Mannosamine-Engineered Nanoparticles for Precision Rifapentine Delivery to Macrophages: Advancing Targeted Therapy Against Mycobacterium Tuberculosis.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-03-19 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S505682

Haopeng Luan, Cong Peng, Parhat Yasin, Qisong Shang, Wei Xiang, Xinghua Song

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Abstract

Background: Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death among infectious diseases. Enhancing the ability of anti-tuberculosis drugs to eradicate Mycobacterium tuberculosis within host cells remains a significant challenge.

Methods: A mannosamine-modified nanoparticle delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) copolymers to enhance the targeted delivery of rifapentine (RPT) to macrophages. D-mannosamine was conjugated to PLGA-polyethylene glycol (PLGA-PEG) copolymers through EDC/NHS coupling chemistry, and the resultant RPT-MAN-PLGA-PEG nanoparticles (NPs) were prepared through a combination of phacoemulsification and solvent evaporation methods. The physicochemical properties, toxicity, in vitro drug release profiles, stability, cellular uptake, and anti-TB efficacy of the NPs were systematically evaluated.

Results: The RPT-MAN-PLGA-PEG NPs had a mean particle size of 108.2 ± 7.2 nm, with encapsulation efficiency and drug loading rates of 81.2 ± 6.3% and 13.7 ± 0.7%, respectively. RPT release from the NPs was sustained for over 60 hours. Notably, the phagocytic uptake of the MAN-PLGA NPs by macrophages was significantly higher compared to PLGA-PEG NPs. Both NPs improved pharmacokinetic parameters without inducing significant organ toxicity. The minimum inhibitory concentration for the NPs was 0.047 μg/mL, compared to 0.2 μg/mL for free RPT.

Conclusion: The engineered RPT-MAN-PLGA-PEG NPs effectively enhanced macrophage uptake in vitro and facilitated the intracellular clearance of Mtb. This nanoparticle-based delivery system offers a promising approach for improving the precision of anti-TB therapy, extending drug release, optimizing pharmacokinetic profiles, augmenting antimicrobial efficacy, and mitigating drug-related toxicities.

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用于巨噬细胞利福喷丁精确递送的甘露胺工程纳米颗粒：推进针对结核分枝杆菌的靶向治疗。

背景：由结核分枝杆菌（Mtb）引起的结核病仍然是传染病中导致死亡的主要原因之一。提高抗结核药物根除宿主细胞内结核分枝杆菌的能力仍然是一个重大挑战。方法：利用聚乳酸-羟基乙酸共聚物（PLGA）构建甘露糖胺修饰的纳米颗粒递送系统，以增强利福喷丁（RPT）对巨噬细胞的靶向递送。通过EDC/NHS偶联化学将d -甘露糖胺偶联到plga -聚乙二醇（PLGA-PEG）共聚物上，并通过超声乳化和溶剂蒸发相结合的方法制备了RPT-MAN-PLGA-PEG纳米颗粒（NPs）。系统评价了NPs的理化性质、毒性、体外药物释放谱、稳定性、细胞摄取和抗结核疗效。结果：RPT-MAN-PLGA-PEG NPs平均粒径为108.2±7.2 nm，包封率为81.2±6.3%，载药率为13.7±0.7%。从NPs释放RPT持续超过60小时。值得注意的是，巨噬细胞对MAN-PLGA NPs的吞噬摄取明显高于PLGA-PEG NPs。两种NPs都改善了药代动力学参数，但没有引起明显的器官毒性。NPs的最低抑制浓度为0.047 μg/mL，而游离RPT的最低抑制浓度为0.2 μg/mL。结论：RPT-MAN-PLGA-PEG NPs能有效增强体外巨噬细胞对Mtb的摄取，促进细胞内Mtb的清除。这种基于纳米颗粒的给药系统为提高抗结核治疗的精度、延长药物释放、优化药代动力学谱、增强抗菌功效和减轻药物相关毒性提供了一种有希望的方法。

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公司名称

产品信息

索莱宝

Rifapentine (RPT)

来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.