Sustained and Step-Wise Drug Release by a Novel Double Responsive Dendrimer‑N‑Acetylcysteine Conjugate

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2025-07-14 DOI:10.1021/acs.biomac.5c00283

Ozgul Gok , Anjali Sharma , Siva P. Kambhampati , Elizabeth Smith Khoury , Sujatha Kannan , Rangaramanujam M. Kannan

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Abstract

Polyamidoamine (PAMAM) dendrimers have emerged as promising vehicles for targeting the brain due to their intrinsic ability to penetrate through the injured blood–brain barrier. Herein, we present a novel drug delivery system based on a fourth generation PAMAM dendrimer as a brain targeting nanomedicine for the delivery of an anti-inflammatory drug N-acetyl cysteine with a sustained drug release profile. This D_“ester”(NAC_“ss”NAC) design enables NACs conjugated to the periphery of PAMAM dendrimers in the dimer form with ester and disulfide bonds to be sequentially released in a stepwise manner, responding to environmental pH and redox potential. Moreover, in vitro studies were conducted with a fluorescently labeled conjugate to confirm its nontoxic behavior and time-dependent cellular uptake, together with improved anti-inflammatory and antioxidative effects over endotoxin-activated microglia. These findings demonstrate that the DNACNAC conjugate has a high potential to be utilized as a promising dendrimer-based nanomedicine platform for prolonged treatment of neuroinflammation-related CNS disorders.

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一种新型双反应树突状分子- n -乙酰半胱氨酸缀合物的持续和分步药物释放。

聚酰胺胺（PAMAM）树状大分子由于其固有的穿透损伤血脑屏障的能力而成为靶向大脑的有前途的载体。在此，我们提出了一种基于第四代PAMAM树状大分子作为脑靶向纳米药物的新型药物递送系统，用于递送具有持续药物释放特征的抗炎药物n -乙酰半胱氨酸。这种D“酯”（NAC“ss”NAC）设计使NAC以二聚体形式结合到PAMAM树状大分子的外围，具有酯和二硫键，以逐步的方式顺序释放，响应环境pH和氧化还原电位。此外，用荧光标记的缀合物进行了体外研究，以确认其无毒行为和时间依赖性细胞摄取，以及对内毒素激活的小胶质细胞改善的抗炎和抗氧化作用。这些发现表明，DNACNAC缀合物具有很高的潜力，可作为一种有前途的基于树突的纳米药物平台，用于长期治疗神经炎症相关的中枢神经系统疾病。

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来源期刊

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.