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However, angiogenesis inhibitors alone cannot meet the needs of tumor therapy. This study prepared a new drug conjugate (PTX\u2010GSHP\u2010CYS\u2010ES2, PGCE) by combining polysaccharides (heparin without anticoagulant activity, GSHP), chemotherapeutic drugs (paclitaxel, PTX), and antiangiogenic drugs (ES2). Furthermore, a tumor\u2010targeted prodrug nanoparticle delivery system is established. The nanoparticles appear to accumulate in the mitochondrial of tumor cells and achieve ES2 and PTX release under high glutathione and acidic environment. It has been confirmed that PGCE inhibited the expression of multiple metastasis\u2010related proteins by targeting the tumor cell mitochondrial apparatus and disrupting their structure. Furthermore, PGCE nanoparticles inhibit migration, invasion, and angiogenesis in B16F10 tumor\u2010bearing mice and suppress tumor growth and metastasis in vitro. Further in vitro and in vivo experiments show that PGCE has strong antitumor growth and metastatic effects and exhibits efficient anti\u2010angiogenesis properties. This multi\u2010targeted nanoparticle system potentially enhances the antitumor and anti\u2010metastatic effects of combination chemotherapy and antiangiogenic drugs.<\/jats:p>","DOI":"10.1002\/smll.202206491","type":"journal-article","created":{"date-parts":[[2023,3,25]],"date-time":"2023-03-25T15:40:34Z","timestamp":1679758834000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Glycol\u2010Split Heparin\u2010Linked Prodrug Nanoparticles Target the Mitochondrion Apparatus for Cancer Metastasis Treatment"],"prefix":"10.1002","volume":"19","author":[{"given":"Feng","family":"Sun","sequence":"first","affiliation":[{"name":"National Glycoengineering Research Center Shandong University  Qingdao Shandong 266237 China"},{"name":"NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate\u2010Based Medicine Shandong University  Qingdao 266237 China"},{"name":"Shandong Provincial Technology Innovation Center 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