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Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin.

Publication ,  Journal Article
Yousefpour, P; Ahn, L; Tewksbury, J; Saha, S; Costa, SA; Bellucci, JJ; Li, X; Chilkoti, A
Published in: Small (Weinheim an der Bergstrasse, Germany)
March 2019

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.

Duke Scholars

Published In

Small (Weinheim an der Bergstrasse, Germany)

DOI

EISSN

1613-6829

ISSN

1613-6810

Publication Date

March 2019

Volume

15

Issue

12

Start / End Page

e1804452

Related Subject Headings

  • Tissue Distribution
  • Thermodynamics
  • Peptides
  • Nanoscience & Nanotechnology
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Hydrazones
  • Humans
  • Doxorubicin
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Yousefpour, P., Ahn, L., Tewksbury, J., Saha, S., Costa, S. A., Bellucci, J. J., … Chilkoti, A. (2019). Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin. Small (Weinheim an Der Bergstrasse, Germany), 15(12), e1804452. https://doi.org/10.1002/smll.201804452
Yousefpour, Parisa, Lucie Ahn, Joel Tewksbury, Soumen Saha, Simone A. Costa, Joseph J. Bellucci, Xinghai Li, and Ashutosh Chilkoti. “Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin.Small (Weinheim an Der Bergstrasse, Germany) 15, no. 12 (March 2019): e1804452. https://doi.org/10.1002/smll.201804452.
Yousefpour P, Ahn L, Tewksbury J, Saha S, Costa SA, Bellucci JJ, et al. Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin. Small (Weinheim an der Bergstrasse, Germany). 2019 Mar;15(12):e1804452.
Yousefpour, Parisa, et al. “Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin.Small (Weinheim an Der Bergstrasse, Germany), vol. 15, no. 12, Mar. 2019, p. e1804452. Epmc, doi:10.1002/smll.201804452.
Yousefpour P, Ahn L, Tewksbury J, Saha S, Costa SA, Bellucci JJ, Li X, Chilkoti A. Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin. Small (Weinheim an der Bergstrasse, Germany). 2019 Mar;15(12):e1804452.
Journal cover image

Published In

Small (Weinheim an der Bergstrasse, Germany)

DOI

EISSN

1613-6829

ISSN

1613-6810

Publication Date

March 2019

Volume

15

Issue

12

Start / End Page

e1804452

Related Subject Headings

  • Tissue Distribution
  • Thermodynamics
  • Peptides
  • Nanoscience & Nanotechnology
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Hydrazones
  • Humans
  • Doxorubicin