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

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.

Lipidic Cubic-Phase Nanoparticles (Cubosomes) Loaded with Doxorubicin and Labeled with 177Lu as a Potential Tool for Combined Chemo and Internal Radiotherapy for Cancers

“…The partition coefficient of the DOTAGA-OA- 177 Lu complex was measured in a biphasic system of n -octanol/PBS (pH 7.4). After labeling DOTAGA-OA (34 nmol) with 4.5 MBq of 177 Lu in acetate buffer (0.1 M, pH 5.5), the radioconjugate was transferred to the prepared biphasic mixture, vortexed for 1 min, and then centrifuged (14,000 rpm, 5 min) [ 40 ]. The phases were separated, and the activity of each phase was determined by measuring the radiation in a NaI(Tl) scintillation detector.…”

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

“…In this sense, recent therapeutic strategies in which the SP/NK-1R is involved have shown promising results. Thus, in a patient treated with radiotherapy and a NK-1R antagonist (aprepitant, 1140 mg/day for 45 days), the tumor mass disappeared after six months and no serious side-effects were observed [50], and in patients with cancer, the efficacy (promoting apoptosis) of targeted alpha therapy with 213 Bi-DOTA-SP (radionuclide tumor therapy) against tumor cells has been reported [51][52][53][54][55]. Another important finding is that SP, in cancer cells, augmented the expression of the NK-1R, but not that of other receptors (e.g., NK-2R) [56].…”

Physicochemical and Biological Study of 99mTc and 68Ga Radiolabelled Ciprofloxacin and Evaluation of [99mTc]Tc-CIP as Potential Diagnostic Radiopharmaceutical for Diabetic Foot Syndrome Imaging

“…As can be seen, the numerical data obtained by the use of different calculation programs were radically different and certainly cannot be strictly accepted as values for the lipophilicity parameters of the studied radiocompounds. Nevertheless, these values, calculated for all three radioconjugates with the same assumptions of the calculating program, allow the trend in the lipophilicity parameter of these radiopreparations to be estimated [24]. Comparing the structures of [ 68 Ga]Ga-DOTA-CIP, [ 68 Ga]Ga-DOTA-Bz-SCN-PA-CIP, and [ 68 Ga]Ga-NOTA-Bz-SCN-PA-CIP, and based on our own experience, we believe that the lipophilicity of these three radiocompounds is represented by the arrangement presented in Table 3.…”