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

TY - JOUR

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

VL - 29

SP - 3856

EP - 3865

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

IS - 11

ER -