Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Yousefpour, P; Ahn, L; Tewksbury, J; Saha, S; Costa, SA; Bellucci, JJ; Li, X; Chilkoti, A

Published Date

  • March 2019

Published In

Volume / Issue

  • 15 / 12

Start / End Page

  • e1804452 -

PubMed ID

  • 30756483

Pubmed Central ID

  • 30756483

Electronic International Standard Serial Number (EISSN)

  • 1613-6829

International Standard Serial Number (ISSN)

  • 1613-6810

Digital Object Identifier (DOI)

  • 10.1002/smll.201804452

Language

  • eng