{"title":"Natural polymer derivative-based pH-responsive nanoformulations with entrapped diketo-tautomers of 5-fluorouracil for enhanced cancer therapy.","authors":"Anbazhagan Thirumalai, Koyeli Girigoswami, Karthick Harini, Venkatakrishnan Kiran, Pazhani Durgadevi, Agnishwar Girigoswami","doi":"10.5599/admet.2554","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and purpose: </strong>Despite significant advancements in cancer therapies, chemotherapeutics continue to be the mainstay for treating cancer patients, with 5-fluorouracil (5-FU) being commonly used for various cancers. However, its limited ability to penetrate cell membranes and its short half-life, caused by rapid metabolism, necessitate frequent administration of high doses to maintain effective therapeutic levels. This study aimed to synthesize oxidized sodium alginate (OSA) derivatives to create OSA nanoparticles loaded with 5-FU (OSANP@ 5-FU), promoting diketo tautomers, and evaluate their photophysical properties, release profile, and anticancer activity with minimal toxicity.</p><p><strong>Experimental approach: </strong>The investigation encompassed physicochemical characterization, encapsulation efficiency, 5-FU release kinetics at pH 2.2 and 7.4, cell viability assessment via MTT assay in V79 cells, and in vitro anticancer efficacy in the A375 cell line.</p><p><strong>Key results: </strong>Steady-state absorption and emission confirmed the presence of advantageous diketone tautomers of 5-FU, indicating radiative transitions from the second singlet excited state to the ground state (S2→S0) and the drug's encapsulation within the polymeric nanostructure. Dynamic light scattering revealed that OSA nanoparticles, initially 177.8 nm, grew to 226.6 nm after encapsulating 5-FU, retaining high zeta potential for stability. With a 68% encapsulation efficiency, in vitro studies showed 46 to 54 % of 5-FU released across different pH levels within 510 minutes.</p><p><strong>Conclusion: </strong>In acidic conditions, there is a greater release of 5-FU than neutral pH levels, indicating a pH-responsive release profile beneficial for cancer treatment, with the release mechanism of OSANPs following Fickian diffusion as identified by a Korsmeyer-Peppas mathematical model and the formulation showing improved therapeutic efficacy.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 1","pages":"2554"},"PeriodicalIF":3.4000,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954142/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ADMET and DMPK","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.5599/admet.2554","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background and purpose: Despite significant advancements in cancer therapies, chemotherapeutics continue to be the mainstay for treating cancer patients, with 5-fluorouracil (5-FU) being commonly used for various cancers. However, its limited ability to penetrate cell membranes and its short half-life, caused by rapid metabolism, necessitate frequent administration of high doses to maintain effective therapeutic levels. This study aimed to synthesize oxidized sodium alginate (OSA) derivatives to create OSA nanoparticles loaded with 5-FU (OSANP@ 5-FU), promoting diketo tautomers, and evaluate their photophysical properties, release profile, and anticancer activity with minimal toxicity.
Experimental approach: The investigation encompassed physicochemical characterization, encapsulation efficiency, 5-FU release kinetics at pH 2.2 and 7.4, cell viability assessment via MTT assay in V79 cells, and in vitro anticancer efficacy in the A375 cell line.
Key results: Steady-state absorption and emission confirmed the presence of advantageous diketone tautomers of 5-FU, indicating radiative transitions from the second singlet excited state to the ground state (S2→S0) and the drug's encapsulation within the polymeric nanostructure. Dynamic light scattering revealed that OSA nanoparticles, initially 177.8 nm, grew to 226.6 nm after encapsulating 5-FU, retaining high zeta potential for stability. With a 68% encapsulation efficiency, in vitro studies showed 46 to 54 % of 5-FU released across different pH levels within 510 minutes.
Conclusion: In acidic conditions, there is a greater release of 5-FU than neutral pH levels, indicating a pH-responsive release profile beneficial for cancer treatment, with the release mechanism of OSANPs following Fickian diffusion as identified by a Korsmeyer-Peppas mathematical model and the formulation showing improved therapeutic efficacy.
期刊介绍：
ADMET and DMPK is an open access journal devoted to the rapid dissemination of new and original scientific results in all areas of absorption, distribution, metabolism, excretion, toxicology and pharmacokinetics of drugs. ADMET and DMPK publishes the following types of contributions: - Original research papers - Feature articles - Review articles - Short communications and Notes - Letters to Editors - Book reviews The scope of the Journal involves, but is not limited to, the following areas: - physico-chemical properties of drugs and methods of their determination - drug permeabilities - drug absorption - drug-drug, drug-protein, drug-membrane and drug-DNA interactions - chemical stability and degradations of drugs - instrumental methods in ADMET - drug metablic processes - routes of administration and excretion of drug - pharmacokinetic/pharmacodynamic study - quantitative structure activity/property relationship - ADME/PK modelling - Toxicology screening - Transporter identification and study
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