Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery

Avgi Tsolou,1 Eftychia Angelou,2 Stylianos Didaskalou,1 Dimitrios Bikiaris,3 Konstantinos Avgoustakis,4 Bogos Agianian,2 Maria D Koffa1 1Laboratory of Molecular Cell Biology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece; 2Biomolecular S...

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Autores principales:	Tsolou A, Angelou E, Didaskalou S, Bikiaris D, Avgoustakis K, Agianian B, Koffa MD
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	folate-ppsu-peg copolymers nanoparticles drug delivery paclitaxel targeted chemotherapy breast cancer Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/4caf7a7b4fe54b84a560a137b7cfdd67
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id	oai:doaj.org-article:4caf7a7b4fe54b84a560a137b7cfdd67
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	folate-ppsu-peg copolymers nanoparticles drug delivery paclitaxel targeted chemotherapy breast cancer Medicine (General) R5-920
spellingShingle	folate-ppsu-peg copolymers nanoparticles drug delivery paclitaxel targeted chemotherapy breast cancer Medicine (General) R5-920 Tsolou A Angelou E Didaskalou S Bikiaris D Avgoustakis K Agianian B Koffa MD Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery
description	Avgi Tsolou,1 Eftychia Angelou,2 Stylianos Didaskalou,1 Dimitrios Bikiaris,3 Konstantinos Avgoustakis,4 Bogos Agianian,2 Maria D Koffa1 1Laboratory of Molecular Cell Biology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece; 2Biomolecular Structure and Function Group, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece; 3Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece; 4Department of Pharmacy, University of Patras, Patras 26500, GreeceCorrespondence: Maria D KoffaLaboratory of Molecular Cell Biology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, GreeceTel/ Fax +0030-25510-30661Email mkoffa@mbg.duth.grPurpose: The use of chemotherapeutic agents to combat cancer is accompanied by high toxicity due to their inability to discriminate between cancer and normal cells. Therefore, cancer therapy research has focused on the targeted delivery of drugs to cancer cells. Here, we report an in vitro study of folate-poly(ethylene glycol)-poly(propylene succinate) nanoparticles (FA-PPSu-PEG-NPs) as a vehicle for targeted delivery of the anticancer drug paclitaxel in breast and cervical cancer cell lines.Methods: Paclitaxel-loaded-FA-PPSu-PEG-NPs characterization was performed by in vitro drug release studies and cytotoxicity assays. The NPs cellular uptake and internalization mechanism were monitored by live-cell imaging in different cancer cell lines. Expression of folate receptor-α (FOLR1) was examined in these cell lines, and specific FOLR1-mediated entry of the FA-PPSu-PEG-NPs was investigated by free folic acid competition. Using inhibitors for other endocytic pathways, alternative, non-FOLR1 dependent routes for NPs uptake were also examined.Results: Drug release experiments of Paclitaxel-loaded PPSu-PEG-NPs indicated a prolonged release of Paclitaxel over several days. Cytotoxicity of Paclitaxel-loaded PPSu-PEG-NPs was similar to free drug, as monitored in cancer cell lines. Live imaging of cells treated with either free Paclitaxel or Paclitaxel-loaded PPSu-PEG-NPs demonstrated tubulin-specific cell cycle arrest, with similar kinetics. Folate-conjugated NPs (FA-PPSu-PEG-NPs) targeted the FOLR1 receptor, as shown by free folic acid competition of the FA-PPSu-PEG-NPs cellular uptake in some of the cell lines tested. However, due to the differential expression of FOLR1 in the cancer cell lines, as well as the intrinsic differences between the different endocytic pathways utilized by different cell types, other mechanisms of nanoparticle cellular entry were also used, revealing that dynamin-dependent endocytosis and macropinocytosis pathways mediate, at least partially, cellular entry of the FA-PPSu-PEG NPs.Conclusion: Our data provide evidence that Paclitaxel-loaded-FA-PPSu-PEG-NPs can be used for targeted delivery of the drug, FA-PPSu-PEG-NPs can be used as vehicles for other anticancer drugs and their cellular uptake is mediated through a combination of FOLR1 receptor-specific endocytosis, and macropinocytosis. The exploration of the different cellular uptake mechanisms could improve treatment efficacy or allow a decrease in dosage of anticancer drugs.Keywords: Folate-PPSu-PEG copolymers, nanoparticles, drug delivery, Paclitaxel, targeted chemotherapy, breast cancer
format	article
author	Tsolou A Angelou E Didaskalou S Bikiaris D Avgoustakis K Agianian B Koffa MD
author_facet	Tsolou A Angelou E Didaskalou S Bikiaris D Avgoustakis K Agianian B Koffa MD
author_sort	Tsolou A
title	Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery
title_short	Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery
title_full	Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery
title_fullStr	Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery
title_full_unstemmed	Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery
title_sort	folate and pegylated aliphatic polyester nanoparticles for targeted anticancer drug delivery
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/4caf7a7b4fe54b84a560a137b7cfdd67
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spelling	oai:doaj.org-article:4caf7a7b4fe54b84a560a137b7cfdd672021-12-02T08:48:19ZFolate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery1178-2013https://doaj.org/article/4caf7a7b4fe54b84a560a137b7cfdd672020-07-01T00:00:00Zhttps://www.dovepress.com/folate-and-pegylated-aliphatic-polyester-nanoparticles-for-targeted-an-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Avgi Tsolou,1 Eftychia Angelou,2 Stylianos Didaskalou,1 Dimitrios Bikiaris,3 Konstantinos Avgoustakis,4 Bogos Agianian,2 Maria D Koffa1 1Laboratory of Molecular Cell Biology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece; 2Biomolecular Structure and Function Group, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece; 3Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece; 4Department of Pharmacy, University of Patras, Patras 26500, GreeceCorrespondence: Maria D KoffaLaboratory of Molecular Cell Biology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, GreeceTel/ Fax +0030-25510-30661Email mkoffa@mbg.duth.grPurpose: The use of chemotherapeutic agents to combat cancer is accompanied by high toxicity due to their inability to discriminate between cancer and normal cells. Therefore, cancer therapy research has focused on the targeted delivery of drugs to cancer cells. Here, we report an in vitro study of folate-poly(ethylene glycol)-poly(propylene succinate) nanoparticles (FA-PPSu-PEG-NPs) as a vehicle for targeted delivery of the anticancer drug paclitaxel in breast and cervical cancer cell lines.Methods: Paclitaxel-loaded-FA-PPSu-PEG-NPs characterization was performed by in vitro drug release studies and cytotoxicity assays. The NPs cellular uptake and internalization mechanism were monitored by live-cell imaging in different cancer cell lines. Expression of folate receptor-α (FOLR1) was examined in these cell lines, and specific FOLR1-mediated entry of the FA-PPSu-PEG-NPs was investigated by free folic acid competition. Using inhibitors for other endocytic pathways, alternative, non-FOLR1 dependent routes for NPs uptake were also examined.Results: Drug release experiments of Paclitaxel-loaded PPSu-PEG-NPs indicated a prolonged release of Paclitaxel over several days. Cytotoxicity of Paclitaxel-loaded PPSu-PEG-NPs was similar to free drug, as monitored in cancer cell lines. Live imaging of cells treated with either free Paclitaxel or Paclitaxel-loaded PPSu-PEG-NPs demonstrated tubulin-specific cell cycle arrest, with similar kinetics. Folate-conjugated NPs (FA-PPSu-PEG-NPs) targeted the FOLR1 receptor, as shown by free folic acid competition of the FA-PPSu-PEG-NPs cellular uptake in some of the cell lines tested. However, due to the differential expression of FOLR1 in the cancer cell lines, as well as the intrinsic differences between the different endocytic pathways utilized by different cell types, other mechanisms of nanoparticle cellular entry were also used, revealing that dynamin-dependent endocytosis and macropinocytosis pathways mediate, at least partially, cellular entry of the FA-PPSu-PEG NPs.Conclusion: Our data provide evidence that Paclitaxel-loaded-FA-PPSu-PEG-NPs can be used for targeted delivery of the drug, FA-PPSu-PEG-NPs can be used as vehicles for other anticancer drugs and their cellular uptake is mediated through a combination of FOLR1 receptor-specific endocytosis, and macropinocytosis. The exploration of the different cellular uptake mechanisms could improve treatment efficacy or allow a decrease in dosage of anticancer drugs.Keywords: Folate-PPSu-PEG copolymers, nanoparticles, drug delivery, Paclitaxel, targeted chemotherapy, breast cancerTsolou AAngelou EDidaskalou SBikiaris DAvgoustakis KAgianian BKoffa MDDove Medical Pressarticlefolate-ppsu-peg copolymersnanoparticlesdrug deliverypaclitaxeltargeted chemotherapybreast cancerMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 4899-4918 (2020)

Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer Drug Delivery

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