Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation

Journal of Medicinal Chemistry
Huicong ZhangJin Sun

Abstract

To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromolecular prodrugs after intravenous administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, respectively), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, especially the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.

References

Nov 5, 1997·The Journal of Biological Chemistry·C TiruppathiA B Malik
Feb 5, 2003·The Journal of Experimental Medicine·Chaity ChaudhuryClark L Anderson
Oct 27, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jennifer SpratlinJohn R Mackey
Jul 9, 2005·Expert Review of Anticancer Therapy·Volker Heinemann
Apr 12, 2006·Biochemistry·Chaity ChaudhuryClark L Anderson
Jun 4, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jan H BeumerMerrill J Egorin
Jun 11, 2008·Cancer Metastasis Reviews·Osvaldo L PodhajcerAndrea S Llera
Apr 7, 2009·Nano Letters·Steven D PerraultWarren C W Chan
Oct 29, 2009·Journal of Medicinal Chemistry·David M BenderJames R McCarthy
Feb 19, 2011·Cancer Treatment Reviews·Feng YangDeliang Fu
Dec 14, 2011·Journal of Controlled Release : Official Journal of the Controlled Release Society·Felix Kratz, Bakheet Elsadek
Feb 12, 2013·Chemical Communications : Chem Comm·Verena PichlerChristian R Kowol
Mar 7, 2013·Journal of the American Chemical Society·Sukhendu MaitiJong Seung Kim
May 29, 2014·Journal of Medicinal Chemistry·Jason T WeissAsier Unciti-Broceta
Aug 16, 2016·Biomaterials·Alice GaudinW Mark Saltzman
Feb 1, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Gebremariam BirhanuAli Zandi-Karimi
Jul 2, 2017·Journal of Controlled Release : Official Journal of the Controlled Release Society·Huipeng LiMinjie Sun

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Citations

Aug 20, 2019·Current Medicinal Chemistry·He MiaoYepeng Luan
Sep 4, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Qing YaoLongfa Kou
Jul 30, 2021·Advanced Science·Yuezhou ZhangWei Huang
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan

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