TY - JOUR
T1 - Profiling target engagement and cellular uptake of cRGD-decorated clinical-stage core-crosslinked polymeric micelles
AU - De Lorenzi, Federica
AU - Rizzo, Larissa Yokota
AU - Daware, Rasika
AU - Motta, Alessandro
AU - Baues, Maike
AU - Bartneck, Matthias
AU - Vogt, Michael
AU - van Zandvoort, Marc
AU - Kaps, Leonard
AU - Hu, Qizhi
AU - Thewissen, Marielle
AU - Casettari, Luca
AU - Rijcken, Cristianne J F
AU - Kiessling, Fabian
AU - Sofias, Alexandros Marios
AU - Lammers, Twan
N1 - © 2022. The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - Polymeric micelles are increasingly explored for tumor-targeted drug delivery. CriPec® technology enables the generation of core-crosslinked polymeric micelles (CCPMs) based on thermosensitive (mPEG-b-pHPMAmLacn) block copolymers, with high drug loading capacity, tailorable size, and controlled drug release kinetics. In this study, we decorated clinical-stage CCPM with the αvβ3 integrin-targeted cyclic arginine-glycine-aspartic acid (cRGD) peptide, which is one of the most well-known active targeting ligands evaluated preclinically and clinically. Using a panel of cell lines with different expression levels of the αvβ3 integrin receptor and exploring both static and dynamic incubation conditions, we studied the benefit of decorating CCPM with different densities of cRGD. We show that incubation time and temperature, as well as the expression levels of αvβ3 integrin by target cells, positively influence cRGD-CCPM uptake, as demonstated by immunofluorescence staining and fluorescence microscopy. We demonstrate that even very low decoration densities (i.e., 1 mol % cRGD) result in increased engagement and uptake by target cells as compared to peptide-free control CCPM, and that high cRGD decoration densities do not result in a proportional increase in internalization. In this context, it should be kept in mind that a more extensive presence of targeting ligands on the surface of nanomedicines may affect their pharmacokinetic and biodistribution profile. Thus, we suggest a relatively low cRGD decoration density as most suitable for in vivo application.
AB - Polymeric micelles are increasingly explored for tumor-targeted drug delivery. CriPec® technology enables the generation of core-crosslinked polymeric micelles (CCPMs) based on thermosensitive (mPEG-b-pHPMAmLacn) block copolymers, with high drug loading capacity, tailorable size, and controlled drug release kinetics. In this study, we decorated clinical-stage CCPM with the αvβ3 integrin-targeted cyclic arginine-glycine-aspartic acid (cRGD) peptide, which is one of the most well-known active targeting ligands evaluated preclinically and clinically. Using a panel of cell lines with different expression levels of the αvβ3 integrin receptor and exploring both static and dynamic incubation conditions, we studied the benefit of decorating CCPM with different densities of cRGD. We show that incubation time and temperature, as well as the expression levels of αvβ3 integrin by target cells, positively influence cRGD-CCPM uptake, as demonstated by immunofluorescence staining and fluorescence microscopy. We demonstrate that even very low decoration densities (i.e., 1 mol % cRGD) result in increased engagement and uptake by target cells as compared to peptide-free control CCPM, and that high cRGD decoration densities do not result in a proportional increase in internalization. In this context, it should be kept in mind that a more extensive presence of targeting ligands on the surface of nanomedicines may affect their pharmacokinetic and biodistribution profile. Thus, we suggest a relatively low cRGD decoration density as most suitable for in vivo application.
KW - BIODISTRIBUTION
KW - COMPLETE REGRESSION
KW - Core-crosslinked polymeric micelles
KW - CriPec (R)
KW - Cyclic arginine-glycine-aspartic acid (cRGD)
KW - DELIVERY
KW - IN-VIVO
KW - INTEGRINS
KW - Nanomedicine
KW - Nanoparticles
KW - RGD PEPTIDE
KW - SILICA NANOPARTICLES
KW - THERAPEUTICS
KW - THERAPY
KW - TUMOR ANGIOGENESIS
KW - Tumor targeting
U2 - 10.1007/s13346-022-01204-8
DO - 10.1007/s13346-022-01204-8
M3 - Article
C2 - 35816231
SN - 2190-393X
VL - 13
SP - 1195
EP - 1211
JO - Drug Delivery and Translational Research
JF - Drug Delivery and Translational Research
IS - 5
ER -