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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Costa, SA; Mozhdehi, D; Dzuricky, MJ; Isaacs, FJ; Brustad, EM; Chilkoti, A

Published Date

  • January 2019

Published In

Volume / Issue

  • 19 / 1

Start / End Page

  • 247 - 254

PubMed ID

  • 30540482

Pubmed Central ID

  • PMC6465085

Electronic International Standard Serial Number (EISSN)

  • 1530-6992

International Standard Serial Number (ISSN)

  • 1530-6984

Digital Object Identifier (DOI)

  • 10.1021/acs.nanolett.8b03837


  • eng