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Self-assembling chimeric polypeptide–doxorubicin conjugate nanoparticles that abolish tumours after a single injection

Nature Materials volume 8, pages 993–999 (2009)Cite this article

Abstract

New strategies to self-assemble biocompatible materials into nanoscale, drug-loaded packages with improved therapeutic efficacy are needed for nanomedicine. To address this need, we developed artificial recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into sub-100-nm-sized, near-monodisperse nanoparticles on conjugation of diverse hydrophobic molecules, including chemotherapeutics. These CPs consist of a biodegradable polypeptide that is attached to a short Cys-rich segment. Covalent modification of the Cys residues with a structurally diverse set of hydrophobic small molecules, including chemotherapeutics, leads to spontaneous formation of nanoparticles over a range of CP compositions and molecular weights. When used to deliver chemotherapeutics to a murine cancer model, CP nanoparticles have a fourfold higher maximum tolerated dose than free drug, and induce nearly complete tumour regression after a single dose. This simple strategy can promote co-assembly of drugs, imaging agents and targeting moieties into multifunctional nanomedicines.

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Figure 1: Structure of CP–Dox conjugate.
Figure 2: Characterization of CP–Dox nanoparticles.
Figure 3: Internalization of CP–Dox and delivery of drug to the nucleus.
Figure 4: Plasma pharmacokinetics and tissue biodistribution.
Figure 5: Anti-tumour activity of CP–Dox nanoparticles.
Figure 6: Genomic profiles of CP–Dox- and free-Dox-treated tumour tissues.

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Acknowledgements

This work was supported with NIH grant 5F32-CA-123,889 to J.A.M. and NIH grant R01-EB-00188 to A.C. We thank M. Dewhirst, M. Zalutsky and M. Dreher for advice regarding experimental design and analysis. We thank F. C. Szoka Jr, for the use of C26 cells and B. Papahadjopoulos-Sternberg for preparation of freeze-fracture electron microscopy images. We thank S. Morales, M. Schneiderman, K. Fitzgerald and K. Liang for expression and purification of CPs used in this study.

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  1. J. Andrew MacKay and Mingnan Chen: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, 90033-9121, USA

    J. Andrew MacKay

  2. Department of Biomedical Engineering, Duke University, Durham, North Carolina, 27708-0281, USA

    Mingnan Chen, Jonathan R. McDaniel, Wenge Liu, Andrew J. Simnick & Ashutosh Chilkoti

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  1. J. Andrew MacKay
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J.A.M., M.C. and A.C. designed experiments, analysed data and prepared the manuscript. J.A.M., M.C., J.R.M., W.L. and A.J.S carried out experiments and analysed data.

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Correspondence to Ashutosh Chilkoti.

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Competing interests

A. C. has a financial interest in Phase Biopharmaceuticals, which has licensed the technology for drug delivery using elastin-like biopolymers from Duke University.

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Andrew MacKay, J., Chen, M., McDaniel, J. et al. Self-assembling chimeric polypeptide–doxorubicin conjugate nanoparticles that abolish tumours after a single injection. Nature Mater 8, 993–999 (2009). https://doi.org/10.1038/nmat2569

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