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Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin
Author(s) -
Yousefpour Parisa,
Ahn Lucie,
Tewksbury Joel,
Saha Soumen,
Costa Simone A.,
Bellucci Joseph J.,
Li Xinghai,
Chilkoti Ashutosh
Publication year - 2019
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.201804452
Subject(s) - albumin , pharmacokinetics , conjugate , doxorubicin , prodrug , biodistribution , pharmacology , chemistry , serum albumin , in vivo , linker , bioavailability , human serum albumin , peptide , biochemistry , medicine , biology , chemotherapy , in vitro , mathematical analysis , mathematics , microbiology and biotechnology , computer science , operating system
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.