Abstract LB-A16: Imaging of glioblastoma using LDLR-based targeted delivery system
Authors: Tworowska Izabela , II Leo G Flores , Zielinski Rafal , Nowak Jonathan , Lecorche Pascaline , Malicet Cedric , Khrestchatisky Michel , Temsamani Jamal , Delpassand Ebrahim 
Published: March 2020

Introduction: Glioblastoma is the most agressive brain tumor with average life expectancy of 12-15 months from diagnosis. One of the factors that limit efficacy of drug, especially in primary brain tumor is permeability of the blood brain barrier (BBB). The low-density lipoprotein receptor (LDLR) expressed at the BBB mediates the transport of endogenous ligands through the BBB, a process referred to as receptor-mediated transcytosis. VECT-HORUS (VH) has identified and chemically optimized a family of peptide-vectors targeting both the human and murine LDLR and able i) to cross the BBB and ii) to target tumors such as glioblastoma that express high levels of the LDLR. The objective of this study was to determine the LDLR targeting properties of 68Ga/177Lu- radiolabeled peptide vectors developed by the VH proprietary platform using a glioblastoma model that expresses the human LDLR (hLDLR) at high levels. Methods: The LDLR targeted DOTA-conjugates (VH-DO31, VH-DO33) and NODAGA conjugate (VH-NO31), (10-30ug, VECT-HORUS SAS, France) were labeled with 68Ga (1.5mCi) eluted from 68Ge/68Ga generator (100mCi, ITG GmBH, Germany) or with 177Lu n.c.a (1mCi, ITG GmBH, Germany). The U87MG cell line has been shown to express high levels of the hLDLR. The LDLR targeting properties of these conjugates were thus determined in vitro in U87MG cellular uptake studies, as well as in vivo in U87MG xenografted mice. The PET/CT images of U87MG xenograft generated in athymic nude mice (10 weeks, n=3) were acquired using G4 PET/Xray camera (Sofie Biosciences; 10min/scan) at 1h, 2h, 3h and 4h post-injection. Results: All 68Ga/177Lu-labeled conjugates were synthesized with radiochemical purity higher than 91 % as determined by radio-HPLC. Radiolytic stability of agents was increased using C18 ethanol purification of the final products. 177Lu-VH-DO33 showed the highest retention of the agent in U87MG cell line at 1h (13.88± 1.6 %ID/mg) and 21h incubation time (8.7± 4 %ID/mg) compared to 177Lu-VH-DO31 (8.28 ±6.2 %ID/mg) The microPET imaging studies showed rapid accumulation and retention of all VH derivatives in tumor as monitored up to 4h post injection. All agents were eliminated through bladder and kidneys. There was no accumulation of agents in the bone marrow. The image based biodistribution studies of 68Ga-VH-DO31, 68Ga-VH-DO33 and 68Ga-VH-NO31 showed that the tumor to muscle ratios (SUV ratio) after 30 min post-injection were 4.12, 5.07 and 3.88, respectively and remained at the same levels up to 3h post-injection. The SUV ratios of tumor to kidneys were as follows: 68Ga-VH-DO31 (0.46), 68Ga-VH-DO33 (0.84) and 68Ga-VH-NO31 (0.46) confirming renal elimination of the agents. Conclusions: VH derivatives showed favorable hLDLR and tumor-targeting properties both in in vitro as well as in vivo in U87MG xenografts. These results can postulate that hLDLR may serve as a target for the development of theranostic probes for the diagnosis and radiotherapy of glioblastoma.

Citation Format: Izabela Tworowska, Leo G Flores II, Rafal Zielinski, Jonathan Nowak, Pascaline Lecorche, Cedric Malicet, Michel Khrestchatisky, Jamal Temsamani, Ebrahim Delpassand. Imaging of glioblastoma using LDLR-based targeted delivery system [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A16. doi:10.1158/1535-7163.TARG-19-LB-A16