β-casein nanovehicles for oral delivery of chemotherapeutic drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells

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Abstract

Multidrug resistance (MDR) is a primary obstacle to curative cancer therapy. We have previously demonstrated that β-casein (β-CN) micelles (β-CM) can serve as nanovehicles for oral delivery and target-activated release of hydrophobic drugs in the stomach. Herein we introduce a novel nanosystem based on β-CM, to orally deliver a synergistic combination of a chemotherapeutic drug (Paclitaxel) and a P-glycoprotein-specific transport inhibitor (Tariquidar) individually encapsulated within β-CM, for overcoming MDR in gastric cancer. Light microscopy, dynamic light scattering and zeta potential analyses revealed solubilization of these drugs by β-CN, suppressing drug crystallization. Spectrophotometry demonstrated high loading capacity and good encapsulation efficiency, whereas spectrofluorometry revealed high affinity of these drugs to β-CN. In vitro cytotoxicity assays exhibited remarkable synergistic efficacy against human MDR gastric carcinoma cells with P-glycoprotein overexpression. Oral delivery of β-CN - based nanovehicles carrying synergistic drug combinations to the stomach constitutes a novel efficacious therapeutic system that may overcome MDR in gastric cancer.

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Most cited references 54

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Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention.

Siddavaram Nagini (2012)

Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitation and hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future.

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Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues.

J Boccia, C Cordon-Cardo, B. O’Brien … (1990)

We have characterized the normal human tissue distribution and tumor expression of the human multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) by immunohistochemical staining of frozen tissue sections of human normal and tumor tissues, using three mouse monoclonal antibodies (MAb) which recognize at least two different epitopes of Pgp. Pgp expression on normal human tissues was detected in specialized epithelial cells with secretory/excretory functions, trophoblasts in the placenta, and on endothelial cells of capillary blood vessels at blood-tissue barrier sites. There were significant differences in the staining patterns of these MAb. Mouse MAb HYB-241 and HYB-612 each recognize an extracellular epitope of Pgp, whereas mouse MAb C219 detects a carboxy terminal intracellular epitope and has recently been reported to crossreact with the MDR3 gene product. HYB-241 and HYB-612 strongly stain endothelial cells and trophoblasts, whereas C219 is weakly positive or unreactive on these cells. Likewise, C219 strongly stains the biliary pole of hepatocytes, skeletal and heart muscle fibers, whereas HYB-241 and HYB-612 are unreactive on these cells. Immunopathological studies were performed on a wide variety of human tumors. Pgp expression on human tumors was most commonly detected in colon. renal, and adrenal carcinomas; rarely in lung and gastric carcinomas and certain germ cell tumors; and was undetectable in breast and endometrial carcinomas tested. Few sarcomas and none of the melanomas, neuroblastomas, gliomas, and pheochromocytomas had detectable Pgp expression. Intensity and pattern of staining varied among different cases of a given tumor type; although homogeneous immunoreactivity was observed, heterogeneity of expression in a single histological section was more common. The finding of Pgp expression in a variety of normal tissues with diverse physiological functions suggests that the role of Pgp may not be limited to excretion of xenobiotics. Pgp expression in capillaries of the brain and testis may explain the failure of drugs such as vincristine and actinomycin-D to penetrate into these tissues, allowing them to remain as pharmacological sanctuaries for malignant cells. Although Pgp expression can now be detected in a variety of human tumors, further studies are needed to establish the possible significance of this finding.

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Oral delivery of anticancer drugs: challenges and opportunities.

Kaushik Thanki, Rahul P Gangwal, Abhay T. Sangamwar … (2013)

The present report focuses on the various aspects of oral delivery of anticancer drugs. The significance of oral delivery in cancer therapeutics has been highlighted which principally includes improvement in quality of life of patients and reduced health care costs. Subsequently, the challenges incurred in the oral delivery of anticancer agents have been especially emphasized. Sincere efforts have been made to compile the various physicochemical properties of anticancer drugs from either literature or predicted in silico via GastroPlus™. The later section of the paper reviews various emerging trends to tackle the challenges associated with oral delivery of anticancer drugs. These invariably include efflux transporter based-, functional excipient- and nanocarrier based-approaches. The role of drug nanocrystals and various others such as polymer based- and lipid based-nanocarriers in the bioavailability enhancement along with their clinical outcomes has also been discussed exhaustively. Furthermore, an insight on the various absorption mechanisms of these nanocarriers across the gastrointestinal tract has also been highlighted.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 26 April 2016

Publication date (Electronic): 10 March 2016

Volume: 7

Issue: 17

Pages: 23322-23334

Affiliations

¹ Russell Berrie Nanotechnology Institute, Technion - Israel Institute of Technology, Haifa 3200000, Israel

² The Laboratory of Food Physical Chemistry and Biopolymeric Delivery Systems for Health, Department of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa 3200000, Israel

³ The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion - Israel Institute of Technology, Haifa 3200000, Israel

Author notes

Correspondence to: Yoav D. Livney, livney@ 123456technion.ac.il

Yehuda G. Assaraf, assaraf@ 123456technion.ac.il

Article

Publisher ID: 8019

DOI: 10.18632/oncotarget.8019

PMC ID: 5029629

PubMed ID: 26989076

SO-VID: 1c063ad6-f90a-4bab-befe-7d3f1389f647

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

β-casein nanovehicles for oral delivery of chemotherapeutic drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells

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Karger: Oncology

Most cited references 54

Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention.

Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues.

Oral delivery of anticancer drugs: challenges and opportunities.

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