211 At labeled substance P (5–11) as potential radiopharmaceutical for glioma treatment

Lyczko, Monika; Pruszyński, Marek; Majkowska-Pilip, Agnieszka; Łyczko, Krzysztof; Wąs, Bogdan; Męczyńska-Wielgosz, Sylwia; Kruszewski, Marcin; Szkliniarz, Katarzyna; Jastrzȩbski, J.; Stolarz, A.; Bilewicz, Aleksander

doi:10.1016/j.nucmedbio.2017.05.008

Cited by 19 publications

(25 citation statements)

References 36 publications

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“…Our results confirmed the anticipated highly efficient cell-killing of HER2-expressing breast carcinoma cells by 211 At-AuNP-trastuzumab at concentrations similar to those described in the literature with other combinations of 211 At-labeled molecules and tumor cells [64,65,66]. The observed lower cytotoxicity of 211 At bioconjugates to glioblastoma cells was related to the very high radioresistance of glioblastoma cancer cells.…”

Section: Resultssupporting

confidence: 89%

Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer

et al. 2019

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Highly localized radiotherapy with radionuclides is a commonly used treatment modality for patients with unresectable solid tumors. Herein, we propose a novel α-nanobrachytherapy approach for selective therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles (AuNPs) labeled with an α-emitter (211At), modified with polyethylene glycol (PEG) chains and attached to HER2-specific monoclonal antibody (trastuzumab). The size, shape, morphology, and zeta potential of the 5 nm synthesized AuNPs were characterized by TEM (Transmission Electron Microscopy) and DLS (Dynamic Light Scattering) techniques. The gold nanoparticle surface was modified by PEG and subsequently used for antibody immobilization. Utilizing the high affinity of gold for heavy halogens, the bioconjugate was labelled with 211At obtained by α irradiation of the bismuth target. The labeling yield of 211At was greater than 99%. 211At bioconjugates were stable in human serum. Additionally, in vitro biological studies indicated that 211At-AuNP-PEG-trastuzumab exhibited higher affinity and cytotoxicity towards the HER2-overexpressing human ovarian SKOV-3 cell line than unmodified nanoparticles. Confocal and dark field microscopy studies revealed that 211At-AuNP-PEG-trastuzumab was effectively internalized and deposited near the nucleus. These findings show promising potential for the 211At-AuNP-PEG-trastuzumab radiobioconjugate as a perspective therapeutic agent in the treatment of unresectable solid cancers expressing HER2 receptors.

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Section: Resultssupporting

confidence: 89%

Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer

et al. 2019

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“…The fragment SP(5-11) is the most abundant metabolite of native SP and it is still biologically active as the binding site with NK1 receptors is localized in the region of 7–11 amino acids. We have previously shown that this fragment radiolabelled with different radionuclides exhibit high affinity (IC 50 = 38 nM) and interaction with NK1 receptors on T98G cells (Piotrowska et al 2017 ; Lyczko et al 2017 ). Additionally, fragment SP(5-11) contains l -glutamine in position 5 what allows coupling of silane-PEG-NHS via NHS-active ester to form bioconjugate that further is used to functionalize the TiO 2 NPs surface.…”

Section: Resultsmentioning

confidence: 99%

Functionalized TiO2 nanoparticles labelled with 225Ac for targeted alpha radionuclide therapy

et al. 2018

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The 225Ac radioisotope exhibits very attractive nuclear properties for application in radionuclide therapy. Unfortunately, the major challenge for radioconjugates labelled with 225Ac is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-targeted tissues. In the present work, we propose to apply TiO2 nanoparticles (NPs) as carrier for 225Ac and its decay products. The surface of TiO2 nanoparticles with 25 nm diameter was modified with Substance P (5-11), a peptide fragment which targets NK1 receptors on the glioma cells, through the silan-PEG-NHS linker. Nanoparticles functionalized with Substance P (5-11) were synthesized with high yield in a two-step procedure, and the products were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and thermogravimetric analysis (TGA). The obtained results show that one TiO2-bioconjugate nanoparticle contains in average 80 peptide molecules on its surface. The synthesized TiO2-PEG-SP(5-11) conjugates were labelled with 225Ac by ion-exchange reaction on hydroxyl (OH) functional groups on the TiO2 surface. The labelled bioconjugates almost quantitatively retain 225Ac in phosphate-buffered saline (PBS), physiological salt and cerebrospinal fluid (CSF) for up to 10 days. The leaching of 221Fr, a first decay daughter of 225Ac, in an amount of 30% was observed only in CSF after 10 days. The synthesized 225Ac-TiO2-PEG-SP(5-11) has shown high cytotoxic effect in vitro in T98G glioma cells; therefore, it is a promising new radioconjugate for targeted radionuclide therapy of brain tumours.

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“…The number of NK-1 receptors expressed on tumor cells is much greater than that on normal human cells and is correlated with the degree of malignancy [ 5 , 6 , 7 , 8 ]. 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 ]. SP is a neuropeptide containing 11 amino acids (Arg 1 Pro 2 Lys 3 Pro 4 Gln 5 Gln 6 Phe 7 Phe 8 Gly 9 Leu 10 Met 11 ) that is widely distributed in the peripheral and central nervous systems.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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211 At labeled substance P (5–11) as potential radiopharmaceutical for glioma treatment

Cited by 19 publications

References 36 publications

Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer

Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer

Functionalized TiO2 nanoparticles labelled with 225Ac for targeted alpha radionuclide therapy

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

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