<p>Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy</p>

Abstract

Background: Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy. Methods: TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake. Results: The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer. Conclusion: In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.

Development and Evaluation of 1′-Acetoxychavicol Acetate (ACA)-Loaded Nanostructured Lipid Carriers for Prostate Cancer Therapy

“…This time-dependent uptake of NLCs has been similarly shown in other NLC-based systems from previous studies [ 38 , 44 ]. Nevertheless, the superior uptake of both types of NLC carriers in comparison to the free suspension demonstrates the improved function of the carriers in delivering the active compound [ 26 , 45 ].…”

Nanomedicine-Based Delivery Strategies for Breast Cancer Treatment and Management

“…The in vitro viability of SKBR-3 cells after 48 h for neratinib, neratinib-conjugated-dendrimers, and neratinib-loaded-dendrimers-trastuzumab was 40%, 36%, and 33%, respectively. Trastuzumab’s affinity for HER2 receptors expressed in SKBR-3 cells enhanced the internalization of the formulation through receptor-mediated endocytosis [ 92 ].…”

The Therapeutic Efficacy of Dendrimer and Micelle Formulations for Breast Cancer Treatment

“…The combination of trastuzumad with neratinib using dendrimers is also effective against drug resistance and useful for targeted drug delivery. Aleanizy et al formulated trastuzumab-grafted dendrimers loaded with neratinib for dual treatment of breast cancer to reduce drug resistance and promote targeted therapy [ 88 ]. Trastuzumab was conjugated to the surface of the dendrimer via maleimide-poly(ethylene) glycol- N -hydroxysuccinimide linker.…”

“…In vitro analysis of the SKBR-3 cell viability after 48 h was 40%, 36%, and 33% for neratinib, neratinib-conjugated-dendrimers, and neratinib-loaded-dendrimers-trastuzumab, respectively. The affinity of trastuzumab to the HER2 receptors expressed in SKBR-3 cells promoted the internalization of the formulation via receptor-mediated endocytosis [ 88 ]. Chan and co-workers formulated diethylenetriaminepentaacetic acid-modified G4 PAMAM dendrimers conjugated with trastuzumab and nuclear translocation sequence (NTS) for breast cancer therapy.…”

“…Aleanizy et al reported trastuzumab-grafted dendrimers. The drug was conjugated to the surface of dendrimer via maleimide-poly(ethylene) glycol- N -hydroxysuccinimide linker to promote internalization of the formulation via receptor-mediated endocytosis [ 88 ]. Zhang et al reported PEGylated lysine peptide dendrimers loaded with gemcitabine via the enzyme-cleavable linker, glycyl phenylalanyl leucyl glycine tetra-peptide.…”