Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro.

IF 5 3区 医学 Q1 PHARMACOLOGY & PHARMACY
David Lee, Andrew M Shen, Olga B Garbuzenko, Tamara Minko
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Abstract

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.

Abstract Image

用于鼻脑传递的抗阿尔茨海默氏症药物和 siRNA 脂质体制剂:体外设计、安全性和有效性。
β位点淀粉样前体蛋白裂解酶(BACE1)是治疗阿尔茨海默病(AD)的一个关键靶点,因为它是产生有毒的淀粉样β(Aβ)肽的必要条件,而淀粉样β(Aβ)肽在疾病的发展过程中起着至关重要的作用。BACE1抑制剂是降低大脑中Aβ水平和预防AD进展的一种很有前景的方法。然而,由于血脑屏障(BBB)的存在,将此类抑制剂全身性地输送到大脑的疗效有限。鼻脑(NtB)给药有可能克服这一障碍。与传统方法相比,脂质体药物递送系统在从鼻腔向大脑递送药物和核酸方面具有多种优势。本研究旨在制备、表征和评估多奈哌齐、美金刚、BACE-1 siRNA 的体外脂质体形式及其组合,以便通过 NtB 递送治疗注意力缺失症。所有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-淀粉样蛋白斑块和其他促炎细胞因子表达的抑制作用。使用 Calu-3 Transwell 模型作为体外系统,模拟鼻腔上皮细胞的解剖和生理条件,研究拟议制剂在可能的 NtB 递送中的适用性。研究结果表明,脂质体能有效地在细胞内输送治疗药物,具有克服 BBB 紧密连接的潜力,减少了β-淀粉样蛋白斑块的积聚和促炎细胞因子的表达,支持了我们的方法的治疗潜力。
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来源期刊
AAPS Journal
AAPS Journal 医学-药学
CiteScore
7.80
自引率
4.40%
发文量
109
审稿时长
1 months
期刊介绍: The AAPS Journal, an official journal of the American Association of Pharmaceutical Scientists (AAPS), publishes novel and significant findings in the various areas of pharmaceutical sciences impacting human and veterinary therapeutics, including: · Drug Design and Discovery · Pharmaceutical Biotechnology · Biopharmaceutics, Formulation, and Drug Delivery · Metabolism and Transport · Pharmacokinetics, Pharmacodynamics, and Pharmacometrics · Translational Research · Clinical Evaluations and Therapeutic Outcomes · Regulatory Science We invite submissions under the following article types: · Original Research Articles · Reviews and Mini-reviews · White Papers, Commentaries, and Editorials · Meeting Reports · Brief/Technical Reports and Rapid Communications · Regulatory Notes · Tutorials · Protocols in the Pharmaceutical Sciences In addition, The AAPS Journal publishes themes, organized by guest editors, which are focused on particular areas of current interest to our field.
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