) Radiation-induced TGFβ activation in skin fibroblasts triggers the epithelial-to-mesenchymal (EMT) transition in lymphatic IBC emboli, leading to IBC invasion and growth in skin; and (ii) On-demand suppression of TGFβ, using radiation-triggered siRNA delivery, provides a potent and proportional strategy to eliminate cutaneous IBC dissemination. This aim will provide new fundamental information regarding radiation side effects and IBC dissemination, and it will establish preclinical siRNA dose regimens that will suppress radiation-induced metastasis in stroma. Our team combines synergistic expertise in nucleic acid delivery (Sullivan), polymer materials (Epps), metastatic cancer biology (van Golen), and breast cancer treatment (clinical consultant Cristofanilli). In the long-term, our work will foster new additive therapy platforms relevant to a spectrum of radiation-induced skin diseases

项目摘要。皮肤是最容易受到辐射损伤的器官。例如，γ辐射， 通常用于放射治疗，诱导细胞因子如TGFβ的基质表达，这是一种强大的细胞因子。 可以刺激皮肤转移的化学引诱物。不幸的是，无法治疗辐射引起的 表型变化使得皮肤转移成为一种致命的现象， 炎症性乳腺癌（IBC）和其他致命疾病的生活质量差。我们致力于开发 可穿透皮肤并使辐射触发的适应不良信号正常化的siRNA递送剂 通过释放siRNA的“解毒剂”。这些纳米载体将代表一种强大的 该平台技术在广泛的基于皮肤的放射性疾病中具有广泛的相关性。 siRNA作为一种治疗方法提供了巨大的潜力，但它对肝脏以外的器官的递送造成了严重的影响。 技术挑战。我们建议通过融合两种新生的递送方案来解决皮肤中的这个问题， 尖端和互补性质：（i）肽和溶液修饰，促进纳米载体 运输到真皮基质;和（ii）刺激响应聚合物[mPEG-P（APNBMA）]，在我们的实验室设计， 它将siRNA封装到纳米载体中，具有高度可调的特性和多功能的化学转变， 我们以前用光探索过。光引发P（APNBMA）中邻硝基苄基（o-NB）部分的裂解 侧链，导致聚合物电荷逆转和刺激响应基因沉默。我们有令人信服 新的证据表明mPEG-P（APNBMA）中的o-NB键也会在轻度γ辐射下裂解。 在本文中，我们将利用皮肤中的这种令人惊讶的裂解现象，以确定局部mPEG- P（APNBMA）纳米载体响应于γ-辐射释放siRNA，从而阻止IBC皮肤转移。 目标1将开发具有两种所需性质的siRNA纳米载体的局部制剂： 经皮渗透到真皮中，以及γ-辐射触发的siRNA在皮肤成纤维细胞中的释放。它还将 提供关于siRNA纳米载体分布和辐射触发的基因沉默的定量信息 皮肤动力学目的2将评估IBC转移的两个主导假设：（i）辐射诱导的TGFβ 皮肤成纤维细胞中的活化触发淋巴IBC栓塞中的上皮-间充质（EMT）转变， 导致皮肤中的IBC侵入和生长;和（ii）使用辐射触发的 SiRNA递送提供了一种有效且成比例的策略来消除皮肤IBC传播。这一目标 将提供有关辐射副作用和IBC传播的新的基本信息， 建立临床前siRNA剂量方案，其将抑制间质中辐射诱导的转移。我们的团队 结合了核酸输送（Sullivan）、聚合物材料（Epps）、转移性癌症 生物学（货车Golen）和乳腺癌治疗（临床顾问Cristofanilli）。从长远来看，我们的工作 将培育与辐射诱发皮肤病相关的新的添加剂治疗平台