Echogenic polymersomes for triggered contents release

用于触发内容物释放的回声聚合物囊泡

• 批准号: 9974063
• 负责人: Sanku Mallik
• 金额: $ 33.02万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-05 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974063
• 关键词: 3-Dimensional; Air; Altitude; Altitude Sickness; Antineoplastic Agents; Award; Blood Circulation; Book Chapters; Brain Injuries; Breast Cancer Cell; Cell Nucleus; Cell Survival; Cell model; Characteristics; Chemical Structure; Collagen; Cytotoxic agent; Desmoplastic; Development; Diagnostic; Diffusion; Disease; Doctor of Philosophy; Doxorubicin; Drug Controls; Drug Delivery Systems; Drug Transport; Effectiveness; Encapsulated; Exhibits; Extracellular Matrix; Frequencies; Genetic Transcription; Glutathione; Hydrophobicity; Hypoxia; Image; Injury to Kidney; Ischemia; Knowledge; Legal patent; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Mission; Mitochondria; Mus; Neoplasm Metastasis; Organelles; Outcome; Oxygen; Pathologic; Patients; Peer Review; Penetration; Peptides; Pharmaceutical Preparations; Polymers; Preparation; Protocols documentation; Public Health; Publications; Pulmonary Hypertension; Radiation therapy; Recurrent disease; Research; Resistance; Signal Transduction; Solid Neoplasm; Stroke; Structure; Students; System; Time; Tissues; Transplantation; Treatment Efficacy; Ultrasonography; United States National Institutes of Health; Vesicle; Xenograft procedure; amphiphilicity; attenuation; base; cancer cell; cancer stem cell; chemotherapy; copolymer; epithelial to mesenchymal transition; extracellular; fundamental research; human disease; hydrophilicity; imaging agent; inhibitor/antagonist; innovation; interstitial; lung injury; mouse model; nanoparticle; pressure; process optimization; side effect; stemness; triple-negative invasive breast carcinoma; tumor; tumor hypoxia

PROJECT SUMMARY Polymersomes are bilayer vesicles prepared from amphiphilic block copolymers. Although they have many advantages compared to other nanoparticles (such as longer circulation time, higher stability, ability to carry both hydrophilic and hydrophobic drugs), their applications as carriers for cytotoxic drugs and imaging agents remain under-developed. During the previous award (1R01 GM114080), we developed polymersomes for glutathione-triggered contents release. We rendered the polymersomes echogenic by a unique preparation protocol that encapsulated air bubbles in the system, allowing us to image them by a diagnostic ultrasound scanner. By conjugating appropriate ligands, we targeted the polymersomes to cancer cells and intracellular organelles such as the nucleus or mitochondria attaining their penetration at least 200 m in cultured spheroids. They also exhibited 50 dB and 25 dB enhancement in linear and nonlinear ultrasound signals and adequate stability. The previous award resulted in 25 peer-reviewed publications, two book chapters, one patent, and 5 students graduating with Ph.D. degree. In the renewal application, we will prepare targeted, deep-tissue-penetrating echogenic polymersomes responsive to varying degrees of hypoxia (2–10% oxygen) for drug delivery and concurrent ultrasound imaging. Hypoxia develops in many pathological conditions, including solid tumors, pulmonary hypertension, ischemia, altitude sickness, brain injury, stroke, etc. Hypoxia in solid tumors triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, cell survival, metastasis, the formation of the cancer stem cells, and significant resistance to chemo- and radiotherapy. Hypoxia further promotes the development of collagen-rich, fibrous extracellular stroma (desmoplasia), which increases the interstitial pressure and limits the diffusion and transport of the drugs. In this application, we will use triple-negative breast cancer as a surrogate for hypoxic solid tumors. We will conduct mechanistic studies on hypoxia-triggered contents release, echogenicity, ultrasound attenuation and scattering, and the cellular consequences of delivering an anticancer drug along with a stemness inhibitor in the hypoxic regions of solid tumors. We will conduct the proposed studies with three Specific Aims. (1) Synthesize hypoxia-responsive polymers, prepare tissue-penetrating polymersomes and perform mechanistic studies on triggered contents release. (2) Prepare echogenic hypoxia-responsive polymersomes, characterize echogenicity, investigate its mechanism, and optimize imaging to elucidate ultrasound induced content release. (3) Demonstrate the functional efficacy of the hypoxia-responsive echogenic polymersomes using cellular and mouse models of hypoxic niches. Our approach is innovative for the following reasons. It proposes (i) delivery of polymersomes deep into the solid tumors, including hypoxic niches, overcoming the desmoplastic barrier, which remained out of bounds due to diffusional limitations, (ii) hypoxia responsive drug release, which would be useful in many other diseases, (iii) delivery of transcription inhibitor, that can reach and kill cancer stem cells deep inside the tumors, and finally (iv) dual functionality of echogenic polymersomes allowing ultrasound imaging and ultrasound- induced release. The knowledge gained from our studies has the potential also to target other disease conditions where hypoxia-mediated worsening occur, including multiple solid tumors, pulmonary hypertension, ischemia, high-altitude mountain sickness, brain, kidney, and lung injury, especially following transplantation.

项目摘要 聚合物体是由两亲质块共聚物制备的双层蔬菜。虽然他们有 与其他纳米颗粒相比，许多优点（例如较长的循环时间，更高的稳定性，能力 同时携带亲水性和疏水性药物），它们用作细胞毒性药物和成像的载体 代理商仍然不发达。在上一个奖项（1R01 GM114080）期间，我们开发了聚合物组 用于谷胱甘肽触发的内容释放。我们通过独特的制剂使聚合物组成 将气泡封装在系统中的协议，使我们能够通过诊断超声对其进行成像 扫描器。通过结合适当的配体，我们将聚合物组靶向癌细胞和细胞内 细胞核或线粒体等细胞器在培养的球体中至少具有200米的渗透。 他们还在线性和非线性超声信号中暴露了50 dB和25 dB的增强 稳定。以前的奖项获得了25个同行评审的出版物，两个书籍章节，一份专利和5本。 学生毕业于博士学位程度。 在续订应用中，我们将准备有针对性的，深层组织 - 渗透性的回声聚合物组 对不同程度的缺氧（2-10％氧）的反应，用于药物输送和同时进行超声影像。 缺氧在许多病理状况中发展，包括实体瘤，肺动脉高压，缺血， 高原病，脑损伤，中风等。实体瘤的缺氧触发细胞外基质的重塑， 上皮到间质转变，细胞存活，转移，癌症干细胞的形成和 对化学和放射疗法的显着抗药性。缺氧进一步促进胶原蛋白丰富的发展， 纤维细胞外基质（脱木质），这增加了间质压力并限制了扩散和限制 毒品的运输。在此应用中，我们将使用三阴性乳腺癌作为缺氧的替代物 实体瘤。我们将对缺氧触发的内容释放，回声性， 超声衰减和散射，以及递送抗癌药物的细胞后果以及 实体瘤缺氧区域中的干性抑制剂。 我们将以三个特定目标进行拟议的研究。 （1）合成缺氧反应性 聚合物，制备组织渗透聚合物组并对触发内容进行机械研究 发布。 （2）准备回声缺氧响应性聚合物组，表征回声，研究其 机理，并优化成像以阐明超声诱导的含量释放。 （3）演示 使用细胞和小鼠模型的低氧反应回声聚合物的功能效率 低氧壁ni。由于以下原因，我们的方法具有创新性。 IT建议（i）聚合物的传递 深入实体瘤，包括低氧壁ches，克服了脱与肿瘤屏障 由于扩散率的限制而引起的界限，（ii）缺氧反应性药物释放，这在许多其他方面都是有用的 （iii）转录抑制剂的疾病，可以到达并杀死肿瘤深处的癌症干细胞， 最后（iv）回声聚合物组的双重功能允许超声成像和超声检查 诱导释放。从我们的研究中获得的知识也有可能针对其他疾病状况 在缺氧介导的担心会发生的情况下，包括多种实体瘤，肺动脉高压，缺血， 高海拔山脉疾病，大脑，肾脏和肺部受伤，尤其是在移植后。