Original ArticleSequential release of epigallocatechin gallate and paclitaxel from PLGA-casein core/shell nanoparticles sensitizes drug-resistant breast cancer cells
Graphical Abstract
Combination nanomedicine of EGCG and Paclitaxel in a core-shell nanocarrier sensitizes drug-resistant breast cancer cells to low doses of Paclitaxel.
Section snippets
Background
Breast cancer is the most common cancer that afflicts women worldwide and is also a major cause of cancer deaths among them.1 Chemotherapy is a widely accepted option for breast cancer. Of the various cytotoxic drugs administered, the taxane Paclitaxel (Ptx), is an extensively used antineoplastic drug exhibiting a single-agent overall response rate of 44-62%.2 However, several lines of evidence indicate that Ptx treatment can antagonize the therapy by inducing reactive oxygen species (ROS)
Materials and Methods
PLGA-Casein core/shell nanoparticles of 190 ± 12 nm particle size and surface charge − 41 ± 3.4 mV entrapping a combination of Ptx and EGCG at different doses in the core and shell respectively were prepared by an emulsion-precipitation route, as reported earlier.19 Targeted nanoparticles were developed using anti-EGFR and anti-HER2 antibodies for in vitro evaluation on MDA-MB-231 cells (anti-EGFR) and patient-derived tumor cells (anti-EGFR, anti-HER2). Refer to the supporting information for details.
Preparation and characterization of targeted dual drug-loaded core/shell nanoparticles
To prepare antibody-targeted drug-loaded nanoparticles, EDC-NHS coupling chemistry was employed, wherein the carboxyl groups on the surface of Casein shell were activated using EDC followed by stabilization with NHS. This yielded reactive –COO− which interacts with the amine groups in the antibody to form an amide linkage (Figure S1 Supplementary Information). EGFR antibody conjugation efficiency was measured to be ~ 80% by spectrofluorimetry for an optimal antibody concentration of 200 ng/mL. It
Discussion
It is crucial to control Ptx-induced activation of NF-κB and its downstream responses, since this pathway regulates genes central to metastasis, angiogenesis and drug-resistance.8, 9, 10, 11, 20 The overexpression of P-gp, the efflux pump, driven by Ptx-induced activation of NF-κB has been implicated as a mechanism involved in NF-κB induced drug resistance.21, 22 Several other mechanisms downstream of NF-κB are also indicated in Ptx resistance.23, 24, 25 Therefore, the key objective of our
Acknowledgement
Authors thank Mr. Sajin P. Ravi for SEM analysis, Ms. Sreerekha P. R. for FACS analysis, Mr. Sarath S for Confocal analysis, and Ms. Aswathy J for the technical help extended for immunohistochemistry. Authors also thank Amrita Vishwa Vidyapeetham University for providing all infrastructural support for the research work.
References (44)
- et al.
Direct effect of Taxol on free radical formation and mitochondrial permeability transition
Free Radic Biol Med
(2001) - et al.
NF-kappa B-mediated chemoresistance in breast cancer cells
Surgery
(2001) - et al.
Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations
Am J Clin Nutr
(2005) - et al.
Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications
Biochem Pharmacol
(2011) - et al.
Epigallocatechin-3-gallate is absorbed but extensively glucuronidated following oral administration to mice
J Nutr
(2003) - et al.
Sequentially releasing dual-drug-loaded PLGA-casein core/shell nanomedicine: design, synthesis, biocompatibility and pharmacokinetics
Acta Biomater
(2014) - et al.
2-Acetylaminofluorene up-regulates rat mdr1b expression through generating reactive oxygen species that activate NF-kappa B pathway
J Biol Chem
(2001) - et al.
Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells
Cytokine
(2002) - et al.
Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells
Cancer Lett
(2010) - et al.
Combined-modality radioimmunotherapy: synergistic effect of paclitaxel and additive effect of bevacizumab
Nucl Med Biol
(2012)
Activation of NF-kappaB by antineoplastic agents. Role of protein kinase C
J Biol Chem
Nab-paclitaxel efficacy in the orthotopic model of human breast cancer is significantly enhanced by concurrent anti-vascular endothelial growth factor A therapy
Neoplasia
Understanding the biology of triple-negative breast cancer
Ann Oncol
Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer
Ann Oncol
An international comparison of male and female breast cancer incidence rates
Int J Cancer
Single-agent use of Taxol (paclitaxel) in breast cancer
Ann Oncol
Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species
Cancer Res
Managing taxane toxicities
Support Care Cancer
Myalgias and arthralgias associated with paclitaxel
Oncology (Williston Park)
Incidence of taxane-induced pain and distress in patients receiving chemotherapy for early-stage breast cancer: a retrospective, outcomes-based survey
Curr Oncol
Activators and target genes of Rel/NF-kappaB transcription factors
Oncogene
Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells
Cardiovasc Res
Cited by (94)
Green tea: Current trends and prospects in nutraceutical and pharmaceutical aspects
2023, Journal of Herbal MedicineEGCG adjuvant chemotherapy: Current status and future perspectives
2023, European Journal of Medicinal ChemistryProteins and their functionalization for finding therapeutic avenues in cancer: Current status and future prospective
2023, Biochimica et Biophysica Acta - Reviews on CancerCasein-based nanosystems for therapeutic applications
2023, Polymeric Nanosystems: Theranostic Nanosystems: Volume 1
Sources of Support for Research: Indian Council of Medical Research, Government of India.
Conflict of Interest: The authors declare that there are no conflicts of interest.