A fortified lipid bilayer platform for improved drug packaging and therapeutic delivery

用于改进药物包装和治疗递送的强化脂质双层平台

• 批准号: 10654034
• 负责人: Jianqin Lu
• 金额: $ 37.62万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654034
• 关键词: Adsorption; Adverse effects; Affect; Alzheimer' s Disease; Blood; Breast Cancer Model; Charge; Chemistry; Cholesterol; Circulation; Clinic; Disease; Drug Delivery Systems; Drug Kinetics; Drug Packaging; Endocytosis; Endocytosis Induction; Environment; Extracellular Matrix; Extravasation; Future; Gene Delivery; Goals; Infiltration; Intelligence; Intercellular Fluid; Lipid Bilayers; Liposomes; Liquid substance; Lymphoma; Mediating; Membrane; Membrane Fluidity; Membrane Lipids; Pancreas; Penetration; Permeability; Pharmaceutical Preparations; Phospholipids; Physiological; Play; Property; Pulmonary Inflammation; Research; Resistance; Role; Serum Proteins; Site; Sterols; Stimulus; Structure-Activity Relationship; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Treatment Efficacy; Vision; biomaterial compatibility; clinical translation; design; fortification; human disease; improved; nanotherapeutic; premature; pressure; prevent; programs; systemic toxicity; therapy outcome; transcytosis; translational applications; triple-negative invasive breast carcinoma; uptake

Liposome, composed of a lipid bilayer comprising phospholipids (PL) and sterols such as cholesterol (Chol), has been extensively used for packaging and delivery of therapeutic agents due to its intrinsic biocompatibility and biodegradability. While most approved liposomal nanotherapeutics can improve pharmacokinetics (PK) and reduce systemic toxicities, improvements in therapeutic efficacy and overall survival are disappointing, underscoring the urgent need for enhanced therapeutic delivery. Chol plays a critical role in fortifying membrane packing and reducing bilayer fluidity and permeability by promoting the liquid condensed state in lipid membranes, enhancing bilayer rigidity and strength. Lipid bilayers with high levels of Chol are generally more stable than those without or with less Chol. However, under the physiological environment, Chol is rapidly extracted from the bilayer by biomembranes and serum proteins, which jeopardizes bilayer stability and results in premature content leakage, fast blood clearance and unwanted adverse effects, leading to suboptimal clinic efficacy. In addition, although enhanced permeability and retention effect allows nanotherapeutic accumulation to the periphery of diseased tissues, intracellular internalization and tissue penetration remain inefficient due to the tenacious resistance imposed by high interstitial fluid pressure and dense extracellular matrix, compromising the therapeutic outcome. These phenomena present formidable barriers for lipid bilayer-based therapeutic delivery. To tackle these key challenges, the overall vision of my research program is to establish a stabilized lipid bilayer with improved physicochemical properties that can further improve drug delivery and selectively fortify intracellular uptake and infiltration at target sites. We have established a Chol-derived PL via covalently attaching Chol to a PL with varied stimuli-responsive linkages. Via systemic structure activity relationship studies, we demonstrated that Chol-derived PL blocked Chol transfer, prevented payload leakage, prolonged circulation time, and augmented efficacy in treating lung inflammation, Alzheimer’s disease, lymphoma, pancreatic and triple negative breast cancer models, which were linker chemistry dependent. For the next five years, the goals of this proposal are to 1) unravel the underlying mechanisms and principles on how the structural alterations of a sterol-modified PL bilayer that forms liposome but cannot shuttle between biomembranes will affect drug and gene delivery via substituting Chol with other membrane sterols; and 2) establish a universal ultra pH-sensitive charge-reversal delivery platform to boost the cellular uptake and tissue penetration efficiency via incorporating an intelligent build-in cationization mechanism that selectively triggers effective adsorption-mediated endocytosis and transcytosis at diseased tissues. Completing these studies will provide fundamental and functional correlations of bilayer properties with therapeutic delivery, enable us to establish a set of design rules governing the optimal interactions between lipid bilayer and encased drugs, and provide a paradigm-shifting toolbox to advance the drug delivery technologies, facilitating clinical translation of treating human diseases.

脂质体由完成磷脂（PL）和固醇（例如胆固醇）的脂质双层组成 由于其内在的生物相容性和 生物降解性。虽然大多数批准的脂质体纳米疗法可以改善药代动力学（PK）和 降低全身毒性，改善热效率和整体生存率令人失望， 强调迫切需要增强热输送的需求。 CHOL在强化膜上起关键作用 通过促进脂质中的液体冷凝状态，填充和降低双层的流动性和渗透性 膜，增强双层刚度和强度。高水平CHOL的脂质双层通常更多 稳定比没有或没有chol的人稳定。但是，在物理环境下，Chol迅速 通过生物膜和血清蛋白从双层提取，这危害双层稳定性和结果 在过早的内容泄漏中 效力。此外，尽管增强的渗透性和保留效果允许纳米疗法积累 对于解剖组织的外围，细胞内内在化和组织穿透力保持效率降低 高间隙流体压力和密集的细胞外基质施加的顽强阻力，妥协 治疗结果。这些现象具有基于脂质双层治疗的强大障碍 送货。为了应对这些关键挑战，我的研究计划的整体愿景是建立一个稳定的 脂质双层具有改善的物理特性，可以进一步改善药物递送并有选择地 在目标部位加强细胞内摄取和浸润。我们通过共价建立了一个Chol衍生的PL 将CHOL连接到具有多种刺激响应键的PL上。通过全身结构活动关系研究， 我们证明了CHOL来源的PL封锁CHOL转移，防止有效载荷泄漏，延长循环 时间和增强治疗肺部感染，阿尔茨海默氏病，淋巴瘤，胰腺和 三重阴性乳腺癌模型，它们取决于接头化学。在接下来的五年中，目标 该提议的内容是1）阐明有关如何改变结构性改变的基本机制和原则 形成脂质体但不能在生物膜之间穿梭的立体调整PL双层，将影响药物和 通过用其他膜立体声替代Chol的基因递送； 2）建立通用超pH敏感 充电 - 反转输送平台，通过编码来提高细胞摄取和组织渗透效率 一种智能建筑阳离子化机制，有选择地触发有效的吸附介导的内吞作用 和在解剖组织的跨胞菌病。完成这些研究将提供基本和功能 双层属性与治疗交付的相关性，使我们能够建立一组设计规则 脂质双层和包含的药物之间的最佳相互作用，并为 推进药物输送技术，支持治疗人类疾病的临床翻译。