Efficient PEGylated dendrimer nanoplatform for codelivery of hyaluronidase and methotrexate: A new frontier in chemotherapeutic efficacy and tumor penetration
Abstract
The condensed extracellular matrix (ECM) surrounding cancer cells results in the formation of a biophysical barrier versus chemotherapeutic drug penetration into deeper regions of many solid malignancies. To cope with this drawback, the present study inquired the therapeutic potential of a hyaluronidase (Hyal)-modified hyperbranched poly(amide amine) (PAMAM) loaded with an anticancer drug, methotrexate (MTX), to improve breast cancer chemoresistance. The focus is on reducing the hyaluronic acid accumulation as a major component of the tumor ECM. The decoration of the prepared pH-responsive nanoplatform with a relatively low density layer of polyethylene glycol (PEG) improved its stability and performance. These processes were characterized by different instruments and an enzymatic activity assessment. Despite the short half-life of pristine hyaluronidase, the Hyal-immobilized nanoplatform displayed enhanced enzyme stability, especially against protease degradation, and prolonged half-life after incubation in human plasma. The MTX loaded into carboxylate nanocarrier (PAMAM-MTX/SA/Hyal/PEG) exhibited an outstanding ability for controlled release of MTX. The results of the hemolysis assay confirmed the good blood compatibility of the as-prepared nanoplatform. The cytotoxicity assessment of various nanoformulations using an MTS-based assay on MCF-7 and MCF-10A cell lines revealed that PAMAM-MTX/SA/Hyal/PEG was more efficient against tumor cells than free MTX over 72 h. In addition, the effect of PAMAM-MTX/SA/Hyal/PEG against MCF-7 cells showed noteworthy induction of apoptosis and facilitated uptake by MCF-7 cells and penetration in MCF-7 3D tumor spheroids compared to free MTX. Thus, the synthesized nanoplatform indicated in vitro controlled release of MTX with the advantage of an adjuvant Hyal-based nanosystem. This outlook suggests a novel multifunctional nanoplatform to improve anticancer drug delivery systems by effective modulation of the tumor microenvironment.
Keywords
combination therapy, hyaluronic acid, hyaluronidase, methotrexate, tumor penetration
Document Type
Journal Article
Date of Publication
1-1-2024
Volume
7
Issue
15
Publication Title
ACS Applied Nano Materials
Publisher
ACS
School
Mineral Recovery Research Centre / School of Engineering
Funders
University of Isfahan / Biotechnology Development Council of the Islamic Republic of Iran
Grant Number
970704
Copyright
subscription content
First Page
17262
Last Page
17277
Comments
Soozanipour, A., Ejeian, F., Razmjou, A., Asadnia, M., Nasr-Esfahani, M. H., & Taheri-Kafrani, A. (2024). Efficient PEGylated Dendrimer Nanoplatform for Codelivery of Hyaluronidase and Methotrexate: A New Frontier in Chemotherapeutic Efficacy and Tumor Penetration. ACS Applied Nano Materials, 7(15), 17262-17277. https://doi.org/10.1021/acsanm.4c01406