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The primary reason behind the design of a prodrug is to help circumvent challenges associated with the physicochemical properties of a drug molecule, such as solubility, absorption, distribution, and instability. Chemotherapy has been at the forefront of cancer treatment for over 70 years due to its ability to target rapidly proliferating tumor cells. However, a major concern with conventional chemotherapy is the lack of selectivity and its associated side toxicity, which can severely impact patients\u2019 quality of life. In oncology, prodrugs have been explored to enhance the bioavailability, improve efficacy, and minimize systemic toxicity of chemotherapeutic agents. Prodrugs activated by enzymes unique to a tumor microenvironment can significantly increase targeted delivery of chemotherapeutic drugs. This review aims to highlight commonly used chemotherapeutic prodrugs, including both alkylating and non-alkylating agents, and discuss their clinical relevance, mechanisms of bioactivation, and toxicity concerns.<\/jats:p>","DOI":"10.3390\/ijms26030988","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T05:24:31Z","timestamp":1737696271000},"page":"988","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Prodrugs in Oncology: Bioactivation and Impact on Therapeutic Efficacy and Toxicity"],"prefix":"10.3390","volume":"26","author":[{"given":"Ritika","family":"Kurian","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6224-6888","authenticated-orcid":false,"given":"Hongbing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4755","DOI":"10.1002\/jps.22205","article-title":"Prodrugs: Some Thoughts and Current Issues","volume":"99","author":"Stella","year":"2010","journal-title":"J. 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