Selective Targeting of Cancer-Associated Fibroblasts by Engineered H-Ferritin Nanocages Loaded with Navitoclax

Cancer-associated fibroblasts (CAFs) are key actors in regulating cancer progression. They promote tumor growth, metastasis formation, and induce drug resistance. For these reasons, they are emerging as potential therapeutic targets. Here, with the aim of developing CAF-targeted drug delivery agents, we functionalized H-ferritin (HFn) nanocages with fibroblast activation protein (FAP) antibody fragments. Functionalized nanocages (HFn-FAP) have significantly higher binding with FAP+ CAFs than with FAP− cancer cells. We loaded HFn-FAP with navitoclax (Nav), an experimental Bcl-2 inhibitor pro-apoptotic drug, whose clinical development is limited by its strong hydrophobicity and toxicity. We showed that Nav is efficiently loaded into HFn (HNav), maintaining its mechanism of action. Incubating Nav-loaded functionalized nanocages (HNav-FAP) with FAP+ cells, we found significantly higher cytotoxicity as compared to non-functionalized HNav. This was correlated with a significantly higher drug release only in FAP+ cells, confirming the specific targeting ability of functionalized HFn. Finally, we showed that HFn-FAP is able to reach the tumor and to target CAFs in a mouse syngeneic model of triple negative breast cancer after intravenous administration. Our data show that HNav-FAP could be a promising tool to enhance specific drug delivery into CAFs, thus opening new therapeutic possibilities focused on tumor microenvironment.

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References

51

[1]

Hui "Tumor microenvironment: Sanctuary of the devil" Cancer Lett. (2015) 10.1016/j.canlet.2015.07.039

[2]

(2020, November 02). The Tumor Microenvironment: Current Biology. Available online: https://www.cell.com/current-biology/pdf/S0960-9822(20)30933-7.pdf.

[3]

Truffi "Fibroblasts in the Tumor Microenvironment" Adv. Exp. Med. Biol. (2020) 10.1007/978-3-030-37184-5_2

[4]

Luo "Cancer-associated fibroblasts: A multifaceted driver of breast cancer progression" Cancer Lett. (2015) 10.1016/j.canlet.2015.02.018

[5]

The biology and function of fibroblasts in cancer

Raghu Kalluri

Nature Reviews Cancer 2016 10.1038/nrc.2016.73

[6]

LeBleu "A peek into cancer-associated fibroblasts: Origins, functions and translational impact" Dis. Models Mech. (2018) 10.1242/dmm.029447

[7]

Li "The cancer-associated fibroblasts and drug resistance" Eur. Rev. Med. Pharmacol. Sci. (2015)

[8]

Chen "Turning foes to friends: Targeting cancer-associated fibroblasts" Nat. Rev. Drug Discov. (2019) 10.1038/s41573-018-0004-1

[9]

Chen "Remodeling the Tumor Microenvironment with Emerging Nanotherapeutics" Trends Pharm. Sci. (2018) 10.1016/j.tips.2017.10.009

[10]

Truffi, M., Mazzucchelli, S., Bonizzi, A., Sorrentino, L., Allevi, R., Vanna, R., Morasso, C., and Corsi, F. (2019). Nano-Strategies to Target Breast Cancer-Associated Fibroblasts: Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy. Int. J. Mol. Sci., 20. 10.3390/ijms20061263

[11]

Kelly "Fibroblast activation protein-α and dipeptidyl peptidase IV (CD26): Cell-surface proteases that activate cell signaling and are potential targets for cancer therapy" Drug Resist. Updates (2005) 10.1016/j.drup.2005.03.002

[12]

Old "Cell Surface Glycoprotein of Reactive Stromal Fibroblasts as a Potential Antibody Target in Human Epithelial Cancers" Proc. Natl. Acad. Sci. USA (1990) 10.1073/pnas.87.18.7235

[13]

Ariga "Stromal Expression of Fibroblast Activation Protein/Seprase, a Cell Membrane Serine Proteinase and Gelatinase, Is Associated with Longer Survival in Patients with Invasive Ductal Carcinoma of Breast" Int. J. Cancer (2001) 10.1002/1097-0215(20010120)95:1<67::aid-ijc1012>3.0.co;2-u

[14]

Chen "Seprase complexes in cellular invasiveness" Cancer Metastasis Rev. (2003) 10.1023/a:1023055600919

[15]

Huang "Seprase Promotes Rapid Tumor Growth and Increased Microvessel Density in a Mouse Model of Human Breast Cancer" Cancer Res. (2004) 10.1158/0008-5472.can-03-3184

[16]

Kraman "Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α" Science (2010) 10.1126/science.1195300

[17]

Narra "Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer" Cancer Biol. Ther. (2007) 10.4161/cbt.6.11.4874

[18]

Scott "A Phase I Dose-Escalation Study of Sibrotuzumab in Patients with Advanced or Metastatic Fibroblast Activation Protein-positive Cancer" Clin. Cancer Res. (2003)

[19]

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

Christin Tse, Alexander R. Shoemaker, Jessica Adickes et al.

Cancer Research 2008 10.1158/0008-5472.can-07-5836

[20]

Sarosiek "Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics—Recent successes, current challenges and future promise" FEBS J. (2016) 10.1111/febs.13714

[21]

Gandhi "Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors" J. Clin. Oncol. (2011) 10.1200/jco.2010.31.6208

[22]

Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer

Charles M. Rudin, Christine L. Hann, Edward B. Garon et al.

Clinical Cancer Research 2012 10.1158/1078-0432.ccr-11-3090

[23]

Tahir "Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines" Mol. Cancer Ther. (2010) 10.1158/1535-7163.mct-09-0651

[24]

The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized

Mark F. van Delft, Andrew H. Wei, Kylie D. Mason et al.

Cancer Cell 2006 10.1016/j.ccr.2006.08.027

[25]

Campbell "Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance" Blood (2010) 10.1182/blood-2010-04-281071

[26]

Beroukhim "The landscape of somatic copy-number alteration across human cancers" Nature (2010) 10.1038/nature08822

[27]

Ding "Myeloid Cell Leukemia-1 Inversely Correlates with Glycogen Synthase Kinase-3β Activity and Associates with Poor Prognosis in Human Breast Cancer" Cancer Res. (2007) 10.1158/0008-5472.can-06-1788

[28]

Mertens "Therapeutic Effects of Deleting Cancer-Associated Fibroblasts in Cholangiocarcinoma" Cancer Res. (2013) 10.1158/0008-5472.can-12-2130

[29]

Lagares, D., Santos, A., Grasberger, P.E., Liu, F., Probst, C.K., Rahimi, R.A., Sakai, N., Kuehl, T., Ryan, J., and Bhola, P. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci. Transl. Med., 9. 10.1126/scitranslmed.aal3765

[30]

Rodila "HPLC-MS/MS determination of a hardly soluble drug in human urine through drug-albumin binding assisted dissolution" J. Chromatogr. B Anal. Biomed. Life Sci. (2008) 10.1016/j.jchromb.2008.07.027

[31]

Macias "Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity" Aging Cell (2020) 10.1111/acel.13142

[32]

Kile "The role of apoptosis in megakaryocytes and platelets" Br. J. Haematol. (2014) 10.1111/bjh.12757

[33]

Fan "Human ferritin for tumor detection and therapy" Wires Nanomed. Nanobiotechnol. (2013) 10.1002/wnan.1221

[34]

Truffi "Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer" Pharmacol. Res. (2016) 10.1016/j.phrs.2016.03.002

[35]

Bonizzi, A., Truffi, M., Sevieri, M., Allevi, R., Sitia, L., Ottria, R., Sorrentino, L., Sottani, C., Negri, S., and Grignani, E. (2019). EverolimusNanoformulation in Biological Nanoparticles Increases Drug Responsiveness in Resistant and Low-Responsive Breast Cancer Cell Lines. Pharmaceutics, 11. 10.3390/pharmaceutics11080384

[36]

Falvo "Antibody–drug conjugates: Targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin" Nanoscale (2013) 10.1039/c3nr04268e

[37]

Sitia "Development of Tumor-Targeted Indocyanine Green-Loaded Ferritin Nanoparticles for Intraoperative Detection of Cancers" ACS Omega (2020) 10.1021/acsomega.0c00244

[38]

Mazzucchelli "H-Ferritin-nanocagedolaparib: A promising choice for both BRCA-mutated and sporadic triple negative breast cancer" Sci. Rep. (2017) 10.1038/s41598-017-07617-7

[39]

Sitia "In Vitro Blood-Brain Barrier Models for Nanomedicine: Particle-Specific Effects and Methodological Drawbacks" ACS Appl. Bio Mater. (2019) 10.1021/acsabm.9b00305

[40]

Truffi "Inhibition of Fibroblast Activation Protein Restores a Balanced Extracellular Matrix and Reduces Fibrosis in Crohn’s Disease Strictures Ex Vivo" Inflamm. Bowel Dis. (2018) 10.1093/ibd/izx008

[41]

Mazzucchelli "Nanometronomic treatment of 4T1 breast cancer with nanocaged doxorubicin prevents drug resistance and circumvents cardiotoxicity" Oncotarget (2016) 10.18632/oncotarget.14204

[42]

Gu "Targeted nanoparticles for cancer therapy" Nano Today (2007) 10.1016/s1748-0132(07)70083-x

[43]

Salama, L., Pastor, E.R., Stone, T., and Mousa, S.A. (2020). Emerging Nanopharmaceuticals and Nanonutraceuticals in Cancer Management. Biomedicines, 8. 10.3390/biomedicines8090347

[44]

Pape "Cancer-associated fibroblasts mediate cancer progression and remodel the tumouroid stroma" Br. J. Cancer (2020) 10.1038/s41416-020-0973-9

[45]

Lee, Y.T., Tan, Y.J., Falasca, M., and Oon, C.E. (2020). Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic Intervention in Breast Cancer. Cancers, 12. 10.3390/cancers12102949

[46]

Liu "Cancer-associated fibroblasts: An emerging target of anti-cancer immunotherapy" J. Hematol. Oncol. (2019) 10.1186/s13045-019-0770-1

[47]

A framework for advancing our understanding of cancer-associated fibroblasts

Erik Sahai, Igor Astsaturov, Edna Cukierman et al.

Nature Reviews Cancer 2020 10.1038/s41568-019-0238-1

[48]

Harryvan, T.J., Verdegaal, E.M.E., Hardwick, J.C.H., Hawinkels, L.J.A.C., and van der Burg, S.H. (2019). Targeting of the Cancer-Associated Fibroblast—T-Cell Axis in Solid Malignancies. J. Clin. Med., 8. 10.3390/jcm8111989

[49]

Lindner, T., Loktev, A., Giesel, F., Kratochwil, C., Altmann, A., and Haberkorn, U. (2019). Targeting of activated fibroblasts for imaging and therapy. EJNMMI Radiopharm. Chem., 4. 10.1186/s41181-019-0069-0

[50]

Hofheinz "Stromal Antigen Targeting by a Humanised Monoclonal Antibody: An Early Phase II Trial of Sibrotuzumab in Patients with Metastatic Colorectal Cancer" Oncol. Res. Treat. (2003) 10.1159/000069863

Showing 50 of 51 references

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Details

Published: Feb 05, 2021
Vol/Issue: 10(2)
Pages: 328
License: View

Authors

L

Leopoldo Sitia

Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, 20157 Milan, Italy

A

Arianna Bonizzi

Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, 20157 Milan, Italy

S

Serena Mazzucchelli

Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, 20157 Milan, Italy

S

Sara Negri

Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy

C

Cristina Sottani

Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy

E

Elena Grignani

Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy

M

Maria Antonietta Rizzuto

Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126 Milan, Italy

D

Davide Prosperi

Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126 Milan, Italy

L

Luca Sorrentino

Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milan, Italy

C

Carlo Morasso

Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy

R

Raffaele Allevi

Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, 20157 Milan, Italy

M

Marta Sevieri

Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, 20157 Milan, Italy

F

Filippo Silva

Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, 20157 Milan, Italy

M

Marta Truffi

Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy

F

Fabio Corsi

Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, 20157 Milan, Italy; Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy

Funding

Associazione Italiana per la Ricerca sul Cancro Award: AIRC IG 2017 - ID.20172

Cite This Article

Leopoldo Sitia, Arianna Bonizzi, Serena Mazzucchelli, et al. (2021). Selective Targeting of Cancer-Associated Fibroblasts by Engineered H-Ferritin Nanocages Loaded with Navitoclax. Cells, 10(2), 328. https://doi.org/10.3390/cells10020328

Selective Targeting of Cancer-Associated Fibroblasts by Engineered H-Ferritin Nanocages Loaded with Navitoclax

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