Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin. Issue 12 (13th February 2019)

• Record Type: Journal Article
• Authors: Yousefpour, Parisa; Ahn, Lucie; Tewksbury, Joel; Saha, Soumen; Costa, Simone A.; Bellucci, Joseph J.; Li, Xinghai; Chilkoti, Ashutosh
• Is Part Of: Small. Volume 15:Issue 12(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-02-13
• Subjects: albumin binding -- cancer -- doxorubicin -- drug delivery -- peptides; Nanotechnology -- Periodicals; Nanoparticles -- Periodicals; Microtechnology -- Periodicals; 620.5
• DOI: 10.1002/smll.201804452
• Languages: English
• ISSNs: 1613-6810

Abstract

Abstract: Short circulation time and off‐target toxicity are the main challenges faced by small‐molecule chemotherapeutics. To overcome these shortcomings, an albumin‐binding peptide conjugate of chemotherapeutics is developed that binds specifically to endogenous albumin and harnesses its favorable pharmacokinetics and pharmacodynamics for drug delivery to tumors. A protein‐G‐derived albumin‐binding domain (ABD) is conjugated with doxorubicin (Dox) via a pH‐sensitive linker. One to two Dox molecules are conjugated to ABD without loss of aqueous solubility. The albumin‐binding ABD–Dox conjugate exhibits nanomolar affinity for human and mouse albumin, and upon administration in mice, shows a plasma half‐life of 29.4 h, which is close to that of mouse albumin. Additionally, 2 h after administration, ABD–Dox exhibits an approximately 4‐fold higher concentration in the tumor than free Dox. Free Dox clears quickly from the tumor, while ABD–Dox maintains a steady concentration in the tumor for at least 72 h, so that its relative accumulation at 72 h is ≈120‐fold greater than that of free Dox. The improved pharmacokinetics and biodistribution of ABD–Dox result in enhanced therapeutic efficacy in syngeneic C26 colon carcinoma and MIA PaCa‐2 pancreatic tumor xenografts, compared with free Dox and aldoxorubicin, an albumin‐reactive Dox prodrug currently in clinical development. Abstract : An albumin‐binding peptide conjugate of small‐molecule chemotherapeutics that binds and co‐opts albumin in vivo for drug delivery to tumors is developed. A protein‐G‐derived albumin‐binding domain is conjugated with doxorubicin via a pH‐sensitive linker, and the resulting conjugate shows superior therapeutic efficacy compared with the free drug and an albumin‐reactive doxorubicin formulation currently in clinical development.