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Delivery of chemotherapeutic drug targeting folate receptor to oral cancer cells using functionalized carbon nanospheres

DOI:10.1088/1748-605X/ace8de
Authors:
Dwaipayan Bhattacharya at BITS Pilani, Hyderabad
Dwaipayan Bhattacharya
Kalyani Sakhare at BITS Pilani, Hyderabad
Kalyani Sakhare
Chhavi Dhiman at BITS Pilani, Hyderabad
Chhavi Dhiman
Aasia Ansari
Aasia Ansari
Aasia Ansari
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Abstract and Figures

Folate receptor (FR) has long been the subject of active interest as regards its potential to serve as a target for cancer therapy. FR is overexpressed in several cancers, including clinical samples of different stages from Oral Squamous Cell Carcinoma (OSCC) patients. However, no clear correlation or conclusive finding has been obtained so far which might indicate the efficacy of FR as a credible target for the treatment of OSCC. Methods: All cell lines to be used were assessed for FR expression. Subsequently, we developed glucose-derived carbon nanospheres (CSPs) and primed them with a Folate-based cationic lipid FA8 and the chemotherapeutic drug doxorubicin (DOX). CSP-based delivery systems along with the pristine drug Doxorubicin were characterized and treated subsequently to in vitro cultures of OSCC cells and assessed for cancer cell targetability as well as cell death. Subsequently, treatment was administered to immunocompetent C57 mice carrying MOC2-based syngeneic OSCC tumors and assessed for tumor regression and toxicity. Results: Ligand-primed targeted CSPs exhibited commendable drug uptake as well as efficient induction of cell death. Further, receptor-blocking studies revealed FR-mediated uptake, preferentially in cancer cells. Drug once delivered by ligand-primed CSPs was retained longer inside cells than the pristine drug alone, indicating possibilities of better therapeutic outcome. In animal studies, CSP-FA8-DOX (Ligand primed targeted CSP) demonstrated significant regression in tumor size compared to pristine Doxorubicin as well as CSP-DOX (non-targeted CSP) treated animals. Conclusions: FR-mediated system CFD demonstrated targeted drug uptake and apoptotic death selectively in cancer cells. Significant tumor regression was also observed in vivo. Overall, it may be presumed that the Folate receptor is a therapeutic target with substantial potential in OSCC treatment. &#xD.
Characterization data for CSPs: panel (A) table presenting size, zeta potential, and PDI values for all CSP formulations as measured using Zeta-sizer (Malvern). (B) The binding curve for Folate-based ligand FA8. (C) The binding curve for doxorubicin. Panels (D)–(F) represent SEM images for CSP, CD (CSP-DOX) and CFD (CSP-FA8-DOX), respectively at varying concentrations. Size and zeta potential data are represented as Average ± SEM values.
Characterization data for CSPs: panel (A) table presenting size, zeta potential, and PDI values for all CSP formulations as measured using Zeta-sizer (Malvern). (B) The binding curve for Folate-based ligand FA8. (C) The binding curve for doxorubicin. Panels (D)–(F) represent SEM images for CSP, CD (CSP-DOX) and CFD (CSP-FA8-DOX), respectively at varying concentrations. Size and zeta potential data are represented as Average ± SEM values.
… 
Western blotting to compare levels of soluble folate receptor at varying time points: cells were treated in-vitro with folate (FA) at a concentration of 100 μM for 30 min and lysate was collected from samples at different time points post treatment 0 h, 3 h and 5 h. Lysates for UT (untreated) and folate treated cells were separated by SDS-PAGE and probed post-transfer with FR1-antibody (Invitrogen). Graphs represent densitometry data for different time points plotted as Average ± SEM values of FR1 normalized with corresponding GAPDH values. Blots developed by chemiluminescence were quantified using Image-J software. Statistical significance with respect to untreated control is represented by * where p < 0.05-* and p < 0.01-**.
Western blotting to compare levels of soluble folate receptor at varying time points: cells were treated in-vitro with folate (FA) at a concentration of 100 μM for 30 min and lysate was collected from samples at different time points post treatment 0 h, 3 h and 5 h. Lysates for UT (untreated) and folate treated cells were separated by SDS-PAGE and probed post-transfer with FR1-antibody (Invitrogen). Graphs represent densitometry data for different time points plotted as Average ± SEM values of FR1 normalized with corresponding GAPDH values. Blots developed by chemiluminescence were quantified using Image-J software. Statistical significance with respect to untreated control is represented by * where p < 0.05-* and p < 0.01-**.
… 
Flow cytometric quantification (comparative) of doxorubicin uptake between folate pre-treated and untreated OSCC cells: for pre-treatment, folate was treated at a concentration of 100 μM for 30 min. CSP formulations CFD (CSP-FA8-DOX) and CD (CSP-DOX) alongside free drug DOX (doxorubicin) were then treated to cells at a concentration of 6.4 μM (drug equivalent). After 6 h of treatment, cells were washed, collected by trypsinization, and analysed by flow cytometry (BD FACS ARIA III). Panel (I): graphs represent data as Average ± SEM values representing the percent uptake of the total population. Panel (II): graphs represent data as Average ± SEM values representing mean area under Dox fluorescence along with representative histograms. Statistical analysis was carried out w.r.t CFD treated group as control using students t-test where *-p < 0.05 and **-p < 0.01.
Flow cytometric quantification (comparative) of doxorubicin uptake between folate pre-treated and untreated OSCC cells: for pre-treatment, folate was treated at a concentration of 100 μM for 30 min. CSP formulations CFD (CSP-FA8-DOX) and CD (CSP-DOX) alongside free drug DOX (doxorubicin) were then treated to cells at a concentration of 6.4 μM (drug equivalent). After 6 h of treatment, cells were washed, collected by trypsinization, and analysed by flow cytometry (BD FACS ARIA III). Panel (I): graphs represent data as Average ± SEM values representing the percent uptake of the total population. Panel (II): graphs represent data as Average ± SEM values representing mean area under Dox fluorescence along with representative histograms. Statistical analysis was carried out w.r.t CFD treated group as control using students t-test where *-p < 0.05 and **-p < 0.01.
… 
FR mediated doxorubicin uptake through membrane bound FR1: MOC2 cells were treated at a concentration of 100 μM for 30 min, and lysates were collected at different time points- 0 h, 3 h and 5 h. Lysates for UT (untreated), CFD (CSP-FA8-DOX), and CD (CSP-DOX) with and without folate (FA) were run in SDS-PAGE and probed with FR1-antibody. Corresponding Western blotting results were matched with flow cytometry data for DOX uptake in MOC2 (different time points). All graphs represent data as Average ± SEM values. Blot images were quantified using Image-J software. Statistical analysis was carried out wherever applicable using students t-test where *p < 0.05, **p < 0.01 with UT as control.
FR mediated doxorubicin uptake through membrane bound FR1: MOC2 cells were treated at a concentration of 100 μM for 30 min, and lysates were collected at different time points- 0 h, 3 h and 5 h. Lysates for UT (untreated), CFD (CSP-FA8-DOX), and CD (CSP-DOX) with and without folate (FA) were run in SDS-PAGE and probed with FR1-antibody. Corresponding Western blotting results were matched with flow cytometry data for DOX uptake in MOC2 (different time points). All graphs represent data as Average ± SEM values. Blot images were quantified using Image-J software. Statistical analysis was carried out wherever applicable using students t-test where *p < 0.05, **p < 0.01 with UT as control.
… 
Flow cytometric quantification (comparative) of doxorubicin uptake in cancerous and normal cells: CSP formulations CFD (CSP-FA8-DOX) and CD (CSP-DOX) alongside free drug DOX (doxorubicin) were treated to OSCC cells FaDu, CAL27, MOC2 with normal cell line HEK293. After 6 h of treatment cells were analysed by flow cytometry. Panel (I): graphs represent data as Average ± SEM values of percentage of total. Panel (II): graphs represent data as Average ± SEM values representing mean area under Dox fluorescence along-with representative histograms. Statistical analysis was carried out using students’ t-test where *-p < 0.05, **-p < 0.01 with UT as control, $- p < 0.05 with DOX as control and #- p < 0.05, ##-p < 0.01 with CD as control.
+8
Flow cytometric quantification (comparative) of doxorubicin uptake in cancerous and normal cells: CSP formulations CFD (CSP-FA8-DOX) and CD (CSP-DOX) alongside free drug DOX (doxorubicin) were treated to OSCC cells FaDu, CAL27, MOC2 with normal cell line HEK293. After 6 h of treatment cells were analysed by flow cytometry. Panel (I): graphs represent data as Average ± SEM values of percentage of total. Panel (II): graphs represent data as Average ± SEM values representing mean area under Dox fluorescence along-with representative histograms. Statistical analysis was carried out using students’ t-test where *-p < 0.05, **-p < 0.01 with UT as control, $- p < 0.05 with DOX as control and #- p < 0.05, ##-p < 0.01 with CD as control.
… 
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Biomed. Mater. 18 (2023) 055012 https://doi.org/10.1088/1748-605X/ace8de
Biomedical Materials
RECEIVED
12 March 2023
REVISED
9 July 2023
ACC EPT ED FOR PUB LICATI ON
19 July 2023
PUBLISHED
2 August 2023
PAPER
Delivery of chemotherapeutic drug targeting folate receptor to oral
cancer cells using functionalized carbon nanospheres
Dwaipayan Bhattacharya1, Kalyani Sakhare1, Chhavi Dhiman1, Aasia Ansari2,4, Tapas Kumar Kundu3,
Kumar Pranav Narayan1,∗and Rajkumar Banerjee2,4,∗
1Department of Biological Science, Birla Institute of Technology & Science Pilani, Hyderabad Campus, Jawaharnagar, Kapra Mandal,
Hyderabad, Telangana 500078, India
2Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, Telangana 500076, India
3Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centrefor Advanced Scientific Research,
Bangalore 560064, India
4Academy of Scientific & Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad 201002, India
∗Authors to whom any correspondence should be addressed.
E-mail: pranav@hyderabad.bits-pilani.ac.in and banerjee@iict.res.in
Keywords: carbon nanospheres, folate receptor, oral squamous cell carcinoma, targeted drug retention, apoptosis, EMT,
tumour regression
Supplementary material for this article is available online
Abstract
Folate receptor (FR) (α) has long been the subject of active interest as regards its potential to serve
as a target for cancer therapy. FR has been found to be overexpressed in several cancers, including
clinical samples of different stages from OSCC (oral squamous cell carcinoma) patients. However,
no clear correlation or conclusive finding has been obtained so far which might indicate the
efficacy of FR as a credible target for the treatment of OSCC. All cell lines to be used were assessed
for FR-expression. Subsequently, we developed glucose-derived carbon nanospheres (CSPs) and
primed them with a Folate-based cationic lipid FA8 and the chemotherapeutic drug doxorubicin
(DOX). CSP based delivery systems along with pristine drug DOX were characterized and treated
subsequently to in vitro cultures of OSCC cells and assessed for cancer cell targetability as well as
cell death. Subsequently, treatment was administered to immunocompetent C57 mice carrying
MOC2 based syngeneic OSCC tumours and assessed for tumour regression and toxicity. Ligand
primed targeted CSPs exhibited commendable drug uptake as well as efficient induction of cell
death. Further, receptor blocking studies revealed FR-mediated uptake, preferentially in cancer
cells. Drug once delivered by ligand-primed CSPs was retained longer inside cells than pristine
drug alone, indicating possibilities of better therapeutic outcome. In animal studies,
CSP-FA8-DOX (Ligand primed targeted CSP) demonstrated significant regression in tumour size
compared to pristine DOX as well as CSP-DOX (non-targeted CSP) treated animals. FR-mediated
system CFD demonstrated targeted drug uptake and apoptotic death selectively in cancer cells.
Significant tumour regression was also observed in vivo. Overall, it may be presumed that the FR is
a therapeutic target with substantial potential in OSCC treatment.
1. Introduction
Cancer drug delivery is no longer about just wrap-
ping drugs in new formulations to suit differ-
ent routes of delivery. Surface functionalization for
optimal utilization of advanced nanomaterials is of
paramount interest to today’s researchers and medical
professionals.
Currently, the sixth most common cancer in
the world, head, and neck cancer continues to
take its toll on the lives of millions [1]. When
oral cancer stops responding to radiation and
chemotherapy, targeted therapy may be used to
help control the disease. Targeted drugs often
alter particular aspects of cancer cell growth.
These drugs may be used alone or in combination
© 2023 IOP Publishing Ltd
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