Anti insulin-like growth factor I receptor immunoliposomes: a single formulation combining two anticancer treatments with enhanced therapeutic efficiency.
BACKGROUND
Through overexpression and aberrant activation in many human tumors, the IGF system plays a key role in tumor development and tumor cell proliferation. Different strategies targeting IGF-I receptor (IGFI-R) have been developed, and recent studies demonstrated that combined treatments with cytostatic drugs enhance the potency of anti-IGFI-R therapies.


OBJECTIVE
The objective of the study was to examine the IGFI-R expression status in neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) in comparison with healthy tissues and use potential overexpression as a target for novel anti-IGFI-R immunoliposomes.


METHODS
A human tumor tissue array and samples from different normal tissues were investigated by immunohistochemistry. An IGFI-R antagonistic antibody (1H7) was coupled to the surface of sterically stabilized liposomes loaded with doxorubicin. Cell lines from different tumor entities were investigated for liposomal association studies in vitro. For in vivo experiments, neuroendocrine tumor xenografts were used for evaluation of pharmacokinetic and therapeutic properties of the novel compound.


RESULTS
Immunohistochemistry revealed significant IGFI-R overexpression in all investigated GEP-NETs (n = 59; staining index, 229.1 +/- 3.1%) in comparison with normal tissues (115.7 +/- 3.7%). Furthermore, anti-IGFI-R immunoliposomes displayed specific tumor cell association (44.2 +/- 1.6% vs. IgG liposomes, 0.8 +/- 0.3%; P < 0.0001) and internalization in human neuroendocrine tumor cells in vitro and superior antitumor efficacy in vivo (life span 31.5 +/- 2.2 d vs. untreated control, 19 +/- 0.6, P = 0.008).


CONCLUSIONS
IGFI-R overexpression seems to be a common characteristic of otherwise heterogenous NETs. Novel anti-IGFI-R immunoliposomes have been developed and successfully tested in a preclinical model for human GEP-NETs. Moreover in vitro experiments indicate that usage of this agent could also present a promising approach for other tumor entities.
Hantel
Constanze
C
Endocrine Research Unit, Medizinische Klinik-Innenstadt, Ludwig-Maximilians-University, D-80336 Munich, Germany.
Lewrick
Felicitas
F
Schneider
Sebastian
S
Zwermann
Oliver
O
Perren
Aurel
A
Reincke
Martin
M
Süss
Regine
R
Beuschlein
Felix
F
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000906:Antibodies / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D008081:Liposomes; D051379:Mice; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D008081:Liposomes; D004317:Doxorubicin; D017526:Receptor, IGF Type 1