Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer

Abstract

Dasatinib (DAS) is a multikinase inhibitor that acts on several signaling kinases. DAS is used as a second-line treatment for chronic accelerated myeloid and Philadelphia chromosome-positive acute lymphoblastic leukemia. The therapeutic potential of DAS in other solid tumours is under evaluation. As for many other compounds, an improvement in their pharmacokinetic and delivery properties would potential augment the efficacy. Antibody-targeted biodegradable nanoparticles can be useful in targeted cancer therapy. DAS has shown activity in human epidermal growth factor receptor 2 (HER2) positive tumors, so conjugation of this compound with the anti-HER2 antibody trastuzumab (TAB) with the use of nanocarriers could improve its efficacy. TAB-targeted DAS-loaded nanoparticles were generated by nanotechnology. The guided nanocarriers enhanced in vitro cytotoxicity of DAS against HER2 human breast cancer cell lines. Cellular mechanistic, release studies and nanoparticles stability were undertaken to provide evidences for positioning DAS-loaded TAB-targeted nanoparticles as a potential strategy for further development in HER2-overexpressing breast cancer therapy.

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

“…Polylactide (PLA) and Polyethyleneimine (PEI), FDA-approved polymers, were selected as building blocks for the generation of MZ1-loaded NPs (MZ1-NPs), as described elsewhere [ 30 ]. NPs were loaded with MZ1 and conjugated with Trastuzumab by covalent coupling via zero-cross-linker carbodiimide chemistry to generate MZ1-loaded ACNPs ( Scheme 1 ).…”

“…The standard protocol of Bradford assay was employed for quantifying the concentration of the antibody in the supernatant (see Section 2 ). 1.6 nM was the trastuzumab cargo over the NP surface selected in accordance with previously published results [ 30 ]. The trastuzumab conjugation was confirmed by the decrease in the surface charge of NPs (Z-potential) from +46.3 mV (MZ1-NPs) to +31.8 mV (MZ1-ACNPs).…”

“…MZ1-loaded ACNPs (MZ1-ACNPs). Trastuzumab was chemically conjugated to PEI coating NPs via carbodiimide chemistry [ 30 ]. Briefly, tratuzumab (21 mg mL −1 in 0.1 M PBS, pH 7.4) were activated in 4 mL of PBS (0.1 M, pH 5.8) using 40 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and 9.7 mg of N-hydroxysuccinimide (NHS).…”

“…Viability. Cells were seeded onto 48-well plates at a dilution of 10,000 cells by well, for 24 h in the conditions described before [ 30 ]. HER2+ cells were treated with vehicle (Ctl), MZ1 (50, 100, 200 and 400 nM), MZ1- NPs (5, 25, 50 and 100 nM) and and MZ1-ACNPs (5, 25, 50 and 100 nM of MZ1).…”

Extra-Small Gold Nanospheres Decorated With a Thiol Functionalized Biodegradable and Biocompatible Linear Polyamidoamine as Nanovectors of Anticancer Molecules

“…Aiming to assess the activities of Au@P functionalized with Trastuzumab, SKBR-3, human breast cancer cell line was selected as target cell model. This cell line overexpresses HER2, itself the target of Trastuzumab, and has been used extensively as an in vitro model for evaluating the anticancer targeting of nanoparticles as tool to enhance the selectivity and specificity of therapies against cancer cells (Kim et al, 2011;Martínez-Jothar et al, 2019;Niza et al, 2019). Moreover, to confirm the selective effect of Au@PT toward the HER2-receptor, others two cell lines were included for comparative analysis: MCF-7, a human breast cancer expressing low HER-2 as control, and the murine fibroblasts cell line, NIH-3T3, as health cell model.…”