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.

脂质体由脂质双层组成，其中磷脂（PL）和甾醇（例如胆固醇（Chol））具有 由于其固有的生物相容性和 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，治疗效果和总体生存率的改善令人失望， 强调加强治疗传递的迫切需要。 通过促进脂质中的液体凝聚态来堆积并降低双层流动性和渗透性 具有高水平胆固醇的脂质双层通常更多。 比没有或含有较少胆碱的稳定，但在生理环境下，胆碱会迅速变化。 通过生物膜和血清蛋白从双层中提取，这会危及双层的稳定性和结果 过早的内容物泄漏、快速的血液清除和不良副作用，导致临床效果不佳 此外，虽然增强的渗透性和保留作用允许纳米治疗药物的积累。 对于病变组织的外围，由于以下原因，细胞内内化和组织渗透仍然效率低下： 高间质液压力和致密的细胞外基质所施加的顽强抵抗力，损害了 这些现象为基于脂质双层的治疗带来了巨大的障碍。 为了应对这些关键挑战，我的研究计划的总体愿景是建立一个稳定的交付。 脂质双层具有改善的理化性质，可以进一步改善药物输送和选择性 我们通过共价键建立了 Chol 衍生的 PL。 通过系统结构活动关系研究，将 Chol 连接到 PL 上。 我们证明了 Chol 衍生的 PL Chol 转移，防止有效负载泄漏，延长循环 时间，并增强治疗肺部炎症、阿尔茨海默氏病、淋巴瘤、胰腺癌和 三阴性乳腺癌模型，其未来五年的目标取决于连接体化学。 该提案的目的是 1）揭示结构性改变的基本机制和原则 甾醇修饰的 PL 双层形成脂质体但不能在生物膜之间穿梭，会影响药物和 通过用其他膜甾醇替代 Chol 进行基因传递；以及 2) 建立通用的超 pH 敏感性； 电荷反转传递平台，通过整合提高细胞摄取和组织渗透效率 智能内置阳离子化机制，选择性触发有效的吸附介导的内吞作用 完成这些研究将提供基础和功能性的研究。 双层特性与治疗传递的相关性使我们能够建立一套设计规则来控制 脂质双层和包裹药物之间的最佳相互作用，并提供范式转换工具箱 推进药物输送技术，促进治疗人类疾病的临床转化。