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.

脂质体由包含磷脂（PL）和甾醇如胆固醇（Chol）的脂质双层组成，具有 由于其固有的生物相容性， 生物降解性虽然大多数批准的脂质体纳米治疗剂可以改善药代动力学（PK）和 降低全身毒性，治疗效果和总生存期的改善令人失望， 强调了对增强治疗递送的迫切需要。Chol在强化膜中起着关键作用 通过促进脂质中的液体凝聚态来填充和降低双层流动性和渗透性 膜，增强双层刚性和强度。具有高水平Chol的脂质双层通常更多 比不含或含较少Chol的那些稳定。然而，在生理环境下， 生物膜和血清蛋白从双层中提取，这会危及双层的稳定性， 过早的内容物泄漏、快速的血液清除和不希望的副作用，导致次优的临床 功效此外，尽管渗透性和滞留作用的增强使得纳米颗粒的积累 对于患病组织的外周，细胞内内化和组织渗透仍然是低效的， 由高间质液压力和致密的细胞外基质施加的顽强抵抗， 治疗效果。这些现象为基于脂质双层的治疗性药物提供了巨大的障碍。 交付.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 具有改进的物理化学性质的脂质双层， 加强靶位点的细胞内摄取和浸润。我们已经建立了一个Chol衍生的PL通过共价键 将Chol连接到具有不同刺激响应性连接的PL上。通过系统构效关系研究， 我们证明，Chol衍生的PL阻断Chol转移，防止有效载荷泄漏，延长循环， 治疗肺部炎症、阿尔茨海默病、淋巴瘤、胰腺炎和 三阴性乳腺癌模型，其是接头化学依赖性的。未来五年，目标 这一建议的目的是：1）揭示结构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甾醇修饰的PL双层将影响药物， 通过用其他膜固醇取代Chol的基因递送;和2）建立通用的超pH敏感的 电荷反转递送平台，以通过结合 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 和在病变组织的转胞吞作用。完成这些研究将提供基础和功能 双层性质与治疗传递的相关性，使我们能够建立一套设计规则， 脂质双层和包裹药物之间的最佳相互作用，并提供了一个范式转换工具箱， 推进药物输送技术，促进人类疾病治疗的临床转化。