Active Targeting of Cancer Cells by Nanobody Decorated Polypeptide Micelle with Bio-orthogonally Conjugated Drug

Simone A. Costa, Davoud Mozhdehi, Michael J. Dzuricky, Farren J. Isaacs, Eric M. Brustad, Ashutosh Chilkoti

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Polypeptides are promising carriers for chemotherapeutics: they have minimal toxicity, can be recombinantly synthesized with precise control over molecular weight, and enhance drug pharmacokinetics as self-assembled nanoparticles. Polypeptide-based systems also provide the ability to achieve active targeting with genetically encoded targeting ligands. While passive targeting promotes accumulation of nanocarriers in solid tumors, active targeting provides an additional layer of tunable control and widens the therapeutic window. However, fusion of most targeting proteins to polypeptide carriers exposes the limitations of this approach: the residues that are used for drug attachment are also promiscuously distributed on protein surfaces. We present here a universal methodology to solve this problem by the site-specific attachment of extrinsic moieties to polypeptide drug delivery systems without cross-reactivity to fused targeting domains. We incorporate an unnatural amino acid, p-acetylphenylalanine, to provide a biorthogonal ketone for attachment of doxorubicin in the presence of reactive amino acids in a nanobody-targeted, elastin-like polypeptide nanoparticle. These nanoparticles exhibit significantly greater cytotoxicity than nontargeted controls in multiple cancer cell lines.

Original languageEnglish (US)
JournalNano Letters
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Single-Domain Antibodies
Polypeptides
polypeptides
Micelles
micelles
drugs
cancer
Cells
Peptides
attachment
Pharmaceutical Preparations
Nanoparticles
nanoparticles
amino acids
Amino acids
Drug Residues
elastin
proteins
Proteins
Elastin

Keywords

  • active targeting
  • cancer drug delivery
  • nanoparticles
  • polypeptides
  • self-assembly
  • Unnatural amino acids

ASJC Scopus subject areas

  • Bioengineering
  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics
  • Mechanical Engineering

Cite this

Active Targeting of Cancer Cells by Nanobody Decorated Polypeptide Micelle with Bio-orthogonally Conjugated Drug. / Costa, Simone A.; Mozhdehi, Davoud; Dzuricky, Michael J.; Isaacs, Farren J.; Brustad, Eric M.; Chilkoti, Ashutosh.

In: Nano Letters, 01.01.2018.

Research output: Contribution to journalArticle

Costa, Simone A. ; Mozhdehi, Davoud ; Dzuricky, Michael J. ; Isaacs, Farren J. ; Brustad, Eric M. ; Chilkoti, Ashutosh. / Active Targeting of Cancer Cells by Nanobody Decorated Polypeptide Micelle with Bio-orthogonally Conjugated Drug. In: Nano Letters. 2018.
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