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: 10465072
• 负责人: Sanku Mallik
• 金额: $ 31.1万
• 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/10465072
• 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; 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; amphiphilicity; attenuation; base; cancer cell; cancer stem cell; chemotherapy; copolymer; epithelial to mesenchymal transition; extracellular; fundamental research; human disease; hydrophilicity; imaging agent; inhibitor; innovation; interstitial; lung injury; mouse model; nanoparticle; patient derived xenograft model; pressure; process optimization; side effect; stemness; triple-negative invasive breast carcinoma; tumor; tumor hypoxia; ultrasound

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.

项目概要 聚合物囊泡是由两亲性嵌段共聚物制备的双层囊泡。虽然他们有 与其他纳米粒子相比有许多优点（例如更长的循环时间、更高的稳定性、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 代理仍然不发达。在上一个奖项（1R01 GM114080）期间，我们开发了聚合物囊泡 用于谷胱甘肽触发的内容物释放。我们通过独特的制备方法使聚合物囊泡具有回声效果 将气泡封装在系统中的协议，使我们能够通过诊断超声波对它们进行成像 扫描器。通过缀合适当的配体，我们将聚合物囊泡靶向癌细胞和细胞内 细胞核或线粒体等细胞器在培养球体中的渗透深度至少为 200 µm。 他们还展示了线性和非线性超声信号的 50 dB 和 25 dB 增强以及足够的 稳定。上一届奖项产生了 25 篇同行评审出版物、两本书章节、一项专利和 5 项专利。 获得博士学位的学生程度。 在更新应用中，我们将制备有针对性的、深层组织穿透的回声聚合物囊泡 对不同程度的缺氧（2-10% 氧气）做出反应，以进行药物输送和并发超声成像。 许多病理状况都会出现缺氧，包括实体瘤、肺动脉高压、缺血、 高原反应、脑损伤、中风等。实体瘤中的缺氧会引发细胞外基质的重塑， 上皮-间质转化、细胞存活、转移、癌症干细胞的形成，以及 对化疗和放疗有显着的抵抗力。缺氧进一步促进富含胶原蛋白的发育， 纤维细胞外基质（结缔组织增生），增加间质压力并限制扩散和 药物的运输。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。我们将对缺氧引发的内容物释放、回声、 超声衰减和散射，以及传递抗癌药物的细胞后果 实体瘤缺氧区域的干细胞抑制剂。 我们将针对三个具体目标开展拟议的研究。 (1)合成缺氧反应性 聚合物，制备组织穿透聚合物囊泡并对触发内容进行机理研究 发布。 (2) 制备回声缺氧响应聚合物囊泡，表征回声性，研究其回声 机制，并优化成像以阐明超声波诱导的内容释放。 (3) 展示 使用细胞和小鼠模型研究缺氧反应性回声聚合物囊泡的功能功效 缺氧生态位。我们的方法具有创新性，原因如下。它建议（i）聚合物囊泡的递送 深入实体瘤，包括缺氧环境，克服残留的促纤维增生屏障 由于扩散限制而导致的界限，（ii）缺氧反应性药物释放，这将在许多其他方面有用 疾病，(iii) 递送转录抑制剂，它可以到达并杀死肿瘤深处的癌症干细胞， 最后（iv）回声聚合物囊泡的双重功能，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 发生缺氧介导的恶化，包括多发性实体瘤、肺动脉高压、缺血、 高山病、脑、肾和肺损伤，尤其是移植后。