Liposomes targeting the cancer cell-exposed receptor, claudin-4, for pancreatic cancer chemotherapy.
Journal
Biomaterials research
ISSN: 1226-4601
Titre abrégé: Biomater Res
Pays: England
ID NLM: 101650636
Informations de publication
Date de publication:
26 May 2023
26 May 2023
Historique:
received:
08
11
2022
accepted:
15
05
2023
medline:
27
5
2023
pubmed:
27
5
2023
entrez:
26
5
2023
Statut:
epublish
Résumé
Claudin-4 (CLDN4), a tight junction protein, is overexpressed in several types of cancer, and is considered a biomarker for cancer-targeted treatment. CLDN4 is not exposed in normal cells, but becomes accessible in cancer cells, in which tight junctions are weakened. Notably, surface-exposed CLDN4 has recently been found to act as a receptor for Clostridium perfringens enterotoxin (CPE) and fragment of CPE (CPE17) that binds to the second domain of CLDN4. Here, we sought to develop a CPE17-containing liposome that targets pancreatic cancers through binding to exposed CLDN4. Doxorubicin (Dox)-loaded, CPE17-conjugated liposomes (D@C-LPs) preferentially targeted CLDN4-expressing cell lines, as evidenced by greater uptake and cytotoxicity compared with CLDN4-negative cell lines, whereas uptake and cytotoxicity of Dox-loaded liposomes lacking CPE17 (D@LPs) was similar for both CLDN4-positive and negative cell lines. Notably, D@C-LPs showed greater accumulation in targeted pancreatic tumor tissues compared with normal pancreas tissue; in contrast, Dox-loaded liposomes lacking CPE17 (D@LPs) showed little accumulation in pancreatic tumor tissues. Consistent with this, D@C-LPs showed greater anticancer efficacy compared with other liposome formulations and significantly extended survival. We expect our findings will aid in the prevention and treatment of pancreatic cancer and provide a framework for identifying cancer-specific strategies that target exposed receptors.
Sections du résumé
BACKGROUND
BACKGROUND
Claudin-4 (CLDN4), a tight junction protein, is overexpressed in several types of cancer, and is considered a biomarker for cancer-targeted treatment. CLDN4 is not exposed in normal cells, but becomes accessible in cancer cells, in which tight junctions are weakened. Notably, surface-exposed CLDN4 has recently been found to act as a receptor for Clostridium perfringens enterotoxin (CPE) and fragment of CPE (CPE17) that binds to the second domain of CLDN4.
METHODS
METHODS
Here, we sought to develop a CPE17-containing liposome that targets pancreatic cancers through binding to exposed CLDN4.
RESULTS
RESULTS
Doxorubicin (Dox)-loaded, CPE17-conjugated liposomes (D@C-LPs) preferentially targeted CLDN4-expressing cell lines, as evidenced by greater uptake and cytotoxicity compared with CLDN4-negative cell lines, whereas uptake and cytotoxicity of Dox-loaded liposomes lacking CPE17 (D@LPs) was similar for both CLDN4-positive and negative cell lines. Notably, D@C-LPs showed greater accumulation in targeted pancreatic tumor tissues compared with normal pancreas tissue; in contrast, Dox-loaded liposomes lacking CPE17 (D@LPs) showed little accumulation in pancreatic tumor tissues. Consistent with this, D@C-LPs showed greater anticancer efficacy compared with other liposome formulations and significantly extended survival.
CONCLUSIONS
CONCLUSIONS
We expect our findings will aid in the prevention and treatment of pancreatic cancer and provide a framework for identifying cancer-specific strategies that target exposed receptors.
Identifiants
pubmed: 37237291
doi: 10.1186/s40824-023-00394-7
pii: 10.1186/s40824-023-00394-7
pmc: PMC10214683
doi:
Types de publication
Journal Article
Langues
eng
Pagination
53Informations de copyright
© 2023. The Author(s).
Références
Nat Rev Drug Discov. 2021 Feb;20(2):101-124
pubmed: 33277608
Nat Rev Drug Discov. 2015 Mar;14(3):203-19
pubmed: 25698644
Adv Mater. 2020 Dec;32(51):e2002197
pubmed: 33051905
Nat Commun. 2018 Apr 12;9(1):1410
pubmed: 29650952
J Control Release. 2017 Jan 10;245:1-14
pubmed: 27889393
Nat Rev Gastroenterol Hepatol. 2020 Aug;17(8):487-505
pubmed: 32393771
Gastroenterology. 2001 Feb;120(2):411-22
pubmed: 11159882
Ann N Y Acad Sci. 2017 Jun;1397(1):5-16
pubmed: 28415141
Infect Immun. 2010 Jan;78(1):505-17
pubmed: 19884339
Am J Clin Pathol. 2004 Feb;121(2):226-30
pubmed: 14983936
Nat Rev Gastroenterol Hepatol. 2018 Jun;15(6):333-348
pubmed: 29717230
J Pharmacol Exp Ther. 2010 Aug;334(2):576-82
pubmed: 20442222
Cell Mol Biol Lett. 2011 Sep;16(3):385-97
pubmed: 21573709
Gastroenterology. 2001 Sep;121(3):678-84
pubmed: 11522752
Asian Pac J Cancer Prev. 2015;16(10):4387-92
pubmed: 26028104
Cancer Cell. 2018 Apr 9;33(4):752-769.e8
pubmed: 29606349
Angew Chem Int Ed Engl. 2012 Nov 19;51(47):11836-40
pubmed: 23081905
Adv Drug Deliv Rev. 2012 Oct;64(13):1447-58
pubmed: 22772034
Appl Immunohistochem Mol Morphol. 2014;22(2):125-31
pubmed: 23702644
Angew Chem Int Ed Engl. 2016 Nov 14;55(47):14698-14703
pubmed: 27762044
Biomaterials. 2014 Mar;35(10):3416-26
pubmed: 24439417
Traffic. 2001 Feb;2(2):93-8
pubmed: 11247307
BMC Cancer. 2010 Jul 02;10:349
pubmed: 20598131
Mol Pharm. 2014 Nov 3;11(11):4059-68
pubmed: 25271780
Sci Transl Med. 2019 Sep 11;11(509):
pubmed: 31511426
J Control Release. 2021 Mar 10;331:434-442
pubmed: 33508352
Eur J Pharm Biopharm. 2010 Jun;75(2):213-7
pubmed: 20226859
Adv Drug Deliv Rev. 2005 Apr 25;57(6):919-28
pubmed: 15820559
J Nucl Med. 2020 Dec;61(12):1756-1763
pubmed: 32414951
ACS Nano. 2014 Mar 25;8(3):2048-63
pubmed: 24499346
Nat Rev Clin Oncol. 2020 Sep;17(9):527-540
pubmed: 32398706
Physiol Rev. 2013 Apr;93(2):525-69
pubmed: 23589827
Am J Physiol. 1987 Dec;253(6 Pt 1):C749-58
pubmed: 3322036
Pancreatology. 2019 Jan;19(1):88-96
pubmed: 30416041
Cancer. 2009 Aug 15;115(16):3640-50
pubmed: 19514088