Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment.
The epidermal growth factor receptor (EGFR) is a validated target for anti-cancer therapy and several EGFR inhibitors are used in the clinic. Over the years, an increasing number of studies have reported on the crosstalk between EGFR and other receptors that can contribute to accelerated cancer development or even acquisition of resistance to anti-EGFR therapies. Combined targeting of EGFR and insulin-like growth factor 1 receptor (IGF-1R) is a rational strategy to potentiate anti-cancer treatment and possibly retard resistance development. In the present study, we have pursued this by encapsulating the kinase inhibitor AG538 in anti-EGFR nanobody-liposomes. The thus developed dual-active nanobody-liposomes associated with EGFR-(over)expressing cells in an EGFR-specific manner and blocked both EGFR and IGF-1R activation, due to the presence of the EGFR-blocking nanobody EGa1 and the anti-IGF-1R kinase inhibitor AG538 respectively. AG538-loaded nanobody-liposomes induced a strong inhibition of tumor cell proliferation even upon short-term exposure followed by a drug-free wash-out period. Therefore, AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobody-liposomes.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Roy
R
van der Meel
Sabrina
S
Oliveira
Isil
I
Altintas
Rob
R
Haselberg
Joris
J
van der Veeken
Rob C
RC
Roovers
Paul M P
PM
van Bergen en Henegouwen
Gert
G
Storm
Wim E
WE
Hennink
Raymond M
RM
Schiffelers
Robbert J
RJ
Kok
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001667:Binding, Competitive; D015153:Blotting, Western; D002396:Catechols / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004339:Drug Compounding; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000008:administration & dosage* / Q000494:pharmacology; D008081:Liposomes; D051379:Mice; D018613:Microscopy, Confocal; D041681:NIH 3T3 Cells; D053758:Nanoparticles; D010316:Particle Size; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D013499:Surface Properties; D020032:Tyrphostins / Q000008:administration & dosage* / Q000494:pharmacology
C419770:AG 538; D000970:Antineoplastic Agents; D002396:Catechols; D007143:Immunoglobulin Heavy Chains; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1