Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with Lu

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2016 Dec 18

PMID 27987070

Citations 29

Authors

Zhongli Cai

Simmyung Yook

Yijie Lu

Dane Bergstrom

Mitchell A Winnik

Jean-Philippe Pignol

Raymond M Reilly

Affiliations

Soon will be listed here.

Abstract

Purpose: To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with Lu (trastuzumab-AuNP-Lu) targeted to HER2 with non-targeted AuNP-Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection.

Methods: AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex Lu. The binding and internalization of trastuzumab-AuNP-Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-Lu or AuNP-Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-Lu, AuNP-Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated.

Results: Trastuzumab-AuNP-Lu was bound and internalized by HER2 positive BC cells (K = 7.6 ± 2.0 nM). Trastuzumab-AuNP-Lu was 42.9 and 2.6-fold more effective than AuNP-Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 10 HER2/cell) and MDA-MB-361 (5.1 × 10 HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-Lu than AuNP-Lu. Trastuzumab-AuNP-Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-Lu or AuNP-Lu treatments.

Conclusion: Trastuzumab-AuNP-Lu enables an efficient local radiation treatment of HER2-positive BC.

Citing Articles

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In Vitro Assessment of Lu-Labeled Trastuzumab-Targeted Mesoporous Carbon@Silica Nanostructure for the Treatment of HER2-Positive Breast Cancer.

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