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However, its application is often limited because of severe toxicity and drug resistance. Herein, a high\u2010dose therapy of pro\u2010apoptotic doxorubicin (DOX) prodrug\u2010encapsulated PEGylated liposomes (Aposomes) is presented for the treatment of pancreatic cancer. The prodrug is synthesized by conjugating DOX with a second mitochondria\u2010derived activator of caspases mimetic peptide (SMAC\u2010P\u2010FRRL; AVPIAQ\u2010FRRL: antagonist of inhibitor of apoptosis proteins), in which the cathepsin B\u2010cleavable \u2010RR\u2010 sequence enables selective release. The resulting SMAC\u2010P\u2010FRRL\u2010DOX is efficiently encapsulated into PEGylated liposomes (87.7 \u00b1 0.48\u00a0nm), which induced apoptosis specifically in cathepsin B\u2010overexpressing pancreatic cancer cells. In KPC960 tumor\u2010bearing mice, repeated administration of high\u2010dose Aposomes facilitates preferential tumor accumulation via the enhanced permeability and retention (EPR) effect and exerts potent antitumor activity with minimal toxicity in normal tissues. Moreover, the therapeutic efficacy and safety profile of high\u2010dose Aposomes are validated in humanized NOD scid gamma (NSG) mice. Notably, high\u2010dose Aposomes significantly reduce orthotopic pancreatic tumor size in NSG mice without toxicity in the blood, immune system, and normal tissues. This high\u2010dose therapy of Aposomes can greatly improve the therapeutic index of pancreatic cancer chemotherapy without causing severe toxicity and potential drug resistance.<\/jats:p>","DOI":"10.1002\/adhm.202502018","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T07:06:44Z","timestamp":1753081604000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cancer\u2010Specific and Pro\u2010Apoptotic PEGylated Liposomes Containing SMAC\u2010Mimetic Doxorubicin Prodrug for Safe High\u2010Dose Delivery in Pancreatic Cancer"],"prefix":"10.1002","volume":"14","author":[{"given":"Yeonjin","family":"Kim","sequence":"first","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Ewha Womans University  Seoul 03760 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinseong","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Ewha Womans University  Seoul 03760 Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence Ewha Womans University  Seoul 03760 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hye","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Ulsan College of Medicine Asan Medical Center  Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inki","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Convergence Medicine ASAN Medical Center  Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayeon","family":"Shim","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Ewha Womans University  Seoul 03760 Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence Ewha Womans University  Seoul 03760 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeonji","family":"Yoo","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Ewha Womans University  Seoul 03760 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunsung","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Ulsan College of Medicine Asan Medical Center  Seoul 05505 Republic of Korea"},{"name":"Department of Convergence Medicine ASAN Medical Center  Seoul 05505 Republic of Korea"},{"name":"Division of Hepato\u2010Biliary and Pancreatic Surgery Department of Surgery University of Ulsan College of Medicine Asan Medical Center  Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-188X","authenticated-orcid":false,"given":"Kwangmeyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Ewha Womans University  Seoul 03760 Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence Ewha Womans University  Seoul 03760 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.22"},{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00141-0"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2010.08.027"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201303123"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.279201"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-021-01181-z"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.3c00195"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.09.140"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602001"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2017.09.026"},{"key":"e_1_2_8_8_1","first-page":"3583","volume":"22","author":"Syrigos K. 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