Preferential drug delivery to tumor cells than normal cells using a tunable niosome–chitosan double package nanodelivery system: a novel in vitro model

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors for which the overall survival rate worldwide is around 60%. The tumor microenvironment, including cancer-associated fibroblasts (CAFs), is believed to affect the treatment response and migration of HNSCC. The aim of this study was to create a biologically relevant HNSCC in vitro model consisting of both tumor cells and CAFs cultured in 3D to establish predictive biomarkers for treatment response, as well as to investigate the impact of CAFs on phenotype, proliferation and treatment response in HNSCC cells. Methods Three different HNSCC patient-derived tumor cell lines were cultured with and without CAFs in a 3D model. Immunohistochemistry of the proliferation marker Ki67, epidermal growth factor receptor (EGFR) and fibronectin and a TUNEL-assay were performed to analyze the effect of CAFs on both tumor cell proliferation and response to cisplatin and cetuximab treatment in tumor spheroids (3D). mRNA expression of epithelial-mesenchymal transition (EMT) and cancer stem cells markers were analyzed using qRT-PCR. Results The results demonstrated increased cell proliferation within the tumor spheroids in the presence of CAFs, correlating with increased expression of EGFR. In spheroids with increased expression of EGFR, a potentiated response to cetuximab treatment was observed. Surprisingly, an increase in Ki67 expressing tumor cells were observed in spheroids treated with cisplatin for 3 days, correlating with increased expression of EGFR. Furthermore, tumor cells co-cultured with CAFs presented an increased EMT phenotype compared to tumor cells cultured alone in 3D. Conclusion Taken together, our results reveal increased cell proliferation and elevated expression of EGFR in HNSCC tumor spheroids in the presence of CAFs. These results, together with the altered EMT phenotype, may influence the response to cetuximab or cisplatin treatment.

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Establishment and characterization of an in vitro model of human Polyomavirus BK (BKV) infected prostate normal cells

Journal of Clinical Virology ◽

10.1016/j.jcv.2016.08.279 ◽

2016 ◽

Vol 82 ◽

pp. S138

Author(s):

S. Villani ◽

N. Gagliano ◽

P. Procacci ◽

M. Dolci ◽

L. Signorini ◽

...

Keyword(s):

In Vitro Model ◽

Human Polyomavirus ◽

Normal Cells ◽

Polyomavirus Bk ◽

Vitro Model

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Nasal drug delivery – evaluation of an in vitro model using porcine nasal mucosa

European Journal of Pharmaceutical Sciences ◽

10.1016/s0928-0987(98)00023-2 ◽

1999 ◽

Vol 7 (3) ◽

pp. 197-206 ◽

Cited By ~ 47

Author(s):

Cecilia Wadell ◽

Erik Björk ◽

Ola Camber

Keyword(s):

Drug Delivery ◽

Nasal Mucosa ◽

In Vitro Model ◽

Nasal Drug Delivery ◽

Vitro Model

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Growth of tumor cells within microporous hollow fibers: An in vitro model system for studies of immunoprotein transport

Biotechnology and Bioengineering ◽

10.1002/bit.260350813 ◽

1990 ◽

Vol 35 (8) ◽

pp. 843-849 ◽

Cited By ~ 4

Author(s):

Ty R. Shockley ◽

Martin L. Yarmush

Keyword(s):

Tumor Cells ◽

In Vitro Model ◽

Model System ◽

Hollow Fibers ◽

In Vitro Model System ◽

Vitro Model ◽

Growth Of Tumor

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Biocompatibility study of quaternized chitosan on the proliferation and differentiation of Caco-2 cells as an in vitro model of the intestinal barrier

Journal of Bioactive and Compatible Polymers ◽

10.1177/0883911516658780 ◽

2016 ◽

Vol 32 (1) ◽

pp. 92-107 ◽

Cited By ~ 4

Author(s):

Ratjika Wongwanakul ◽

Suree Jianmongkol ◽

Pattarapond Gonil ◽

Warayuth Sajomsang ◽

Rawiwan Maniratanachote ◽

...

Keyword(s):

Drug Delivery ◽

In Vitro Model ◽

Oral Drug Delivery ◽

Intestinal Barrier ◽

Oral Drug ◽

Chitosan Derivatives ◽

Quaternized Chitosan ◽

Proliferative Effect ◽

Vitro Model

The development of different chitosan derivatives for medical applications has increased recently. Among these chitosan derivatives, quaternized chitosan was designed to improve the solubility of chitosan in biological fluids for oral drug delivery while retaining the cationic character for mucoadhesion. However, the biocompatibility of quaternized chitosan on the human intestine is unknown. In this study, we aimed to examine the potential biological effects of quaternized chitosan on the intestinal barrier, in terms of cell proliferation and cell differentiation, using the Caco-2 cell line as an in vitro model. The lower the degree of substitution of quaternized chitosan, the lower the cytotoxic and anti-proliferative effect on Caco-2 cells. In addition, the anti-proliferative effect of quaternized chitosan might induce a cell cycle disturbance and differentiation delay. Long-term continuous exposure (9 days) to quaternized chitosan caused a delay in differentiation of the Caco-2 cells even at non-cytotoxic quaternized chitosan doses (0.005% (w/v)), as shown by the low level of alkaline phosphatase in the quaternized chitosan–treated group compared to the control cells. In contrast, short-term discontinuous exposure to quaternized chitosan (0.005% (w/v) for 4 h/day over 9 days) that more realistically mimics the daily intestinal exposure did not inhibit the intestinal differentiation of Caco-2 cells. Thus, the use of a low degree of substitution and a low concentration of quaternized chitosan resulted in a good biocompatibility to the intestinal barrier supporting the potential usefulness of quaternized chitosan in the application of an oral drug delivery system.

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