Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure

Approximately 3.3 billion people live with the threat of Plasmodium vivax malaria. Infection can result in liver-localized hypnozoites, which when reactivated cause relapsing malaria. This is the first demonstration of an enzyme-cleavable polymeric prodrug of tafenoquine (TQ) that addresses key requirements for a mass administration, eradication campaign: excellent subcutaneous bioavailability, complete parasite control after a single dose, improved therapeutic window compared to the parent oral drug, and low Cost of Goods Sold (COGS) at less than $1.50/dose. Liver-targeting and subcutaneous dosing resulted in improved liver:plasma exposure profiles, with increased efficacy and reduced Glucose 6-Phosphate Dehydrogenase (G6PD)-dependent hemotoxicity in validated preclinical models. A COGS and manufacturability analysis demonstrated global scalability, affordability, and the ability to redesign this fully synthetic polymeric prodrug specifically to increase global equity and access. Taken..., , , # Liver-Targeted Polymeric Prodrugs Delivered Subcutaneously Improve Tafenoquine Therapeutic Window for Malaria Radical Cure

## Description of the data and file structure

Premise: Tafenoquine (TQ) is an drug used to treat *Plasmodium vivax* malaria, however it can also cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD-deficiency). pVCTQ is a polymer we have previously synthesized to treat *P. vivax* malaria without causing hemolytic anemia in those with G6PD-deficiency. We have synthesized a new polymer, pSVCTQ, which has a plasma-stable peptide linker. The goal was to create a polymer that reduces the drug release in plasma even further than the previous pVCTQ polymer, thereby reducing risk of hemotoxicity without decreasing drug activity. Each bolded section below corresponds to a different sheet in the excel file, and each sheet in the file corresponds to a figure in the manuscript or supplemental materials section and was used to create the...

全球约有33亿人口面临间日疟原虫（Plasmodium vivax）疟疾的威胁。感染后可形成肝脏定植的休眠子（hypnozoite），该休眠子再度激活后会引发疟疾复发。本研究首次证明了一款针对他非诺喹（tafenoquine，TQ）的酶可裂解聚合物前药，可满足大规模给药、疟疾根除行动的核心要求：优异的皮下生物利用度、单剂量即可实现寄生虫的完全清除、相较于口服原药更宽的治疗窗口，且货物销售成本（Cost of Goods Sold，COGS）低于1.5美元/剂。肝脏靶向与皮下给药可优化肝脏-血浆暴露谱，在经过验证的临床前模型中提升了治疗疗效，并降低了葡萄糖-6-磷酸脱氢酶（Glucose 6-Phosphate Dehydrogenase，G6PD）依赖性溶血性毒性。货物销售成本与可制造性分析表明，该药物具备全球规模化生产能力与可及性，且可对这款全合成聚合物前药进行定向改造，以进一步提升全球用药公平性与可及性。
# 皮下递送的肝脏靶向聚合物前药可提升他非诺喹用于疟疾根治的治疗窗口

## 数据与文件结构说明
研究背景：他非诺喹（tafenoquine，TQ）是一款用于治疗间日疟原虫疟疾的药物，但葡萄糖-6-磷酸脱氢酶缺乏（G6PD缺乏）患者使用后可能引发溶血性贫血。pVCTQ是我们此前合成的一款聚合物，可用于治疗间日疟原虫疟疾，且不会在G6PD缺乏患者中引发溶血性贫血。本次研究中我们合成了一款新型聚合物pSVCTQ，其带有血浆稳定型肽连接子。本研究的目标是开发一款相较于此前的pVCTQ聚合物，可进一步降低药物在血浆中释放速率的载体，从而在不降低药物活性的前提下降低溶血性毒性风险。下文每一处加粗区域对应Excel文件中的一个独立工作表，而文件内的每个工作表均对应论文手稿或补充材料中的一幅图表，用于生成……