Department of Pharmaceutics, Ernest Mario School of Pharmacy, the State University of New Jersey, 160 Frelinghuysen Road, Rutgers, Piscataway, NJ, 08854, USA.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA.
AAPS J. 2024 Sep 4;26(5):99. doi: 10.1208/s12248-024-00967-x.
β-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid β (Aβ) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aβ levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.
β-淀粉样前体蛋白裂解酶（BACE1）是阿尔茨海默病（AD）治疗的一个关键靶点，因为它对于产生有毒的淀粉样β（Aβ）肽至关重要，而 Aβ 肽在疾病的发展中起着关键作用。BACE1 抑制剂是降低大脑中 Aβ 水平和预防 AD 进展的一种有前途的方法。然而，由于血脑屏障（BBB）的存在，全身性给予此类抑制剂到大脑中显示出有限的疗效。鼻内递药（NtB）有潜力克服这一障碍。脂质体药物递送系统在从鼻腔向大脑递药和递送核酸方面相对于传统方法具有几个优势。本研究旨在制备、表征并评估多奈哌齐、美金刚、BACE1siRNA 的脂质体形式及其组合，通过 NtB 递药用于 AD 的可能治疗。所有的脂质体制剂均采用旋转蒸发法制备。研究了它们的细胞内化、细胞毒性以及对β-淀粉样斑块和其他促炎细胞因子表达的抑制作用。Calu-3 转染模型被用作模拟鼻上皮的解剖和生理条件的体外系统，并研究了所提出的制剂用于可能的 NtB 递药的适用性。研究结果表明，脂质体提供了治疗药物的有效细胞内递药，有潜力克服 BBB 中的紧密连接，减少β-淀粉样斑块的积累和促炎细胞因子的表达，支持我们方法的治疗潜力。
