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With sequential click chemistry coupling between the cytotoxic payload and phosphatidylserine-targeting ZnDPA ligand derived from structurally diverse carboxylic acids, aldehyde or ketones, and isocyanides, we demonstrated that this convergent synthetic strategy could furnish conjugates harnessing diversified linkers that exhibited different pharmacokinetic profiles in systemic circulation <jats:italic>in vivo<\/jats:italic>. Among the eight new conjugates, comparative studies on <jats:italic>in vitro<\/jats:italic> cytotoxicities, plasma stabilities, <jats:italic>in vivo<\/jats:italic> pharmacokinetic properties, and maximum tolerated doses were then carried out to identify a potent ZnDPA-based SN-38 conjugate that resulted in pancreatic cancer growth regression with an 80% reduction of cytotoxic payload used when compared to that of the marketed irinotecan. Our work provided the roadmap to construct a variety of theranostic agents in a similar manner for cancer treatment.<\/jats:p>","DOI":"10.3389\/fchem.2021.822587","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T09:16:12Z","timestamp":1644916572000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Click Chemistry and Multicomponent Reaction for Linker Diversification of Zinc Dipicolylamine-Based Drug Conjugates"],"prefix":"10.3389","volume":"9","author":[{"given":"Ching-Hua","family":"Tsai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Yu","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiung-Tong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yu","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Ru","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng-Kuang","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hsun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lun Kelvin","family":"Tsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8751","DOI":"10.1021\/acs.jmedchem.5b00457","article-title":"Antibody-Drug Conjugates and Small Molecule-Drug Conjugates: Opportunities and Challenges for the Development of Selective Anticancer Cytotoxic Agents","volume":"58","author":"Casi","year":"2015","journal-title":"J. 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