Application of Neurokinin-1 Receptor in Targeted Strategies for Glioma Treatment. Part I: Synthesis and Evaluation of Substance P Fragments Labeled with 99mTc and 177Lu as Potential Receptor Radiopharmaceuticals.

Agnieszka Majkowska-Pilip,Przemysław Koźmiński,Tadeusz Budlewski,Anna Wawrzynowska,Ewa Gniazdowska,Bogusław Kostkiewicz

doi:10.3390/molecules23102542

Abstract

Gliomas, particularly WHO grade IV glioblastoma multiforme, are one of the most common and aggressive primary tumors of the central nervous system. The neuropeptide, substance P (SP), is the physiological ligand of the neurokinin-1 (NK-1) receptor that is consistently overexpressed in glioblastoma cells. The aim of this work was to study physico-chemical and biological properties of different SP analogues labeled with technetium-99m and lutetium-177 radionuclides. The synthesized compounds were characterized in vitro by partition coefficients (logP) and their stability was investigated in various physiological solutions. Biological properties (Kd, Bmax) were characterized using the U373 MG cell line. The obtained lipophilicity values of the [99mTc]NS3/CN-SP and [177Lu]DOTA-SP radiobioconjugates were in the range of −0.3 to +0.6 and −2.5 to −5.0, respectively. The studied radiobioconjugates were stable in PBS buffer and CSF, as well as in 10 mM histidine and/or cysteine solutions whereas in human serum showed enzymatic biodegradation. [177Lu]DOTA-[Thi8,Met(O2)11]SP(1–11), [177Lu]DOTA-SP(4–11) and [177Lu]DOTA-[Thi8,Met(O2)11]SP(5–11) radiobioconjugates bound specifically to NK-1 receptors expressed on glioblastoma cells with affinity in the nanomolar range. To conclude, the shorter analogues of SP can be used as vectors, nevertheless they still do not fulfil all requirements for preparations in nuclear medicine.

Highlights

Gliomas are the most common primary brain tumors in adult patients
To characterize the receptor-binding properties of substance P (SP) radiobioconjugates, saturation binding experiments on the U373 MG cells were performed (Figure 7), with determination of Kd and Bmax values (Table 3). These results demonstrated that both newly synthesized 2c and 2e radiobioconjugates bind to NK-1 receptors expressed on glioblastoma multiforme (GBM) cells with high affinity in the nanomolar range
Radiobioconjugates containing shorter SP fragments were characterized by a lower molecular weight and higher lipophilicity, which allows more effective migration into GBM tissue or into the post-surgery cavity walls

Summary

Introduction

Gliomas are the most common primary brain tumors in adult patients. The most malignant of them is glioblastoma multiforme (GBM), called glioblastoma or astrocytoma. A properly chosen vector (in the case of gliomas, the neuropeptide substance P) that has a high affinity for an overexpressed receptor (on the glioma cells, neurokinin-1 receptors) concentrates the therapeutic radionuclide around the target point. This is where the energy of the emitted radiation deposited in tumor tissue selectively destroys tumor cells. Overexpression of NK-1 receptors on tumor cells has allowed use of substance P (SP, the physiological ligand of the NK-1 receptor) in cancer treatment [9,10,11,12]. The released receptor comes back to the cell membrane and the absorbed peptide particles couple with the lysosome where they are processed for further application by the cell (transmission of morphological information) [7]

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Conclusion