title: 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.
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, VIC, 3083 Australia.|Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC, 3001, Australia.|IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, 500607, India.|Medicinal Chemistry &Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, 500607, India.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Kulhari
authors.affiliation: Medicinal Chemistry &Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, 500607, India.
authors.forename: Deep
authors.initials: D
authors.lastname: Pooja
authors.affiliation: Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Hyderabad, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Shrivastava
authors.affiliation: Medicinal Chemistry &Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, 500607, India.
authors.forename: Madhusudana
authors.initials: M
authors.lastname: Kuncha
authors.affiliation: Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Hyderabad, India.
authors.forename: V G M
authors.initials: VGM
authors.lastname: Naidu
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, VIC, 3083 Australia.|Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC, 3001, Australia.
authors.forename: Vipul
authors.initials: V
authors.lastname: Bansal
authors.affiliation: Medicinal Chemistry &Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, 500607, India.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sistla
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, VIC, 3083 Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001672:Biocompatible Materials; D050091:Dendrimers; D016650:Fluorescein-5-isothiocyanate; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C104700:PAMAM Starburst; C508053:ERBB2 protein, human