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Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy

Authors Aleanizy FS, Alqahtani FY, Seto S, Al Khalil N, Aleshaiwi L, Alghamdi M, Alquadeib B, Alkahtani H, Aldarwesh A, Alqahtani QH, Abdelhady HG, Alsarra I

Received 4 April 2020

Accepted for publication 8 July 2020

Published 30 July 2020 Volume 2020:15 Pages 5433—5443

DOI https://doi.org/10.2147/IJN.S256898

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo


Fadilah Sfouq Aleanizy,1,* Fulwah Yahya Alqahtani,1,* Sara Seto,1 Nora Al Khalil,1 Lama Aleshaiwi,1 Manar Alghamdi,1 Bushra Alquadeib,1 Hamad Alkahtani,2 Amal Aldarwesh,3 Qamraa Hamad Alqahtani,4 Hosam Gharib Abdelhady,5 Ibrahim Alsarra1

1Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 2Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 3Department of Optometry, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia; 4Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 5Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA

*These authors contributed equally to this work

Correspondence: Fadilah Sfouq Aleanizy Email faleanizy@ksu.edu.sa

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.

Keywords: neratinib, targeted dendrimer, trastuzumab, Her2-positive, breast cancer

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