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

脂质体由磷脂(PL)和胆固醇(Chol)等甾醇组成的脂双层组成，具有 由于其固有的生物兼容性和广泛用于治疗药物的包装和输送 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物动力学(PK)和 减少全身毒性，治疗效果和总体存活率的改善令人失望， 强调迫切需要加强治疗提供。胆碱在膜强化中起着关键作用 通过促进脂质中的液体凝聚状态来填充和降低双层流动性和通透性 膜，增强双层的刚性和强度。胆固醇水平高的脂质双层通常更多 比不含或少含胆固醇的人稳定。然而，在生理环境下，CHOL迅速 由生物膜和血清蛋白从双层中提取出来，这危及双层的稳定性和结果 内容物过早泄漏、血液清除快和不良反应，导致临床效果不佳 功效。此外，尽管增强的渗透性和滞留效应允许纳米治疗积累 对于病变组织的外围，细胞内内化和组织穿透仍然低效，原因是 高间质流体压力和致密的细胞外基质施加的顽强阻力，妥协 治疗结果。这些现象为基于脂质双分子层的治疗提供了强大的障碍 送货。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，可以进一步改善药物的传递和选择性 加强目标部位的细胞内摄取和渗透。我们已经共价建立了CHOL衍生的PL VIA 将CHOL连接到具有不同刺激反应连接的PL上。通过系统结构活性关系研究， 我们证明了Chol衍生的PL阻止了Chol的转移，防止了有效载荷的泄漏，延长了循环 在治疗肺部炎症、阿尔茨海默病、淋巴瘤、胰腺癌和 三重阴性乳腺癌模型，这是连接化学依赖的。未来五年，我们的目标是 这项提议的目的是1)揭示关于如何进行结构性改变的潜在机制和原则 形成脂质体但不能在生物膜之间穿梭的类固醇修饰的PL双层将影响药物和 通过用其他膜甾醇取代Chol进行基因传递；以及2)建立通用的超pH敏感 通过掺入电荷反转递送平台来提高细胞摄取和组织渗透效率 一种智能的内置阳离子机制，可选择性地触发有效的吸附介导的内吞作用 以及病变组织的细胞穿透。完成这些研究将提供基础和实用的 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来管理 脂质双层与包埋药物之间的最佳相互作用，并提供了一个范式转换工具箱 推进药物传递技术，促进治疗人类疾病的临床翻译。

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.