Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

Abstract

Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem.

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe 99mTc-HYNIC-H6F in Breast Cancer Mouse Models

“…The results of incubation with FITC-trastuzumab clearly demonstrated that MDA-MB-453 cells were HER2-positive whereas MDA-MB-231 cells were HER2-negative ( Figs. 2A and 2B), consistent with the results of previous studies (26,27). The FITC-labeled H6F peptide exhibited similar binding specificity with trastuzumab in selected breast cancer cells (Fig.…”

Polymer nanocarriers for MicroRNA delivery

“…The main reason for this toxicity is that the positive charge of the dendrimers, which enhances cellular uptake, also leads to destabilization of negatively charged cell membranes . When dendrimers are conjugated to targeting antibodies, drug molecules, or nucleic acids, this decreases the number of reactive groups, which subsequently reduces the charge and associated toxicity . One strategy to improve dendrimers' safety is to modify their surface with PEG moieties, which reduces cytotoxicity and extends circulation .…”

Designing Two‐Dimensional Nanosheets for Improving Drug Delivery to Fucose‐Receptor‐Overexpressing Cancer Cells

“…Various receptors such as folate, transferrin, integrins, and epidermal growth factor have been widely targeted for both imaging and drug delivery purposes. Various targeted molecules including saccharides, antibodies, vitamins, peptides, organic molecules, transferrin, etc., are attached to the outer surface of different nanocarriers. These molecules are directly attached to a site‐specific receptor that is overexpressed on the surface of specific cancer cells and tissues.…”