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PAMAM G4.5 dendrimers for targeted delivery of ferulic acid and paclitaxel to overcome P-glycoprotein-mediated multidrug resistance.

Authors
  • Anbazhagan, Rajeshkumar1, 2
  • Muthusamy, Ganesan1, 3
  • Krishnamoorthi, Rajakumari1, 2
  • Kumaresan, Swedha1, 4
  • Nagarajan, Rajendra Prasad3
  • Lai, Juin-Yih1, 2, 5
  • Yang, Jen Ming6, 7
  • Tsai, Hsieh-Chih1, 2
  • 1 Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, 106, Taiwan, ROC. , (Taiwan)
  • 2 Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei, Taiwan, 106, ROC. , (Taiwan)
  • 3 Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, 608002, Tamil Nadu, India. , (India)
  • 4 Women's Christian College, Collage Road, Chennai, 600006, Tamil Nadu, India. , (India)
  • 5 R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Tao-Yuan, 320, Taiwan. , (Taiwan)
  • 6 Department of Chemical and Materials Engineering, Chang Gung University, Tao-Yuan, 333, Taiwan. , (Taiwan)
  • 7 Department of General Dentistry, Chang Gung Memorial Hospital, Tao-Yuan, 333, Taiwan, ROC. , (Taiwan)
Type
Published Article
Journal
Biotechnology and Bioengineering
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 07, 2020
Identifiers
DOI: 10.1002/bit.27645
PMID: 33289076
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

In this study, we prepared ferulic acid (FA) and paclitaxel (PTX) co-loaded polyamidoamine (PAMAM) dendrimers conjugated with arginyl-glycyl-aspartic acid (RGD) to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). FA was released in greater extent (80%) from the outer layer of the dendrimers compared to PTX (70%) from the interior of the dendrimers. FA improved intracellular availability of PTX via P-gp modulation in drug-resistant cells. In vitro drug uptake data show higher PTX delivery with RGD-PAMAM-FP than with PAMAM-FP in drug resistant KB CH-R 8-5 cell lines. This indicates that RGD facilitates intracellular PTX accumulation through active targeting in multidrug-resistant KB CH-R 8-5 cells. The terminal deoxynucleotidyl transferase (TdT) 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assay data and membrane potential analysis in mitochondria confirm the enhanced anticancer potential of RGD-PAMAM-FP nanoaggregates in drug-resistant cells. We also confirmed by the increased protein levels of proapoptotic factors such as caspase 3, caspase 9, p53, and Bax after treatment with RGD-PAMAM-FP nanoaggregates and also downregulates antiapoptotic factors. Hence, FA-PTX co-loaded, RGD-functionalized PAMAM G4.5 dendrimers may be considered as an effective therapeutic strategy to induce apoptosis in P-gp-overexpressing, multidrug-resistant cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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