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

可生物降解的聚合物纳米盘作为新型脂蛋白模拟纳米载体，用于高稳定性和长循环时间的抗癌药物输送

• 批准号: 2213969
• 负责人: Hongjun Liang
• 金额: $ 47.57万
• 依托单位: Texas Tech University Health Science Center
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2213969&HistoricalAwards=false
• 关键词: Biodegradable; Polymer; Nanodiscs; Novel; Lipoprotein

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.

非技术描述是盘状飞碟，大概是从遥远的银河系到达地球的令人敬畏的。通过人类血流导航也不是很小的壮举。通过血液循环有效输送药物以达到深处疾病部位是治疗癌症的最关键挑战之一，癌症是美国和全球死亡的第二大原因。尽管在开发各种纳米载体方面取得了长足的进步，但与常规药物配方相比，有效的患者反应仍然适度。纳米载体的出色表现差异不大，这归因于它们在体内的运输不良。为了解决这种缺陷，该项目旨在开发一个新的纳米载体家族，称为聚合物纳米盘，以模仿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散发，可介导从外围细胞回到肝脏的高效胆固醇转运。有趣的是，椎间盘形颗粒的表现超过了球形循环延长的半衰期和较高的细胞内在化速率的球形颗粒。大多数正在开发的纳米载体的形状都是球形的，因为通过化学合成制备盘状纳米颗粒在技术上具有挑战性。该项目将阐明与膜型蛋白（或膜型组件聚合物）自组装的生物相容性块共聚物的设计原理中，以携带明确的聚合物纳米盘，以携带肿瘤特异性靶向靶向和药物释放。如果成功，它可能会带来另一个进步来利用纳米技术进行癌症诊断和治疗。该设计概念可能在其他相关领域具有广泛的影响，例如基于纳米轴的免疫疗法，基于纳米轴的膜蛋白的结构和功能研究，以及用于在人类健康，清洁能源和环境中应用的仿生二维材料的开发。通过综合教育和外展活动，该项目将帮助激励研究生，本科和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的职业道路上追求职业道路。技术描述纳米技术已被广泛期待，可以使罐头诊断和治疗受益。尽管纳米载体的发育取得了显着的进步，但与常规药物配方相比，有效的患者反应仍然适度。显然，纳米载体设计的知识差距不仅仅是控制其大小。模仿脂蛋白的纳米盘代表了一个新型的二维材料家族，具有巨大的药物输送潜力，因为越来越多的证据表明，盘状颗粒的表现要优于延长血液循环半衰期和较高细胞摄取的球形颗粒。适应抗癌药物输送的脂质纳米盘（LNDS）引起了很多关注，但是随着药物载体LND的稳定性低，保质期短，药物载荷能力有限以及化学修改的难度。该项目的目的是阐明两亲性块与随机共聚物之间的自组装原理，以形成新型的脂蛋白模仿聚合物纳米偶像（PNDS），具有出色的生物相容性和生物降解性，长期稳定性，长期稳定性，高药物载荷能力，高药物载荷能力以及易于抗生素药物的化学。将开发出携带肿瘤特异性靶向和药物释放部分的合成策略，以制备定义明确的两亲性块共聚物，并将阐明模型阻滞共聚物和膜 - 损伤蛋白（MSP）之间的自组装行为。从头设计的合成膜 - 胶质组件聚合物（MSPOLS）也将探索潜在的生物学衍生MSP的局限性，以开发用于抗癌药物递送的完全合成PND。预计PND会破坏LND的局限性，而不会损害其高度渴望的大小和形状，从而有利于长时间的循环半衰期和增强的细胞摄取，从而有可能在利用纳米技术来治疗癌症治疗方面再进一步前进。除了抗癌药物输送外，这项研究还将填补有关合成生物降解的MSPOL的合理设计的关键知识差距，这些知识可与MSP媲美，这些MSPOL与MSP相媲美。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识和更广泛的影响来评估的支持，并被认为是值得通过评估的支持。

项目成果

SMALPs Are Not Simply Nanodiscs: The Polymer-to-Lipid Ratios of Fractionated SMALPs Underline Their Heterogeneous Nature

• DOI: 10.1021/acs.biomac.3c00034
• 发表时间: 2023-03-22
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Kamilar，Elizabeth;Bariwal，Jitender;Liang，Hongjun
• 通讯作者: Liang，Hongjun