Feature Article
HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

https://doi.org/10.1016/j.nano.2016.07.013Get rights and content
Under a Creative Commons license
open access

Abstract

HER2+ breast cancer is one of the most aggressive forms of breast cancer. The new polymalic acid-based mini nanodrug copolymers are synthesized and specifically characterized to inhibit growth of HER2+ breast cancer. These mini nanodrugs are highly effective and in the clinic may substitute for trastuzumab (the marketed therapeutic antibody) and antibody-targeted nanobioconjugates. Novel mini nanodrugs are designed to have slender shape and small size. HER2+ cells were recognized by the polymer-attached trastuzumab-mimetic 12-mer peptide. Synthesis of the nascent cell-transmembrane HER2/neu receptors by HER2+ cells was inhibited by antisense oligonucleotides that prevented cancer cell proliferation and significantly reduced tumor size by more than 15 times vs. untreated control or PBS-treated group. We emphasize that the shape and size of mini nanodrugs can enhance penetration of multiple bio-barriers to facilitate highly effective treatment. Replacement of trastuzumab by the mimetic peptide favors reduced production costs and technical efforts, and a negligible immune response.

Graphical Abstract

Nanodrug trafficking efficacy through tissue and cellular bio-barriers depends on vehicle size and shape. Using slender polymers conjugated with minute-targeting molecules and drugs, we boosted delivery to and treatment efficacy of HER2+ breast cancer using a mini nanodrug with a specific mimetic peptide that replaced the HER2+ antibody.

Image 1
  1. Download : Download high-res image (97KB)
  2. Download : Download full-size image

Key words

HER2+ breast cancer
Polymer nanoconjugate
Trastuzumab mimetic peptide
8-arm starPEG
Polymalic acid

Abbreviations

AHNP
anti-HER2/neu peptide
Alexa
Alexa Fluor 680 (fluorescent dye)
anti-TfR
anti-transferrin receptor
AON
antisense oligonucleotide
ATCC
American Type Culture Collection
BT474
HER2 overexpressing human breast cancer cell line
DCC
N,N′-dicyclohexylcarbodiimide
DOTA
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
EGFR
epidermal growth factor receptor
FBS
fetal bovine serum
HER2
neu, c-erbB2, members of the epidermal growth factor HER family of tyrosine kinase receptors
SEC-HPLC
size exclusion chromatography-high performance liquid chromatography
IV
intravenous
LLL
leucyl-N-leucyl-N-leucine
Mal
maleimide
MEA
2-mercapto-1-ethylamine
NHS
N-hydroxysuccinimide ester
No drug
P/LLL(40%)/PEG3400-starPEG(PEG200-AHNP)2 (2%)
PBS
phosphate-buffered saline
PEG200, PEG2000, PEG3400
polyethylene glycol (PEG) with molecular weights of 200, 2000, and 3400, respectively
PDP
3-(2-pyridyldithio)-propionic acid
PMLA or P
poly(β-L-malic acid)
SPR
surface plasmon resonance
starPEG
8-arm PEG carboxylic acid (−COOH)
TEM
transmission electron microscopy
TLC
thin layer chromatography
RU
resonance unit.

Cited by (0)

Financial support: this work was supported by the Martz Translational Breast Cancer Research Discovery Fund (E.H.) and by the NIH/NCI grant R01CA136841 (J.Y.L.).

Author contributions: E.H. designed and coordinated the project together with J.Y.L. R.M. and P.H. carried out the SPR measurements. H.D. performed the chemical syntheses. R.P. contributed to the chemical synthesis. P.R.G., A.G., and I.F. conducted the biological experiments and contributed to the manuscript preparation.

Conflict of interest: J.Y.L. is co-founder and E.H. is director of chemical synthesis of Arrogene Inc.

1

Authors contributed equally.

2

Senior authors.

© 2016 The Authors. Published by Elsevier Inc.