Evaluation studies of technetium-99m-porphyrin (T3,4BCPP) for tumor imaging

A water-soluble porphyrin, 5,10,15,20-tetrakis[3,4-bis(carboxymethyleneoxy)phenyl] porphyrin (T3,4BCPP), was successfully labeled with 99 m Tc and biodistribution studies were performed in Wistar rats. Scintiimaging and in vivo distribution studies were also carried out in C 6-gliomas and mammary tumor-bearing animals using a gamma camera. Tumor-to-muscle (T/M) ratios were calculated and compared with those obtained with the known tumor-seeking radiopharmaceuticals 99 m Tc (V)- DMSA (DMSA = dimercaptosuccinic acid), 99 m Tc -citrate and 201 TlCl . In the case of C 6-gliomas, the ratios were 4.2, 2.2, 4.00 and 3.0; while in the case of C 3 H / J mammary tumor, the ratios were 9.4, 8.8, 8.1 and 8.5 for T3,4BCPP, 99 m Tc ( V )- DMSA , 99 m Tc -citrate and 201 TlCl , respectively. Similar studies were carried out in N-methyl-N-nitrosourea ( NMU )-induced mammary tumor animals and the T/M ratios obtained were 5.9, 2.0, 5.3 and 3.3 for T3,4BCPP, 99 m Tc ( V )- DMSA , 99 m Tc -citrate and 201 TlCl , respectively. The radiolabeled photosensitizer could perhaps be used to detect cancer non-invasively and could even prove useful in monitoring the progression/regression of tumors before, during, and after chemotherapy, radiation therapy or photodynamic therapy (PDT).

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68Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with 68Ga-NODAGA-AE105

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180316152618 ◽

2019 ◽

Vol 18 (9) ◽

pp. 1289-1294 ◽

Cited By ~ 1

Author(s):

Kusum Vats ◽

Rohit Sharma ◽

Haladhar D. Sarma ◽

Drishty Satpati ◽

Ashutosh Dash

Keyword(s):

Solid Phase ◽

Evaluation Studies ◽

Radiochemical Yield ◽

In Vivo Evaluation ◽

Peptide Conjugates ◽

Biodistribution Studies ◽

Target Organs ◽

U87mg Tumor

Aims: The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes. Method: The peptide conjugates, HBED-CC-AE105-NH2 and NODAGA-AE105-NH2 were manually synthesized by standard Fmoc solid phase strategy and subsequently radiolabeled with 68Ga eluted from a commercial 68Ge/68Ga generator. In vitro cell studies for the two radiotracers were performed with uPAR positive U87MG cells. Biodistribution studies were carried out in mouse xenografts with the subcutaneously induced U87MG tumor. Results: The two radiotracers, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 that were prepared in >95% radiochemical yield and >96% radiochemical purity, exhibited excellent in vitro stability. In vivo evaluation studies revealed higher uptake of 68Ga-HBED-CC-AE105 in U87MG tumor as compared to 68Ga-NODAGAAE105; however, increased lipophilicity of 68Ga-HBED-CC-AE105 resulted in slower clearance from blood and other non-target organs. The uPAR specificity of the two radiotracers was ascertained by significant (p<0.05) reduction in the tumor uptake with a co-injected blocking dose of unlabeled AE-105 peptide. Conclusion: Amongst the two radiotracers studied, the neutral 68Ga-NODAGA-AE105 with more hydrophilic chelator exhibited faster clearance from non-target organs. The conjugation of HBED-CC chelator (less hydrophilic) resulted in negatively charged 68Ga-HBED-CC-AE105 which was observed to have high retention in blood that decreased target to non-target ratios.

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Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor bearing Balb/C mice

Nukleonika ◽

10.1515/nuka-2015-0066 ◽

2015 ◽

Vol 60 (3) ◽

pp. 497-502 ◽

Cited By ~ 6

Author(s):

Javad Razjouyan ◽

Hamidreza Zolata ◽

Omid Khayat ◽

Fereidoun Nowshiravan ◽

Nami Shadanpour ◽

...

Keyword(s):

Folic Acid ◽

Folate Receptor ◽

Superparamagnetic Iron Oxide ◽

Fibroblast Cell ◽

Mouse Fibroblast ◽

Tumor Uptake ◽

Mri Imaging ◽

Tumor Bearing ◽

Biodistribution Studies

Abstract To design a potent agent for positron emission tomography/magnetic resonance imaging (PET/MRI) imaging and targeted magnetic hyperthermia-radioisotope cancer therapy radiolabeled surface modified superparamagnetic iron oxide nanoparticles (SPIONs) were used as nanocarriers. Folic acid was conjugated for increasing selective cellular binding and internalization through receptor-mediated endocytosis. SPIONs were synthesized by the thermal decomposition of tris (acetylacetonato) iron (III) to achieve narrow and uniform nanoparticles. To increase the biocompatibility of SPIONs, they were coated with (3-aminopropyl) triethoxysilane (APTES), and then conjugated with synthesized folic acid-polyethylene glycol (FA-PEG) through amine group of (3-aminopropyl) triethoxysilane. Finally, the particles were labeled with 64Cu (t1/2 = 12.7 h) using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxy succinimide ester) DOTA-NHS chelator. After the characterization of SPIONs, their cellular internalization was evaluated in folate receptor (FR) overexpressing KB (established from a HeLa cell contamination) and mouse fibroblast cell (MFB) lines. Eventually, active and passive targeting effects of complex were assessed in KB tumor-bearing Balb/C mice through biodistribution studies. Synthesized bare SPIONs had low toxicity effect on healthy cells, but surface modification increased their biocompatibility. Moreover, KB cells viability was reduced when using folate conjugated SPIONs due to FR-mediated endocytosis, while having little effect on healthy cells (MFB). Moreover, this radiotracer had tolerable in vivo characteristics and tumor uptake. In the receptor blocked case, tumor uptake was decreased, indicating FR-specific uptake in tumor tissue while enhanced permeability and retention effect was major mechanism for tumor uptake.

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99mTc-citrate-gold nanoparticles as a tumor tracer: synthesis, characterization, radiolabeling and in-vivo studies

Radiochimica Acta ◽

10.1515/ract-2019-3208 ◽

2020 ◽

Vol 108 (10) ◽

pp. 809-819 ◽

Cited By ~ 1

Author(s):

Basma M. Essa ◽

Ahmed A. El-Mohty ◽

Maher A. El-Hashash ◽

Tamer M. Sakr

Keyword(s):

Drug Delivery ◽

Gold Nanoparticles ◽

Drug Delivery System ◽

Delivery System ◽

Solid Tumor ◽

Tumor Imaging ◽

In Vivo Studies ◽

Post Injection ◽

Tumor Bearing

AbstractTargeted drug delivery system can reduce the side effects of high drug concentration by improving drug pharmacokinetics at lower doses. Citrate-gold nanoparticles (AuNPs) as a drug delivery system were synthesized via green nanotechnology technique to be used as a new imaging platform for tumor targeting. Citrate-AuNPs were synthesized with core size of 10 nm. Citrate-AuNPs were labeled with technetium-99m (99mTc) with radiochemical yield of 95.20 ± 2.70% with good in-vitro stability in both saline and human serum and well in-vivo studied in both normal and solid tumor bearing mice. The in-vivo biodistribution study of [99mTc]Tc-citrate-AuNPs in solid tumor bearing mice (as preliminary study) showed a high accumulation in tumor site with tumor/muscle of 4.35 ± 0.22 after 30 min post injection. The direct intratumoral (I.T) injection of [99mTc]Tc-citrate-AuNPs showed that this complex was retained in the tumor up to 77.86 ± 1.90 % at 5 min and still around 50.00 ± 1.42 % after 30 min post injection (p.i.). The newly presented nano-platform could be presented as a new potential radiopharmaceutical tumor imaging probe.

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In Vitro and In Vivo Evaluation of Novel DTX-Loaded Multifunctional Heparin-Based Polymeric Micelles Targeting Folate Receptors and Endosomes

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666201006124604 ◽

2020 ◽

Vol 15 (4) ◽

pp. 341-359

Author(s):

Moloud Kazemi ◽

Jaber Emami ◽

Farshid Hasanzadeh ◽

Mohsen Minaiyan ◽

Mina Mirian ◽

...

Keyword(s):

Drug Delivery ◽

Antitumor Activity ◽

Cellular Uptake ◽

Folate Receptor ◽

Chemotherapeutic Agents ◽

Water Soluble ◽

Growth Monitoring ◽

Tumor Bearing

Background: The development of biocompatible tumor-targeting delivery systems for anticancer agents is essential for efficacious cancer chemotherapy. Nanoparticles, as drug delivery cargoes for cancer therapy, are rapidly improving to overcome the limitations of conventional chemotherapeutic agents. Heparin–modified nanoparticles are currently being considered as one of the favorable carriers for the delivery of chemotherapeutics to cancer tissues. Objective: This study was aimed at evaluating the in vitro and in vivo antitumor activity of a novel targeted, pH-sensitive, heparin-based polymeric micelle loaded with the poorly water-soluble anticancer drug, docetaxel (DTX). The micelles could overcome the limited water solubility, non-specific distribution, and insufficient drug concentration in tumor tissues. Methods: DTX-loaded folate targeted micelles were prepared and evaluated for physicochemical properties, drug release, in vitro cellular uptake and cytotoxicity in folate receptor-positive and folate receptor-negative cells. Furthermore, the antitumor activity of DTX-loaded micelles was evaluated in the tumor-bearing mice. Some related patents were also studied in this research. Results: The heparin-based targeted micelles exhibited higher in vitro cellular uptake and cytotoxicity against folate receptor over-expressed cells due to the specific receptor-mediated endocytosis. DTX-loaded micelles displayed greater antitumor activity, higher anti-angiogenesis effects, and lower systemic toxicity compared with free DTX in a tumor-induced mice model as confirmed by tumor growth monitoring, immunohistochemical evaluation, and body weight shift. DTX-loaded targeting micelles demonstrated no considerable toxicity on major organs of tumor-bearing mice compared with free DTX. Conclusion: Our results indicated that DTX-loaded multifunctional heparin-based micelles with desirable antitumor activity and low toxicity possess great potential as a targeted drug delivery system in the treatment of cancer.

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closo-Dodecaborate-conjugated human serum albumins: preparation and in vivo selective boron delivery to tumor

Pure and Applied Chemistry ◽

10.1515/pac-2017-1104 ◽

2018 ◽

Vol 90 (4) ◽

pp. 745-753 ◽

Cited By ~ 4

Author(s):

Hiroyuki Nakamura ◽

Shunsuke Kikuchi ◽

Kazuki Kawai ◽

Satomu Ishii ◽

Shinichi Sato

Keyword(s):

Serum Albumin ◽

Human Serum ◽

Ring Opening ◽

Serum Albumins ◽

Colon 26 ◽

Tumor Bearing ◽

Ring Opening Reaction ◽

Boron Distribution ◽

Distribution Studies

Abstract Maleimide-functionalized closo-dodecaborate (MID) and isothiocyanate-functionalized closo-dodecaborate (ISD) were synthesized from closo-dodecaborate via ring opening reaction of 1,4-dioxane-closo-dedecaborate complex 1 with ammonia. MID was found to possess highest conjugation efficacy to bovine serum albumin among three closo-dodecaborate derivatives, MID, ISD, and 1. The conjugation reaction of MID to human serum albumin (HSA) proceeded under PBS buffer conditions (pH 7.4). Boron distribution studies in colon 26 tumor-bearing mice revealed that HSA-MID was highly accumulated in tumor (23 ppm B), whereas boron concentrations in other organs such as liver, kidney and spleen were low (3~8 ppm B).

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Preclinical Evaluation of Radiolabeled Peptides for PET Imaging of Glioblastoma Multiforme

Molecules ◽

10.3390/molecules24132496 ◽

2019 ◽

Vol 24 (13) ◽

pp. 2496 ◽

Cited By ~ 1

Author(s):

Zbynek Novy ◽

Jana Stepankova ◽

Michaela Hola ◽

Dominika Flasarova ◽

Miroslav Popper ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Tumor Imaging ◽

Ex Vivo ◽

Tumor Model ◽

Rgd Peptides ◽

Radiolabeled Peptides ◽

Biodistribution Studies ◽

Target Organs

In this study, we have compared four 68Ga-labeled peptides (three Arg-Gly-Asp (RGD) peptides and substance-P) with two 18F-tracers clinically approved for tumor imaging. We have studied in vitro and in vivo characteristics of selected radiolabeled tracers in a glioblastoma multiforme tumor model. The in vitro part of the study was mainly focused on the evaluation of radiotracers stability under various conditions. We have also determined in vivo stability of studied 68Ga-radiotracers by analysis of murine urine collected at various time points after injection. The in vivo behavior of tested 68Ga-peptides was evaluated through ex vivo biodistribution studies and PET/CT imaging. The obtained data were compared with clinically used 18F-tracers. 68Ga-RGD peptides showed better imaging properties compared to 18F-tracers, i.e., higher tumor/background ratios and no accumulation in non-target organs except for excretory organs.

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Bifunctional HPPH-N2S2-99mTc conjugates as tumor imaging agents: synthesis and biodistribution studies

Journal of Porphyrins and Phthalocyanines ◽

10.1142/s108842460300063x ◽

2003 ◽

Vol 07 (07) ◽

pp. 500-507 ◽

Cited By ~ 12

Author(s):

Bing Ma ◽

Guolin Li ◽

Peter Kanter ◽

Dominick Lamonica ◽

Zachary Grossman ◽

...

Keyword(s):

Half Life ◽

Tumor Imaging ◽

Post Injection ◽

Tumor Uptake ◽

In Vivo Biodistribution ◽

Structure Activity ◽

Biodistribution Studies ◽

Activity Screening ◽

Pyropheophorbide A

Pyropheophorbide-a and the corresponding 3-(1'-hexyloxyethyl)-3-devinyl derivative ( HPPH ), the tumor-avid photosensitizers were conjugated with mono- or di-bisaminoethanethiols ( N 2 S 2 ligand). The in vivo biodistribution study of the related 99m Tc complexes was performed in F-344 rats bearing Ward colon tumors at 4 h and 24 h post injection. These data show that the complexes are stable and among four tracers, HPPH di-99 m Tc N 2 S 2 conjugate reaches the highest tumor uptake (%ID/g). The larger tumors reach higher concentrations of the tracer. However, the short 6 h half life of 99 m Tc is incompatible with the 24 h imaging time, suggesting that the use of a longer-lived isotope such as 111 In could still provide a useful scanning agent, or that further structure-activity screening could yield an HPPH analog with more appropriate pharmacokinetics for tumor imaging with 99 m Tc .

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Automatic Production and Preliminary PET Imaging of a New Imaging Agent [18F]AlF-FAPT

Frontiers in Oncology ◽

10.3389/fonc.2021.802676 ◽

2022 ◽

Vol 11 ◽

Author(s):

JiaWen Huang ◽

LiLan Fu ◽

KongZhen Hu ◽

Shun Huang ◽

YanJiang Han ◽

...

Keyword(s):

Pet Imaging ◽

Tumor Imaging ◽

Solid Phase ◽

Synthesis Method ◽

Imaging Agent ◽

Step Method ◽

Abdominal Tumor ◽

Automatic Production ◽

Biodistribution Studies

BackgroundFibroblast activating protein (FAP) has become an important target for cancer diagnostic imaging and targeted radiotherapy. In particular, [18F]FAPI-42 has been successfully applied to positron emission tomography (PET) imaging of various tumors. However, it exhibits high hepatobiliary metabolism and is thus not conducive to abdominal tumor imaging. This study reports a novel 18F-labeled FAP inhibitor, [18F]AlF-FAPT, a better FAPI imaging agent than [18F]FAPI-42.Materials and MethodsThe precursor of [18F]AlF-FAPT (NOTA-FAPT) was designed and synthesized using the standard FMOC solid phase synthesis method. [18F]AlF-FAPT was subsequently synthesized and radiolabeled with 18F using the AllInOne synthesis module. Dynamic MicroPET and biodistribution studies of [18F]AlF-FAPT were then conducted in xenograft tumor mouse models to determine its suitability.ResultsThe precursors NOTA-FAPT were obtained with a chemical purity of > 95%. [18F]AlF-FAPT was synthesized automatically using the cassette-based module AllInOne within 40 min. The non-decay corrected radiochemical yield was 25.0 ± 5.3% (n=3). In vivo imaging and biodistribution studies further demonstrated that compared with [18F]-FAPI-42, [18F]AlF-FAPT had a lower hepatobiliary uptake than [18F]FAPI-42, which was advantageous for imaging abdominal tumors.Conclusion[18F]AlF-FAPT can be synthesized automatically using a one-step method of aluminum fluoride. Collectively, [18F]AlF-FAPT is a better FAPI imaging agent than [18F]FAPI-42. This study proves the feasibility of using [18F]AlF-FAPT as a new radioactive tracer for PET imaging.

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Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics

EJNMMI Research ◽

10.1186/s13550-020-00740-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Alexander Wurzer ◽

Mara Parzinger ◽

Matthias Konrad ◽

Roswitha Beck ◽

Thomas Günther ◽

...

Keyword(s):

Clinical Studies ◽

High Performance ◽

Clinical Investigation ◽

Selection Process ◽

Tumor Bearing ◽

Intraindividual Comparison ◽

Biodistribution Studies ◽

Diastereomeric Mixture ◽

Human Serum Albumin Binding

Abstract Introduction Radiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, can be labeled either with [18F]fluorine via isotopic exchange or with radiometals (such as [68Ga]Gallium, [177Lu]Lutetium, [225Ac]Actinium). Among these, [18F, natGa]rhPSMA-7 has recently entered clinical assessment. Aim Since [18F, natGa]rhPSMA-7 is composed of four stereoisomers ([18F, natGa]rhPSMA-7.1, -7.2, -7.3 and -7.4), we initiated a preclinical selection process to identify the isomer with the most favorable pharmacokinetics for further clinical investigation. Methods A synthetic protocol for enantiopure [19F, natGa]rhPSMA-7 isomers has been developed. The comparative evaluation of the four isomers comprised human serum albumin binding, lipophilicity, IC50, internalization and classical biodistribution studies and competition experiments in LNCaP tumor-bearing CB-17 SCID mice. In addition, a radio high-performance liquid chromatography-based method was developed allowing quantitative, intraindividual comparison of [18F, natGa]rhPSMA-7.1 to -7.4 in LNCaP tumor-bearing mice. Results Cell studies revealed high PSMA affinity and internalization for [18/19F, natGa]rhPSMA-7.2, -7.3 and -7.4, whereas [18/19F, natGa]rhPSMA-7.1 showed approximately twofold lower values. Although the biodistribution profile obtained was typical of PSMA inhibitors, it did not allow for selection of a lead candidate for clinical studies. Thus, an intraindividual comparison of all four isomers in LNCaP tumor-bearing mice was carried out by injection of a diastereomeric mixture, followed by analysis of the differential uptake and excretion pattern of each isomer. Based on its high tumor accumulation and low uptake in blood, liver and kidneys, [18F, natGa]rhPSMA-7.3 was identified as the preferred isomer and transferred into clinical studies. Conclusion [18F, natGa]rhPSMA-7.3 has been selected as a lead compound for clinical development of a [18F]rhPSMA-based candidate. The intraindividual differential uptake and excretion analysis in vivo allowed for an accurate comparison and assessment of radiopharmaceuticals.

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