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.

项目总结 聚合体是由两亲嵌段共聚物制备的双层囊泡。尽管他们有 与其他纳米粒子相比有许多优点(如循环时间更长，稳定性更高，能够 携带亲水性和疏水性药物)，它们作为细胞毒性药物和成像载体的应用 代理商仍然不发达。在前一个奖项(1R01 GM114080)期间，我们开发了聚合体 用于谷胱甘肽触发的内容物释放。我们通过一种独特的制备方法使聚合体产生回声 将气泡封装在系统中的协议，允许我们通过诊断超声对它们进行成像 扫描仪。通过结合适当的配体，我们将聚合体靶向癌细胞和细胞内。 细胞器，如细胞核或线粒体，在培养的球体中达到至少200m的穿透。 在线性和非线性超声信号中，它们也表现出50分贝和25分贝的增强，并且足够 稳定性。之前的奖项产生了25本同行评议的出版物，两本书的章节，一项专利和5项 博士毕业的学生。 在更新应用中，我们将制备靶向的、深层组织穿透的回声多聚体。 对不同程度的缺氧(2-10%氧气)作出反应以进行药物输送和同时进行超声成像。 缺氧在许多病理条件下发生，包括实体瘤，肺高压，缺血， 高原反应、脑损伤、中风等。实体瘤中的缺氧会触发细胞外基质的重塑， 上皮向间充质转化，细胞存活，转移，肿瘤干细胞的形成，以及 对化疗和放射治疗有显著的抗药性。低氧进一步促进富胶原蛋白的发育， 纤维性细胞外间质(结缔组织增生症)，增加间质压力，限制扩散和 毒品的运输。在这个应用中，我们将使用三阴性乳腺癌作为低氧的替代品 实体瘤。我们将对低氧触发的内容释放、回声、 超声波衰减和散射，以及将抗癌药物与 实体瘤缺氧区的一种茎抑制物。 我们会以三个具体目标进行建议的研究。(1)合成对低氧有反应的 聚合物，制备组织穿透多聚体，并对触发内容物进行机理研究 放手。(2)制备低氧响应性回声多聚体，对其回声特性进行研究。 机制，并优化成像以阐明超声诱导的内容物释放。(3)展示 低氧反应的回声多聚体在细胞和小鼠模型中的功能效应 低氧的利基市场。我们的方法是创新的，原因如下。它建议：(I)多聚体的传递 深入实体瘤，包括缺氧的壁龛，克服了结缔组织生长的屏障，这些屏障仍然留在外面 由于扩散限制的界限，(Ii)低氧反应药物释放，这将在许多其他 疾病，(Iii)转录抑制物的传递，它可以到达并杀死肿瘤深处的癌症干细胞， 最后(Iv)回声多聚体的双重功能，允许超声成像和超声- 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情况 发生缺氧介导的恶化，包括多发性实体瘤，肺高压，缺血， 高原反应、脑、肾和肺损伤，尤其是移植后。