Nanoparticle-mediated peptide delivery for breast cancer

描述(申请人提供)：许多形式的癌症，包括乳腺癌，都依赖于血管生成和血管的生长。医学上迫切需要开发一种安全、有效、廉价的抗血管生成治疗方法。一种有希望的方法是使用抗血管生成多肽作为活性物质。在我们的初步研究中，我们已经确定了从几类蛋白质中提取的新多肽，这些多肽可以有效地防止血管生成。我们还发现了其他能够通过其他机制抑制癌症的多肽，包括抗淋巴管生成和细胞凋亡。然而，以它们目前的形式，所有这些多肽在体内的半衰期都很短，不适合全身给药或长期作用。因此，需要以更稳定、更持久的方式包装、保护和传递这些多肽。我们寻求创造新的技术来应对这一挑战，并假设以工程方式提供的这些肽的组合可以协同杀死乳腺癌。根据我们在药物输送纳米颗粒方面的经验，我们将设计一系列安全的、可生物降解的有效聚合物，用于形成含肽纳米颗粒(目标1)。这些生物材料将被用来构建不同生物物理特性和生物学特性的纳米颗粒，包括肿瘤积累和多肽释放。高通量合成和筛选方法将用于筛选新的纳米颗粒配方，包括高效抑制人内皮细胞增殖和迁移、抑制淋巴管内皮细胞增殖和迁移以及促进乳腺癌细胞凋亡的抗血管生成多肽纳米颗粒。我们的初步工作表明，这些方法是可行的，我们可以合成出性能优于游离未包膜多肽的新的纳米生物技术。在目标2中，从目标1的体外筛选中筛选出的含有铅抗癌肽的铅纳米颗粒随后将在体内使用。植入小鼠皮下的血管生成生物反应器将被用来监测纳米颗粒对抗血管生成多肽的输送。性能最好的抗血管生成配方将与其他铅抗癌多肽结合，并在乳腺癌小鼠模型中进行测试。我们的目标是创造新的生物纳米技术，可以安全、有效和相对廉价地治疗乳腺癌。 公共卫生相关性：这项研究旨在创造新的生物纳米技术，使新的抗血管生成、抗淋巴管生成和促凋亡多肽能够有效地传递。这里提出的纳米颗粒可以促进这些多肽的输送，从而系统地治疗乳腺癌。

DESCRIPTION (provided by applicant): Many forms of cancer, including breast cancer, are dependent on angiogenesis, the growth of blood vessels. There is a great medical need for the development of a safe, effective, and inexpensive means of antiangiogenic therapy. One promising approach is the use of antiangiogenic peptides as the active agents. We have identified novel peptides derived from several classes of proteins that are effective at preventing angiogenesis in our preliminary studies. We have also identified other peptides able to inhibit cancer through additional mechanisms including antilymphangiogenesis and apoptosis. However, in their current form, all of these peptides have a short in vivo half-life and they are not suitable for systemic administration or for long-term action. Thus, there is a need to package, protect, and deliver these peptides in a more stable, sustained fashion. We seek to create new technology to meet this challenge and hypothesize that combinations of these peptides delivered in an engineered fashion could enable synergistic killing of breast cancer. Building on our experience with drug delivery nanoparticles, we will design an effective array of safe, biodegradable polymers for use in forming peptide-containing nanoparticles (Aim 1). These biomaterials will be used to construct nanoparticles that vary in their biophysical properties and in biological properties including tumor accumulation and peptide release. High-throughput synthesis and screening methodology will be used to select for novel nanoparticle formulations, including antiangiogenic peptide nanoparticles, highly efficient for inhibition of human endothelial cell proliferation and migration, inhibition lymphatic endothelial cell proliferation and migration, and promotion of breast cancer apoptosis. Our preliminary work shows these methods are practical and that we can synthesize new nanobiotechnology that performs superiorly to free unencapsulated peptide. In Aim 2, lead nanoparticles containing lead anti-cancer peptides from the in vitro screens in Aim 1 will then be utilized in vivo. Angiogenesis bioreactors implanted subcutaneously in mice will be used to monitor delivery of antiangiogenic peptides by the nanoparticles. The top-performing antiangiogenic formulation will be combined with other lead anti-cancer peptides and tested in a breast cancer mouse model. We aim to create new bionanotechnology that can safely, effectively, and relatively inexpensively treat breast cancer. PUBLIC HEALTH RELEVANCE: This research aims to create new bionanotechnologies that enable the efficient delivery of novel antiangiogenic, antilymphangiogenic, and pro-apoptotic peptides. The nanoparticles proposed here can facilitate the delivery of these peptides to systemically treat breast cancer.