{"title":"Temperature switchable linkers suitable for triggered drug release in cancer thermo-chemotherapy","authors":"","doi":"10.1016/j.ijpharm.2024.124757","DOIUrl":null,"url":null,"abstract":"<div><div>In drug delivery systems, a stimuli-responsive linker that attaches a targeting carrier and a cytotoxic payload can be dissociated to release the payload on the target over the action of a stimuli, thereby it would harden the selectivity, specificity and potency of the cytotoxic agent against targeted tissues whilst sparing the drug-induced toxicity on normal cells. Oligonucleotide duplexes can unwind and be separated into single-stranded random coils under a defined temperature, and this property makes the oligonucleotide an appealing thermo-responsive linker. In this work, we studied the melting temperatures of different DNA linkers with various lengths and mismatches inserted in the double helix with either different numbers or positions. We further chose the DNA linkers that can unwind at the hyperthermia temperature and used them in the construction of four different drug delivery systems both <em>in vitro and in vivo</em>. Results showed that the chosen DNA linkers in all of the constructed delivery systems can successfully unwind and release cargos or drugs after application of heat compared to control groups. This research demonstrated the potential applications of DNA duplexes as temperature-sensitive linkers of drug delivery systems for cancer therapy.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0378517324009918","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
In drug delivery systems, a stimuli-responsive linker that attaches a targeting carrier and a cytotoxic payload can be dissociated to release the payload on the target over the action of a stimuli, thereby it would harden the selectivity, specificity and potency of the cytotoxic agent against targeted tissues whilst sparing the drug-induced toxicity on normal cells. Oligonucleotide duplexes can unwind and be separated into single-stranded random coils under a defined temperature, and this property makes the oligonucleotide an appealing thermo-responsive linker. In this work, we studied the melting temperatures of different DNA linkers with various lengths and mismatches inserted in the double helix with either different numbers or positions. We further chose the DNA linkers that can unwind at the hyperthermia temperature and used them in the construction of four different drug delivery systems both in vitro and in vivo. Results showed that the chosen DNA linkers in all of the constructed delivery systems can successfully unwind and release cargos or drugs after application of heat compared to control groups. This research demonstrated the potential applications of DNA duplexes as temperature-sensitive linkers of drug delivery systems for cancer therapy.
在给药系统中,连接靶向载体和细胞毒性有效载荷的刺激响应连接体可在刺激作用下解离,将有效载荷释放到靶点上,从而增强细胞毒剂对靶组织的选择性、特异性和效力,同时避免药物对正常细胞的毒性。寡核苷酸双链体在特定温度下可以解开并分离成单链随机线圈,这一特性使寡核苷酸成为一种有吸引力的热响应连接体。在这项工作中,我们研究了不同长度的 DNA 连接体的熔化温度,以及插入双螺旋中的不同数目或位置的错配。我们进一步选择了能在高热温度下解开的 DNA 连接体,并将其用于构建四种不同的体外和体内给药系统。结果表明,与对照组相比,所有构建的给药系统中选择的 DNA 连接体都能在加热后成功解开并释放载体或药物。这项研究证明了 DNA 双链体作为癌症治疗药物输送系统的温度敏感连接体的潜在应用价值。
期刊介绍:
The International Journal of Pharmaceutics is the third most cited journal in the "Pharmacy & Pharmacology" category out of 366 journals, being the true home for pharmaceutical scientists concerned with the physical, chemical and biological properties of devices and delivery systems for drugs, vaccines and biologicals, including their design, manufacture and evaluation. This includes evaluation of the properties of drugs, excipients such as surfactants and polymers and novel materials. The journal has special sections on pharmaceutical nanotechnology and personalized medicines, and publishes research papers, reviews, commentaries and letters to the editor as well as special issues.