Effect of Cellular and Microenvironmental Multidrug Resistance on Tumor-Targeted Drug Delivery in Triple-Negative Breast cancer.
Drug targeting
EPR effect
Multidrug resistance
Nanomedicine
Tumor microenvironment
Journal
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Titre abrégé: J Control Release
Pays: Netherlands
ID NLM: 8607908
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
26
10
2022
revised:
21
12
2022
accepted:
28
12
2022
pubmed:
5
1
2023
medline:
3
3
2023
entrez:
4
1
2023
Statut:
ppublish
Résumé
Multidrug resistance (MDR) reduces the efficacy of chemotherapy. Besides inducing the expression of drug efflux pumps, chemotherapy treatment alters the composition of the tumor microenvironment (TME), thereby potentially limiting tumor-directed drug delivery. To study the impact of MDR signaling in cancer cells on TME remodeling and nanomedicine delivery, we generated multidrug-resistant 4T1 triple-negative breast cancer (TNBC) cells by exposing sensitive 4T1 cells to gradually increasing doxorubicin concentrations. In 2D and 3D cell cultures, resistant 4T1 cells are presented with a more mesenchymal phenotype and produced increased amounts of collagen. While sensitive and resistant 4T1 cells showed similar tumor growth kinetics in vivo, the TME of resistant tumors was enriched in collagen and fibronectin. Vascular perfusion was also significantly increased. Fluorophore-labeled polymeric (∼10 nm) and liposomal (∼100 nm) drug carriers were administered to mice with resistant and sensitive tumors. Their tumor accumulation and penetration were studied using multimodal and multiscale optical imaging. At the whole tumor level, polymers accumulate more efficiently in resistant than in sensitive tumors. For liposomes, the trend was similar, but the differences in tumor accumulation were insignificant. At the individual blood vessel level, both polymers and liposomes were less able to extravasate out of the vasculature and penetrate the interstitium in resistant tumors. In a final in vivo efficacy study, we observed a stronger inhibitory effect of cellular and microenvironmental MDR on liposomal doxorubicin performance than free doxorubicin. These results exemplify that besides classical cellular MDR, microenvironmental drug resistance features should be considered when aiming to target and treat multidrug-resistant tumors more efficiently.
Identifiants
pubmed: 36599395
pii: S0168-3659(22)00870-7
doi: 10.1016/j.jconrel.2022.12.056
pmc: PMC7614501
mid: EMS173911
pii:
doi:
Substances chimiques
Liposomes
0
Doxorubicin
80168379AG
Polymers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
784-793Subventions
Organisme : European Research Council
ID : 864121
Pays : International
Informations de copyright
Copyright © 2023 Elsevier B.V. All rights reserved.
Références
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4147-53
pubmed: 16857785
Br J Cancer. 2008 Mar 25;98(6):1076-84
pubmed: 18334972
Nat Rev Drug Discov. 2006 Mar;5(3):219-34
pubmed: 16518375
Front Physiol. 2017 Oct 12;8:777
pubmed: 29075197
Nat Rev Drug Discov. 2008 Sep;7(9):771-82
pubmed: 18758474
Int J Oncol. 2007 Aug;31(2):277-83
pubmed: 17611683
Nat Rev Cancer. 2002 Jan;2(1):48-58
pubmed: 11902585
Expert Opin Drug Deliv. 2016 Sep;13(9):1199-202
pubmed: 27461854
Nano Lett. 2020 Nov 11;20(11):8102-8111
pubmed: 33064007
Breast Cancer Res Treat. 1994;31(2-3):325-35
pubmed: 7881109
Oncogene. 2017 Apr 6;36(14):1925-1938
pubmed: 27694892
Cell Tissue Res. 2016 Sep;365(3):495-506
pubmed: 27461257
ACS Appl Mater Interfaces. 2015 May 13;7(18):9691-701
pubmed: 25845545
BMC Cancer. 2012 Mar 19;12:91
pubmed: 22429801
Sci Rep. 2018 Sep 12;8(1):13672
pubmed: 30209405
Nat Rev Clin Oncol. 2017 Oct;14(10):611-629
pubmed: 28397828
Adv Drug Deliv Rev. 2022 Oct;189:114504
pubmed: 35998825
Biomed Pharmacother. 2011 Feb;65(1):40-5
pubmed: 21177063
Physiol Rev. 2006 Oct;86(4):1179-236
pubmed: 17015488
Front Oncol. 2020 Jul 23;10:1195
pubmed: 32793490
J Control Release. 2012 Aug 20;162(1):45-55
pubmed: 22698943
J Control Release. 2012 Jul 20;161(2):175-87
pubmed: 21945285
Cancer Res. 2007 Mar 1;67(5):1979-87
pubmed: 17332325
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
PLoS One. 2016 Jul 28;11(7):e0160042
pubmed: 27467397
JAMA Oncol. 2019 Jul 01;5(7):1020-1027
pubmed: 31145418
Int J Mol Sci. 2017 Jul 21;18(7):
pubmed: 28754000
Bone. 2010 Dec;47(6):1076-9
pubmed: 20817052
Toxicol In Vitro. 2012 Apr;26(3):435-44
pubmed: 22269388
Ann Surg Oncol. 2007 Dec;14(12):3629-37
pubmed: 17909916
Biomaterials. 2017 Jan;114:106-120
pubmed: 27855336
J Control Release. 2018 Jul 28;282:25-34
pubmed: 29730154
Biomed Res Int. 2014;2014:365867
pubmed: 24804215
J Clin Invest. 2003 Dec;112(12):1776-84
pubmed: 14679171
Sci Transl Med. 2019 Apr 17;11(488):
pubmed: 30996079
Oncogene. 2003 Oct 20;22(47):7468-85
pubmed: 14576852
Life (Basel). 2022 Jun 15;12(6):
pubmed: 35743927
Adv Drug Deliv Rev. 2013 Nov;65(13-14):1784-802
pubmed: 23880506
Nat Rev Cancer. 2018 Jul;18(7):452-464
pubmed: 29643473
J Control Release. 2018 Mar 28;274:9-23
pubmed: 29408184
Fibrogenesis Tissue Repair. 2012 Nov 01;5(1):19
pubmed: 23114500
Semin Cancer Biol. 2020 May;62:166-181
pubmed: 31415910
Clin Cancer Res. 2009 Apr 15;15(8):2657-65
pubmed: 19336515
Biomed Pharmacother. 2014 Apr;68(3):357-64
pubmed: 24612689