Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

Authors: Miriana Hijaz, Soumen Das, Ismail Mert, Ankur Gupta, Zaid Al-Wahab, Calvin Tebbe, Sajad Dar, Jasdeep Chhina, Shailendra Giri, Adnan Munkarah, Sudipta Seal, Ramandeep Rattan

Published in: BMC Cancer | Issue 1/2016

Login to get access

Abstract

Background

Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin.

Methods

Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects.

Results

We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model.

Conclusion

Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.
Appendix
Available only for authorised users
Literature
1.
2.
3.
4.
Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J Control Release. 2015;200C:138–57.CrossRef
5.
Estevez AY, Erlichman JS. The potential of cerium oxide nanoparticles (nanoceria) for neurodegenerative disease therapy. Nanomedicine. 2014;9(10):1437–40.CrossRefPubMed
6.
Giri S, Karakoti A, Graham RP, Maguire JL, Reilly CM, Seal S, Rattan R, Shridhar V. Nanoceria: a rare-earth nanoparticle as a novel anti-angiogenic therapeutic agent in ovarian cancer. PLoS One. 2013;8(1):e54578.CrossRefPubMedPubMedCentral
7.
Alili L, Sack M, Karakoti AS, Teuber S, Puschmann K, Hirst SM, Reilly CM, Zanger K, Stahl W, Das S, et al. Combined cytotoxic and anti-invasive properties of redox-active nanoparticles in tumor-stroma interactions. Biomaterials. 2011;32(11):2918–29.CrossRefPubMed
8.
Jana SK, Banerjee P, Das S, Seal S, Chaudhury K. Redox-active nanoceria depolarize mitochondrial membrane of human colon cancer cells. J Nanopart Res. 2014;16(6):2441.CrossRef
9.
Wason MS, Colon J, Das S, Seal S, Turkson J, Zhao J, Baker CH. Sensitization of pancreatic cancer cells to radiation by cerium oxide nanoparticle-induced ROS production. Nanomedicine. 2013;9(4):558–69.PubMedPubMedCentral
10.
Marchetti C, Palaia I, Giorgini M, De Medici C, Iadarola R, Vertechy L, Domenici L, Di Donato V, Tomao F, Muzii L, et al. Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review. OncoTargets Ther. 2014;7:1223–36.CrossRef
11.
Naumann RW, Coleman RL, Burger RA, Sausville EA, Kutarska E, Ghamande SA, Gabrail NY, Depasquale SE, Nowara E, Gilbert L, et al. PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2013;31(35):4400–6.CrossRefPubMed
12.
Elnakat H, Ratnam M. Role of folate receptor genes in reproduction and related cancers. Front Biosci. 2006;11:506–19.CrossRefPubMed
13.
Chen YL, Chang MC, Huang CY, Chiang YC, Lin HW, Chen CA, Hsieh CY, Cheng WF. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response. Mol Oncol. 2012;6(3):360–9.CrossRefPubMed
14.
Armstrong DK, White AJ, Weil SC, Phillips M, Coleman RL. Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer. Gynecol Oncol. 2013;129(3):452–8.CrossRefPubMed
15.
Elit L, Konner JA, Armstrong DK, Buck M, Dean A, Finkler NJ, Hulstine A, Schweizer C, Phillips M, Weil S. A randomized, double-blind, placebo-controlled phase II study of the efficacy and safety of farletuzumab (MORAb-003) in combination with weekly paclitaxel in subjects with platinum-resistant or refractory relapsed ovarian cancer [abstract]. J Clin Oncol. 2010;28(15 Suppl):TPS255.
16.
Das S, Singh S, Dowding JM, Oommen S, Kumar A, Sayle TXT, Saraf S, Patra CR, Vlahakis NE, Sayle DC, et al. The induction of angiogenesis by cerium oxide nanoparticles through the modulation of oxygen in intracellular environments. Biomaterials. 2012;33(31):7746–55.CrossRefPubMedPubMedCentral
17.
Cimini A, D’Angelo B, Das S, Gentile R, Benedetti E, Singh V, Monaco AM, Santucci S, Seal S. Antibody-conjugated PEGylated cerium oxide nanoparticles for specific targeting of Aβ aggregates modulate neuronal survival pathways. Acta Biomater. 2012;8(6):2056–67.CrossRefPubMed
18.
Hirst SM, Karakoti A, Singh S, Self W, Tyler R, Seal S, Reilly CM. Bio-distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice. Environ Toxicol. 2013;28(2):107–18.CrossRefPubMed
19.
Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2011;15(1):166–78.CrossRefPubMedPubMedCentral
20.
Niles AL, Moravec RA, Riss TL. In vitro viability and cytotoxicity testing and same-well multi-parametric combinations for high throughput screening. Curr Chem Genomics. 2009;3:33–41.CrossRefPubMedPubMedCentral
21.
Al-Wahab Z, Tebbe C, Chhina J, Dar SA, Morris RT, Ali-Fehmi R, Giri S, Munkarah AR, Rattan R. Dietary energy balance modulates ovarian cancer progression and metastasis. Oncotarget. 2014;5(15):6063–75.CrossRefPubMedPubMedCentral
22.
Deshpande S, Patil S, Kuchibhatla SVNT, Seal S. Size dependency variation in lattice parameter and valency states in nanocrystalline cerium oxide. Appl Phys Lett. 2005;87(13):133113.CrossRef
23.
Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 2011;13(5):483–91.CrossRefPubMedPubMedCentral
24.
Das S, Chigurupati S, Dowding J, Munusamy P, Baer DR, McGinnis JF, Mattson MP, Self W, Seal S. Therapeutic potential of nanoceria in regenerative medicine. Mrs Bull. 2014;39(11):976–83.CrossRef
25.
Das S, Dowding JM, Klump KE, McGinnis JF, Self W, Seal S. Cerium oxide nanoparticles: applications and prospects in nanomedicine. Nanomedicine. 2013;8(9):1483–508.CrossRefPubMed
26.
Turkowski V, Babu S, Le D, Kumar A, Haldar MK, Wagh AV, Hu Z, Karakoti AS, Gesquiere AJ, Law B, et al. Linker-induced anomalous emission of organic-molecule conjugated metal-oxide nanoparticles. ACS Nano. 2012;6(6):4854–63.CrossRefPubMed
27.
Liu LZ, Hu XW, Xia C, He J, Zhou Q, Shi X, Fang J, Jiang BH. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic Biol Med. 2006;41(10):1521–33.CrossRefPubMed
28.
Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 2007;67(22):10823–30.CrossRefPubMed
29.
Chen J, Patil S, Seal S, McGinnis JF. Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides. Nat Nanotechnol. 2006;1(2):142–50.CrossRefPubMed
30.
Das M, Patil S, Bhargava N, Kang JF, Riedel LM, Seal S, Hickman JJ. Auto-catalytic ceria nanoparticles offer neuroprotection to adult rat spinal cord neurons. Biomaterials. 2007;28(10):1918–25.CrossRefPubMedPubMedCentral
31.
Tarnuzzer RW, Colon J, Patil S, Seal S. Vacancy engineered ceria nanostructures for protection from radiation-induced cellular damage. Nano Lett. 2005;5(12):2573–7.CrossRefPubMed
32.
33.
Lunt SJ, Chaudary N, Hill RP. The tumor microenvironment and metastatic disease. Clin Exp Metastasis. 2009;26(1):19–34.CrossRefPubMed
34.
35.
Gonzalez VM, Fuertes MA, Alonso C, Perez JM. Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol. 2001;59(4):657–63.PubMed
36.
Tanida S, Mizoshita T, Ozeki K, Tsukamoto H, Kamiya T, Kataoka H, Sakamuro D, Joh T. Mechanisms of cisplatin-induced apoptosis and of cisplatin sensitivity: potential of BIN1 to act as a potent predictor of cisplatin sensitivity in gastric cancer treatment. Int J Surg Oncol. 2012;2012:862879.PubMedPubMedCentral
37.
Tebbi A, Guittet O, Tuphile K, Cabrie A, Lepoivre M. Caspase-dependent Proteolysis of Human Ribonucleotide Reductase Small Subunits R2 and p53R2 during Apoptosis. J Biol Chem. 2015;290(22):14077–90.CrossRefPubMed
38.
Petersen DR, Doorn JA. Reactions of 4-hydroxynonenal with proteins and cellular targets. Free Radic Biol Med. 2004;37(7):937–45.CrossRefPubMed
39.
Berndtsson M, Hagg M, Panaretakis T, Havelka AM, Shoshan MC, Linder S. Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int J Cancer. 2007;120(1):175–80.CrossRefPubMed
40.
Kim HJ, Lee JH, Kim SJ, Oh GS, Moon HD, Kwon KB, Park C, Park BH, Lee HK, Chung SY, et al. Roles of NADPH oxidases in cisplatin-induced reactive oxygen species generation and ototoxicity. J Neurosci. 2010;30(11):3933–46.CrossRefPubMed
41.
Schweyer S, Soruri A, Heintze A, Radzun HJ, Fayyazi A. The role of reactive oxygen species in cisplatin-induced apoptosis in human malignant testicular germ cell lines. Int J Oncol. 2004;25(6):1671–6.PubMed
42.
Viswambari Devi R, Doble M, Verma RS. Nanomaterials for early detection of cancer biomarker with special emphasis on gold nanoparticles in immunoassays/sensors. Biosens Bioelectron. 2015;68C:688–98.CrossRef
43.
Prabhu RH, Patravale VB, Joshi MD. Polymeric nanoparticles for targeted treatment in oncology: current insights. Int J Nanomedicine. 2015;10:1001–18.PubMedPubMedCentral
44.
Calugaru V, Magne N, Herault J, Bonvalot S, Le Tourneau C, Thariat J. Nanoparticles and radiation therapy. Bull Cancer. 2015;102(1):83–91.CrossRefPubMed
45.
Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr. 2000;130(2):129–32.PubMed
46.
Markert S, Lassmann S, Gabriel B, Klar M, Werner M, Gitsch G, Kratz F, Hasenburg A. Alpha-folate receptor expression in epithelial ovarian carcinoma and non-neoplastic ovarian tissue. Anticancer Res. 2008;28(6A):3567–72.PubMed
47.
Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444(7122):1083–7.CrossRefPubMed
48.
Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444(7122):1032–7.CrossRefPubMed
49.
Wang Z, Dabrosin C, Yin X, Fuster MM, Arreola A, Rathmell WK, Generali D, Nagaraju GP, El-Rayes B, Ribatti D, et al. Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol. 2015;35 Suppl:S224-43.PubMed
50.
Ambrosio AJ, Suzin D, Palmer EL, Penson RT. Vintafolide (EC145) for the treatment of folate-receptor-alpha positive platinum-resistant ovarian cancer. Exp Rev Clin Pharmacol. 2014;7(4):443–50.CrossRef
51.
Conklin KA. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther. 2004;3(4):294–300.CrossRefPubMed
Metadata
Title
Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer
Authors
Miriana Hijaz
Soumen Das
Ismail Mert
Ankur Gupta
Zaid Al-Wahab
Calvin Tebbe
Sajad Dar
Jasdeep Chhina
Shailendra Giri
Adnan Munkarah
Sudipta Seal
Ramandeep Rattan
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2206-4

Other articles of this Issue 1/2016

BMC Cancer 1/2016 Go to the issue

Research article

Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6–producing lung carcinoma cells

Research article

Genome-wide analyses of long noncoding RNA expression profiles correlated with radioresistance in nasopharyngeal carcinoma via next-generation deep sequencing

Research article

Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists

Research article

The occurrence of non-melanoma malignant skin lesions and non-cutaneous squamous-cell carcinoma among metastatic melanoma patients: an observational cohort study in Denmark

Research article

The prognostic value of stromal and epithelial periostin expression in human breast cancer: correlation with clinical pathological features and mortality outcome

Research article

The anti-oxidative transcription factor Nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells -Nrf2 as determinant of pro-tumorigenic functions of TGF-β1
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits