51. Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer
- Author
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Deep Pooja, Hitesh Kulhari, Shweta Shrivastava, Vegi Ganga Modi Naidu, David J. Adams, Madhusudana Kuncha, Vipul Bansal, and Ramakrishna Sistla
- Subjects
Dendrimers ,Cell Survival ,Receptor, ErbB-2 ,Biocompatible Materials ,Breast Neoplasms ,02 engineering and technology ,Pharmacology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Breast cancer ,Trastuzumab ,In vivo ,Dendrimer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Fluorescein isothiocyanate ,skin and connective tissue diseases ,Cell Proliferation ,Multidisciplinary ,021001 nanoscience & nanotechnology ,medicine.disease ,In vitro ,chemistry ,Docetaxel ,030220 oncology & carcinogenesis ,Cancer cell ,Female ,0210 nano-technology ,Fluorescein-5-isothiocyanate ,medicine.drug - 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.
- Published
- 2016
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