Jia Yizhen, Kong Xiaohan, Li Rui, Wang Han, Li Chujie, Cheng Shihong, Duan Wei, Xiao Yan, Mai Yang, Deng Wenbin, Liu Yang
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, China.
Laboratory Animal Center, Sun Yat-sen University, Guangzhou, 510080, China.
Acta Biomater. 2025 Mar 1;194:411-427. doi: 10.1016/j.actbio.2025.01.036. Epub 2025 Jan 25.
Following cerebral ischemia, reperfusion injury can worsen ischemia-induced functional, metabolic disturbances, and pathological damage upon blood flow restoration, potentially leading to irreversible harm. Yet, there's a dearth of advanced, localized drug delivery systems ensuring active pharmaceutical ingredient (API) efficacy in cerebral protection during ischemia-reperfusion. This study introduces a multivalent bioadhesive nanoparticle-cluster, merging bioadhesive nanoparticles (BNPs) with dendritic polyamidoamine (PAMAM), enhancing nose-to-brain delivery and brain protection efficacy against cerebral ischemia-reperfusion injuries (CIRI). The BNPs-PAMAM cluster exhibits superior adhesion within the rat nasal cavity, prolonged retention, enabling sustained drug release, cerebral transportation, and accumulation, resulting in enhanced intracerebral pharmacokinetic profile. Intranasal administration circumvents systemic delivery challenges, ensuring CIRI protection drugs reach ischemic areas pre-reperfusion, overcoming thrombus-related delays. Administering BNPs-PAMAM loaded with dexmedetomidine (DEX) pre-reperfusion effectively prevents neuron apoptosis by α2-adrenoceptor activation, modulating the ischemic microenvironment, exerting triple neuroprotective effects against cerebral reperfusion injury. Importantly, only therapeutic DEX releases and accumulates in the nasal cavity, averting brain nanomaterial toxicity, promising for repeat administrations. This study presents a translational platform for nasal-to-brain drug delivery in CNS disease treatment. STATEMENT OF SIGNIFICANCE: Innovative Drug Delivery System: This study introduces a multivalent bioadhesive nanoparticle-cluster (BNPs-PAMAM) to enhance nasal-to-brain drug delivery for cerebral ischemia-reperfusion injury (CIRI) treatment. Enhanced Retention and Efficacy: The BNPs-PAMAM system significantly improves drug retention in the nasal cavity and ensures sustained release, thereby enhancing the therapeutic efficacy of the neuroprotective agent dexmedetomidine (DEX). Blood-Brain Barrier Circumvention: By leveraging intranasal administration, the system bypasses the blood-brain barrier, delivering DEX directly to ischemic brain regions before reperfusion and minimizing systemic side effects. Triple Neuroprotective Effects for CIRI protection: DEX delivered via BNPs-PAMAM effectively reduces oxidative stress and inflammation while enhancing mitochondrial autophagy, providing comprehensive protection against neuronal damage.
脑缺血后，再灌注损伤会在血流恢复时加重缺血诱导的功能、代谢紊乱及病理损伤，可能导致不可逆转的损害。然而，缺乏先进的局部给药系统来确保活性药物成分（API）在缺血再灌注期间对脑的保护作用。本研究引入了一种多价生物粘附纳米颗粒簇，将生物粘附纳米颗粒（BNPs）与树枝状聚酰胺胺（PAMAM）相结合，增强鼻脑给药及对脑缺血再灌注损伤（CIRI）的脑保护效果。BNPs-PAMAM簇在大鼠鼻腔内表现出卓越的粘附性、延长的滞留时间，实现药物持续释放、脑内转运及蓄积，从而改善脑内药代动力学特征。鼻内给药规避了全身给药的挑战，确保CIRI保护药物在再灌注前到达缺血区域，克服与血栓相关的延迟。在再灌注前给予负载右美托咪定（DEX）的BNPs-PAMAM可通过激活α2-肾上腺素能受体有效预防神经元凋亡，调节缺血微环境，对脑再灌注损伤发挥三重神经保护作用。重要的是，只有治疗性DEX在鼻腔内释放和蓄积，避免脑纳米材料毒性，有望进行重复给药。本研究为中枢神经系统疾病治疗中的鼻脑给药提供了一个转化平台。意义声明：创新给药系统：本研究引入多价生物粘附纳米颗粒簇（BNPs-PAMAM）以增强鼻脑给药用于治疗脑缺血再灌注损伤（CIRI）。增强滞留和疗效：BNPs-PAMAM系统显著提高药物在鼻腔内的滞留并确保持续释放，从而增强神经保护剂右美托咪定（DEX）的治疗效果。绕过血脑屏障：通过利用鼻内给药，该系统绕过血脑屏障，在再灌注前将DEX直接递送至缺血脑区并使全身副作用最小化。对CIRI保护的三重神经保护作用：通过BNPs-PAMAM递送的DEX有效降低氧化应激和炎症，同时增强线粒体自噬，为神经元损伤提供全面保护。
