Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

Jiaying Han; Andreas F B Räder; Florian Reichart; Brech Aikman; Margot N Wenzel; Ben Woods; Michael Weinmüller; Beatrice S Ludwig; Stefan Stürup; Geny M M Groothuis; Hjalmar P Permentier; Rainer Bischoff; Horst Kessler; Peter Horvatovich; Angela Casini

doi:10.1021/acs.bioconjchem.8b00682

Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

Jiaying Han, Andreas F B Räder, Florian Reichart, Brech Aikman, Margot N Wenzel, Ben Woods, Michael Weinmüller, Beatrice S Ludwig, Stefan Stürup, Geny M M Groothuis, Hjalmar P Permentier, Rainer Bischoff, Horst Kessler, Peter Horvatovich, Angela Casini

21 Citations (Scopus)

Abstract

Cisplatin occupies a crucial role in the treatment of various malignant tumors. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity. Thus, Pd2L4 cages (L = ligand) have been conjugated to four integrin ligands with different binding affinity and selectivity. Cage formation and encapsulation of cisplatin was proven by NMR spectroscopy. Upon encapsulation, cisplatin showed increased cytotoxicity in vitro, in melanoma A375 cells overexpressing αvβ3 integrins. Moreover, ex vivo studies in tissue slices indicated reduced toxicity toward healthy liver and kidney tissues for cage-encapsulated cisplatin. Analysis of metal content by ICP-MS demonstrated that the encapsulated drug is less accumulated in these organs compared to the "free" cisplatin.

Original language	English
Journal	Bioconjugate Chemistry
Volume	29
Issue number	11
Pages (from-to)	3856-3865
Number of pages	10
ISSN	1043-1802
DOIs	https://doi.org/10.1021/acs.bioconjchem.8b00682
Publication status	Published - 21 Nov 2018

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Han, J., Räder, A. F. B., Reichart, F., Aikman, B., Wenzel, M. N., Woods, B., Weinmüller, M., Ludwig, B. S., Stürup, S., Groothuis, G. M. M., Permentier, H. P., Bischoff, R., Kessler, H., Horvatovich, P., & Casini, A. (2018). Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin. Bioconjugate Chemistry, 29(11), 3856-3865. https://doi.org/10.1021/acs.bioconjchem.8b00682

Han, J, Räder, AFB, Reichart, F, Aikman, B, Wenzel, MN, Woods, B, Weinmüller, M, Ludwig, BS, Stürup, S, Groothuis, GMM, Permentier, HP, Bischoff, R, Kessler, H, Horvatovich, P & Casini, A 2018, 'Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin', Bioconjugate Chemistry, vol. 29, no. 11, pp. 3856-3865. https://doi.org/10.1021/acs.bioconjchem.8b00682

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title = "Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin",

abstract = "Cisplatin occupies a crucial role in the treatment of various malignant tumors. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity. Thus, Pd2L4 cages (L = ligand) have been conjugated to four integrin ligands with different binding affinity and selectivity. Cage formation and encapsulation of cisplatin was proven by NMR spectroscopy. Upon encapsulation, cisplatin showed increased cytotoxicity in vitro, in melanoma A375 cells overexpressing αvβ3 integrins. Moreover, ex vivo studies in tissue slices indicated reduced toxicity toward healthy liver and kidney tissues for cage-encapsulated cisplatin. Analysis of metal content by ICP-MS demonstrated that the encapsulated drug is less accumulated in these organs compared to the {"}free{"} cisplatin.",

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T1 - Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

AU - Han, Jiaying

AU - Räder, Andreas F B

AU - Reichart, Florian

AU - Aikman, Brech

AU - Wenzel, Margot N

AU - Woods, Ben

AU - Weinmüller, Michael

AU - Ludwig, Beatrice S

AU - Stürup, Stefan

AU - Groothuis, Geny M M

AU - Permentier, Hjalmar P

AU - Bischoff, Rainer

AU - Kessler, Horst

AU - Horvatovich, Peter

AU - Casini, Angela

PY - 2018/11/21

Y1 - 2018/11/21

N2 - Cisplatin occupies a crucial role in the treatment of various malignant tumors. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity. Thus, Pd2L4 cages (L = ligand) have been conjugated to four integrin ligands with different binding affinity and selectivity. Cage formation and encapsulation of cisplatin was proven by NMR spectroscopy. Upon encapsulation, cisplatin showed increased cytotoxicity in vitro, in melanoma A375 cells overexpressing αvβ3 integrins. Moreover, ex vivo studies in tissue slices indicated reduced toxicity toward healthy liver and kidney tissues for cage-encapsulated cisplatin. Analysis of metal content by ICP-MS demonstrated that the encapsulated drug is less accumulated in these organs compared to the "free" cisplatin.

AB - Cisplatin occupies a crucial role in the treatment of various malignant tumors. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity. Thus, Pd2L4 cages (L = ligand) have been conjugated to four integrin ligands with different binding affinity and selectivity. Cage formation and encapsulation of cisplatin was proven by NMR spectroscopy. Upon encapsulation, cisplatin showed increased cytotoxicity in vitro, in melanoma A375 cells overexpressing αvβ3 integrins. Moreover, ex vivo studies in tissue slices indicated reduced toxicity toward healthy liver and kidney tissues for cage-encapsulated cisplatin. Analysis of metal content by ICP-MS demonstrated that the encapsulated drug is less accumulated in these organs compared to the "free" cisplatin.

U2 - 10.1021/acs.bioconjchem.8b00682

DO - 10.1021/acs.bioconjchem.8b00682

M3 - Journal article

C2 - 30380298

SN - 1043-1802

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SP - 3856

EP - 3865

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

IS - 11

ER -

Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

Abstract

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