Repurposing Tamoxifen for Tumor Microenvironment Priming and Enhanced Tumor-Targeted Drug Delivery

被引：1

作者：

Biancacci, Ilaria ^{[1
]}

De Santis, Daniele ^{[1
,2
]}

Rama, Elena ^{[1
]}

Benderski, Karina ^{[1
]}

Momoh, Jeffrey ^{[1
]}

Pohlberger, Robert ^{[1
]}

Moeckel, Diana ^{[1
]}

Kaps, Leonard ^{[3
,4
,5
]}

Rijcken, Cristianne J. F. ^{[6
]}

Prakash, Jai ^{[7
]}

Thewissen, Marielle ^{[6
]}

Kiessling, Fabian ^{[8
,9
]}

Shi, Yang ^{[1
]}

Pena, Quim ^{[1
]}

Sofias, Alexandros Marios ^{[1
]}

Consolino, Lorena ^{[1
]}

Lammers, Twan ^{[1
]}

机构：

[1] Rhein Westfal TH Aachen, Inst Expt Mol Imaging, Dept Nanomed & Theranost, Forckenbeckstr 55, D-52074 Aachen, Germany

[2] Univ Urbino, Dept Biomol Sci, Piazza Rinascimento 6, I-61029 Urbino, Italy

[3] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Internal Med 1, Langenbeckstr 1, D-55131 Mainz, Germany

[4] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Translat Immunol, Obere Zahlbacher Str 63, D-55131 Mainz, Germany

[5] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Res Ctr Immunotherapy FZI, Obere Zahlbacher Str 63, D-55131 Mainz, Germany

[6] Cristal Therapeut, Oxfordlaan 55, NL-6229 EV Maastricht, Netherlands

[7] Univ Twente, Tech Med Ctr, Dept Adv Organ Bioengn & Therapeut, Engn Therapeut Sect, Drienerlolaan 5, NL-7522 NB Enschede, Netherlands

[8] Rhein Westfal TH Aachen, Inst Expt Mol Imaging, Forckenbeckstr 55, D-52074 Aachen, Germany

[9] Fraunhofer Inst Digital Med MEVIS, Max Von Laue Str 2, D-28359 Bremen, Germany

来源：

ADVANCED THERAPEUTICS | 2023年 / 6卷 / 11期

基金：

欧洲研究理事会;

关键词：

drug delivery; nanomedicine; polymeric micelles; tamoxifen; tumor microenvironment; POLYMERIC MICELLES; CANCER-CELLS; COLLAGEN I; BIODISTRIBUTION; METASTASIS; INHIBITION; MODULATION; PACLITAXEL; STABILITY; DEPLETION;

D O I：

10.1002/adtp.202300098

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The dense stromal matrix in fibrotic tumors hinders tumor-targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, is shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. It is investigated if TMX, administered in free and nano-formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano-formulations in pancreatic ductal adenocarcinoma and triple-negative breast cancer mouse models, evaluated using clinical-stage Cy7-labeled core-crosslinked polymeric micelles (CCPM). Under control conditions, higher levels of Cy7-CCPM are found in PANC-1 tumors (16.7% ID g(-1) at 48 h post i.v. injection) than in 4T1 tumors (11.0% ID g(-1)). In both models, free and nano-formulated TMX failed to improve CCPM delivery. These findings are congruent with the results from histopathological immunofluorescence analysis of tumor tissue, which indicate that TMX treatment does not significantly change vascularization, perfusion, macrophage infiltration, collagen density, and collagen fiber thickness. Altogether, these results demonstrate that in PANC-1 and 4T1 mouse models, TMX treatment does not contribute to beneficial TME priming and enhanced tumor-targeted drug delivery.

引用

页数：11

共 64 条

[11] Pirfenidone inhibits stromal collagen deposition and improves intra-tumoral delivery and antitumor efficacy of Pegylated liposomal doxorubicin [J].

Cai, Tiantian ;

Jiang, Jiali ;

Yao, Wendong ;

Hu, Yan ;

Kong, Sisi ;

Fan, Qiaomei ;

Yan, Xingxing ;

Li, Fanzhu ;

Shi, Zheng .

BIOMEDICINE & PHARMACOTHERAPY, 2023, 157

[12] Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer [J].

Cazet, Aurelie S. ;

Hui, Mun N. ;

Elsworth, Benjamin L. ;

Wu, Sunny Z. ;

Roden, Daniel ;

Chan, Chia-Ling ;

Skhinas, Joanna N. ;

Collot, Raphael ;

Yang, Jessica ;

Harvey, Kate ;

Johan, M. Zahied ;

Cooper, Caroline ;

Nair, Radhika ;

Herrmann, David ;

McFarland, Andrea ;

Deng, Niantao ;

Ruiz-Borrego, Manuel ;

Rojo, Federico ;

Trigo, Jose M. ;

Bezares, Susana ;

Caballero, Rosalia ;

Lim, Elgene ;

Timpson, Paul ;

O'Toole, Sandra ;

Watkins, D. Neil ;

Cox, Thomas R. ;

Samuel, Michael S. ;

Martin, Miguel ;

Swarbrick, Alexander .

NATURE COMMUNICATIONS, 2018, 9

[13] Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels [J].

Chauhan, Vikash P. ;

Martin, John D. ;

Liu, Hao ;

Lacorre, Delphine A. ;

Jain, Saloni R. ;

Kozin, Sergey V. ;

Stylianopoulos, Triantafyllos ;

Mousa, Ahmed S. ;

Han, Xiaoxing ;

Adstamongkonkul, Pichet ;

Popovic, Zoran ;

Huang, Peigen ;

Bawendi, Moungi G. ;

Boucher, Yves ;

Jain, Rakesh K. .

NATURE COMMUNICATIONS, 2013, 4

[14] Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor [J].

Cortes, Ernesto ;

Lachowski, Dariusz ;

Rice, Alistair ;

Thorpe, Stephen D. ;

Robinson, Benjamin ;

Yeldag, Gulcen ;

Lee, David A. ;

Ghemtio, Leo ;

Rombouts, Krista ;

Hernandez, Armando E. del Rio .

ONCOGENE, 2019, 38 (16) :2910-2922

[15] Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival [J].

Cortes, Ernesto ;

Lachowski, Dariusz ;

Robinson, Benjamin ;

Sarper, Muge ;

Teppo, Jaakko S. ;

Thorpe, Stephen D. ;

Lieberthal, Tyler J. ;

Iwamoto, Kazunari ;

Lee, David A. ;

Okada-Hatakeyama, Mariko ;

Varjosalo, Markku T. ;

Hernandez, Armando E. del Rio .

EMBO REPORTS, 2019, 20 (01)

[16] GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment [J].

Cortes, Ernesto ;

Sarper, Muge ;

Robinson, Benjamin ;

Lachowski, Dariusz ;

Chronopoulos, Antonios ;

Thorpe, Stephen D. ;

Lee, David A. ;

Hernandez, Armando E. del Rio .

EMBO REPORTS, 2019, 20 (01)

[17] Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis [J].

Denk, Franziska ;

Ramer, Leanne M. ;

Erskine, Erin L. K. S. ;

Nassar, Mohammed A. ;

Bogdanov, Yury ;

Signore, Massimo ;

Wood, John N. ;

McMahon, Stephen B. ;

Ramer, Matt S. .

ACTA NEUROPATHOLOGICA COMMUNICATIONS, 2015, 3 :74

[18] Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors [J].

Diop-Frimpong, Benjamin ;

Chauhan, Vikash P. ;

Krane, Stephen ;

Boucher, Yves ;

Jain, Rakesh K. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (07) :2909-2914

[19] The role of stroma in pancreatic cancer: diagnostic and therapeutic implications [J].

Erkan, Mert ;

Hausmann, Simone ;

Michalski, Christoph W. ;

Fingerle, Alexander A. ;

Dobritz, Martin ;

Kleeff, Joerg ;

Friess, Helmut .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2012, 9 (08) :454-467

[20] COMPARATIVE BINDING AFFINITIES OF TAMOXIFEN, 4-HYDROXYTAMOXIFEN, AND DESMETHYLTAMOXIFEN FOR ESTROGEN-RECEPTORS ISOLATED FROM HUMAN-BREAST CARCINOMA - CORRELATION WITH BLOOD-LEVELS IN PATIENTS WITH METASTATIC BREAST-CANCER [J].

FABIAN, C ;

TILZER, L ;

STERNSON, L .

BIOPHARMACEUTICS & DRUG DISPOSITION, 1981, 2 (04) :381-390

← 1 2 3 4 5 6 7 →