Biodegradable Polymer Nanodiscs as Novel Lipoprotein-Mimicking Nanocarriers for Anticancer Drug Delivery with High Stability and Long Circulation Time

非技术描述一种盘状飞碟，大概可以从遥远的银河系导航到地球，令人敬畏。在人体血液中导航也是一项不小的壮举。通过血液循环有效地将药物输送到深层疾病部位，是治疗癌症的最关键挑战之一。癌症是美国和全球第二大致死原因。尽管在开发各种纳米载体以帮助实现这一点上取得了重大进展，但与传统药物相比，有效的患者反应仍然有限。纳米载体的表现不那么出色，归因于它们在体内的糟糕传输。为了解决这一不足，该项目旨在开发一种新的纳米载体家族，称为聚合物纳米盘，它模仿人类血液中的高密度脂蛋白纳米颗粒(HDL)。高密度脂蛋白的新生形式是众所周知的脂质纳米盘，它能高效地将胆固醇从外周细胞输送回肝脏。有趣的是，盘状颗粒的性能优于球形颗粒，具有更长的血液循环半衰期和更高的细胞内化率。大多数正在开发的纳米载体是球形的，因为通过化学合成制备盘状纳米粒子在技术上具有挑战性。本项目将阐明生物相容嵌段共聚物的设计原理，这些嵌段共聚物与膜-支架蛋白(或膜-支架聚合物)自组装成定义明确的聚合物纳米盘，以携带肿瘤特异性靶向和药物释放部分。如果成功，它可能会在利用纳米技术进行癌症诊断和治疗方面带来另一项进步。这些设计理念可能会对其他相关领域产生广泛的影响，如基于纳米盘的免疫疗法，基于纳米盘的膜蛋白结构和功能研究，以及用于人类健康、清洁能源和环境应用的仿生二维材料的开发。通过综合教育和推广活动，这个项目将帮助激励研究生、本科生和K-12学生在材料科学、纳米工程和生物医学科学的跨学科领域寻求职业道路。技术描述纳米技术已被广泛预期有利于癌症的诊断和治疗。尽管纳米载体的开发取得了重大进展，但与传统药物相比，有效的患者反应仍然有限。显然，除了简单地控制纳米载体的大小外，在纳米载体设计方面还存在着知识差距。随着越来越多的证据表明，盘状颗粒的性能优于球形颗粒，具有更长的血液循环半衰期和更高的细胞摄取，类脂蛋白纳米盘代表了一类新的二维材料，具有巨大的药物输送潜力。将脂质纳米盘(LND)应用于抗癌药物输送已引起人们的广泛关注，但LND作为药物载体存在稳定性差、保存期短、载药量有限、化学修饰困难等问题。本项目的目的是阐明两亲嵌段与无规共聚物之间的自组装原理，从而形成具有良好的生物相容性和生物降解性、长期稳定性、高载药量和易于修饰的抗癌药物传递化学的新型类脂蛋白聚合物纳米盘(PND)。将开发合成策略来制备具有肿瘤特异性靶向和药物释放部分的两亲性嵌段共聚物，并将阐明模型嵌段共聚物与膜支架蛋白(MSPs)之间的自组装行为。从新设计的合成膜-支架聚合物(MSPol)可能克服生物来源MSPs的限制，也将被探索开发用于抗癌药物输送的全合成PND。PND有望在不影响其备受欢迎的大小和形状的情况下打破LND的限制，这种大小和形状有利于延长循环半衰期和增强细胞摄取，从而可能在利用纳米技术治疗癌症方面带来又一进展。除了抗癌药物的输送，这项研究还将填补在合理设计合成可生物降解MSPol方面的关键知识空白，在包裹纳米盘方面与MSP竞争。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，认为值得支持。

Non-technical descriptionA disc-shaped flying saucer that presumably navigates to Earth from a far away galaxy is awe-inspiring. Navigating through the human blood stream is no small feat either. To efficiently deliver drugs through blood circulation to reach deep-seated disease sites is one of the most critical challenges in treating cancer, the second largest cause of fatality in US and globally. Although significant strides have been made on developing various nanocarriers to help with that, efficacious patient responses remain modest compared to conventional drug formulations. The somewhat less stellar performance of nanocarriers is attributed to their poor transport inside the body. To address the deficiency, this project aims to develop a new family of nanocarrier called polymer nanodiscs that mimic the high-density lipoprotein nanoparticles (HDL) in human blood. The nascent form of HDL is well-known lipid nanodisc that mediates highly efficient cholesterol transport from peripheral cells back to the liver. Intriguingly, disc-shaped particles have been shown to outperform spherical ones with prolonged blood circulation half-lives and higher cellular internalization rates. Most nanocarriers under development are spherical in shape because it is technically challenging to prepare disc-shaped nanoparticles through chemical synthesis. This project will elucidate the design principles of biocompatible block copolymers that self-assemble with membrane-scaffold proteins (or membrane-scaffold polymers) into well-defined polymer nanodiscs to carry tumor-specific targeting and drug release moieties. If successful, it may bring forth another advance in harnessing nanotechnology for cancer diagnostics and treatment. The design concepts may have broad impact in other related fields, such as nanodisc-based immunotherapy, nanodisc-based structural and functional studies of membrane proteins, and the development of biomimetic 2-dimensional materials for applications in human health, clean energy, and environment. Through the integrated education and outreach activities, this project will help motivate graduate, undergraduate, and K-12 students to pursue career paths in the interdisciplinary area of materials science, nanoengineering, and biomedical science.Technical descriptionNanotechnology has been widely anticipated to benefit the diagnostic and treatment of cancers. Despite the significant strides in nanocarrier development, efficacious patient responses remain modest compared to conventional drug formulations. Clearly, a gap of knowledge exists on nanocarrier design beyond simply controlling their sizes. The lipoprotein-mimicking nanodiscs represent a novel family of 2-dimensional materials with great potential for drug delivery, as mounting evidence has suggested that disc-shaped particles outperform spherical ones with prolonged blood circulation half-lives and higher cellular uptake. Adapting lipid nanodiscs (LNDs) for anticancer drug delivery has attracted lots of attention, but as drug carriers LNDs suffer from low stability, short shelf life, limited drug loading capacity, and difficulty for chemical modifications. The objective of this project is to elucidate the self-assembly principle between amphiphilic block and random copolymers toward the formation of novel lipoprotein-mimicking polymer nanodiscs (PNDs) with excellent biocompatibility and biodegradability, long-term stability, high drug loading capacity, and facile modification chemistry for anticancer drug delivery. Synthetic strategies to prepare well-defined amphiphilic block copolymers that carry tumor-specific targeting and drug release moieties will be developed, and the self-assembly behavior between model block copolymers and membrane-scaffold proteins (MSPs) into PNDs will be elucidated. De novo designed synthetic membrane-scaffold polymers (MSPols) that potentially overcome the limitations of biologically-derived MSPs will also be explored to develop fully synthetic PNDs for anticancer drug delivery. PNDs are expected to break the limitations of LNDs without compromising their highly sought-after size and shape that favor prolonged circulation half-lives and enhanced cellular uptake, hence potentially bringing forth another advance in harnessing nanotechnology for cancer treatment. Besides anticancer drug delivery, this study will also fill a critical gap of knowledge on the rational design of synthetic biodegradable MSPols that rival MSPs in encasing nanodiscs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.