Exploiting a type III interferon response to improve chemotherapeutic safety and efficacy

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2024-11-26 DOI:10.1016/j.ejps.2024.106974
Scott G. Tilden , Madison H. Ricco , Emily A. Hemann , Thomas J. Anchordoquy
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Abstract

Immune reactions to nanomedicines can be detrimental to the patient and compromise efficacy. However, our recent study characterizing the effects of a type III interferon (IFN-λ) response to lipid nanoparticles complexed with nucleic acids (lipoplexes) suggests that an IFN-λ pretreatment can increase tumor accumulation while decreasing off-target distribution of chemotherapeutic nanomedicines. This project provides a direct follow-up to our previously published works by clarifying 1) which cell type(s) can produce IFN-λ in response to lipoplexes and how the effects of IFN-λ may be propagated in humans. Additionally, we demonstrate 2) that an IFN-λ pretreatment is also capable of altering the accumulation profile of chemotherapeutic small molecules like doxorubicin. Finally, we determined 3) that the subcutaneous administration route for an IFN-λ pretreatment is the most efficacious, and 4) that an IFN-λ pretreatment can significantly increase the survival time of mice receiving Doxil® in a murine CT26 tumor model. With several chemotherapeutic nanomedicines available in the clinic and an IFN-λ product recently completing late phase clinical trials, this study provides the model for a novel anti-cancer treatment regime that can be rapidly translated to the clinic and improve the efficacy of contemporary treatment protocols.

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利用III型干扰素反应提高化疗安全性和有效性。
对纳米药物的免疫反应可能对患者有害并影响疗效。然而,我们最近的研究表征了III型干扰素(IFN-λ)对脂质纳米颗粒与核酸(脂质复合物)的反应,表明IFN-λ预处理可以增加肿瘤积累,同时减少化疗纳米药物的脱靶分布。该项目为我们之前发表的工作提供了直接的后续研究,阐明了1)哪种细胞类型可以产生IFN-λ以响应脂肪丛,以及IFN-λ的作用如何在人类中传播。此外,我们证明了2)IFN-λ预处理也能够改变化疗小分子(如阿霉素)的积累谱。最后,我们确定了3)IFN-λ预处理的皮下给药途径是最有效的,4)IFN-λ预处理可以显著增加Doxil®小鼠在小鼠CT26肿瘤模型中的存活时间。随着几种化疗纳米药物在临床上可用,IFN-λ产品最近完成了后期临床试验,本研究为一种新的抗癌治疗方案提供了模型,该方案可以快速转化为临床并提高当代治疗方案的疗效。
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来源期刊
CiteScore
9.60
自引率
2.20%
发文量
248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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