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

一个圆盘状的飞碟，大概是从一个遥远的星系导航到地球，这是令人敬畏的。在人体血液中导航也不是一件容易的事。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方面取得了重大进展，但与传统药物制剂相比，有效的患者反应仍然温和。纳米载体的性能稍逊一筹，这是因为它们在体内的运输能力很差。为了解决这一缺陷，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，模拟人体血液中的高密度脂蛋白纳米颗粒（HDL）。HDL的新生形式是众所周知的脂质纳米盘，其介导胆固醇从外周细胞高效转运回肝脏。有趣的是，圆盘形颗粒已经被证明比球形颗粒更好，具有延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都是球形的，因为通过化学合成制备盘形纳米颗粒在技术上具有挑战性。该项目将阐明生物相容性嵌段共聚物的设计原理，该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。如果成功的话，它可能会带来利用纳米技术进行癌症诊断和治疗的另一个进步。这些设计概念可能在其他相关领域产生广泛的影响，例如基于纳米盘的免疫治疗，基于纳米盘的膜蛋白的结构和功能研究，以及仿生二维材料在人类健康，清洁能源和环境中的应用。通过综合教育和外展活动，该项目将有助于激励研究生、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。技术描述纳米技术被广泛预期将有利于诊断和治疗癌症。尽管在纳米载体开发方面取得了重大进展，但与常规药物制剂相比，有效的患者反应仍然适度。显然，除了简单地控制它们的尺寸之外，纳米载体设计存在知识空白。模拟脂蛋白的纳米盘代表了一种具有巨大药物递送潜力的新型二维材料家族，因为越来越多的证据表明，盘形颗粒优于球形颗粒，具有延长的血液循环半衰期和更高的细胞摄取。将脂质纳米盘（LND）用于抗癌药物递送已经引起了很多关注，但是LND作为药物载体具有稳定性低、保质期短、载药量有限以及化学修饰困难的缺点。本项目的目的是阐明两亲性嵌段和无规共聚物之间的自组装原理，以形成新型的脂蛋白模拟聚合物纳米盘（PND），该纳米盘具有优异的生物相容性和生物降解性，长期稳定性，高载药能力，以及用于抗癌药物递送的简易修饰化学。合成策略，以制备定义明确的两亲性嵌段共聚物，携带肿瘤特异性靶向和药物释放部分将被开发，模型嵌段共聚物和膜支架蛋白（MSP）到PND之间的自组装行为将被阐明。从头设计的合成膜支架聚合物（MSPols），有可能克服生物衍生MSP的局限性，也将探索开发用于抗癌药物递送的全合成PND。PND有望打破LND的局限性，而不会影响其备受追捧的尺寸和形状，有利于延长循环半衰期和增强细胞摄取，因此可能会在利用纳米技术治疗癌症方面带来另一个进步。除了抗癌药物输送，这项研究还将填补一个关键的知识空白的合理设计的合成可生物降解的MSPols的竞争对手MSP在封装nanodisces.This奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

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.