scholarly journals Strain-Promoted Azide-Alkyne Cycloaddition-Based PSMA-Targeting Ligands For Multimodal Intraoperative Tumor Detection of Prostate Cancer

2021 ◽  
Author(s):  
Yvonne H.W. Derks ◽  
Mark Rijpkema ◽  
Helene I.V. Amatdjais-Groenen ◽  
Cato Loeff ◽  
Kim E. de Roode ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fluorescence Imaging ◽  
Tumor Targeting ◽  
Solid Phase ◽  
Biodistribution Studies ◽  
Specific Tumor ◽  
Multiple Imaging ◽  
Specific Accumulation ◽  
Modular Platform

Abstract Purpose: Strain-promoted azide-alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. Use of SPAAC to link different functional elements to prostate specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA-targeted imaging and therapy of prostate cancer (PCa). As a first proof-of-concept for the SPAAC chemistry platform we synthesized and characterized four dual-labeled PSMA ligands for intraoperative radiodetection and fluorescence imaging of PCa. Methods: Ligands were synthesized using solid phase chemistry and contained a chelator for 111In or 99mTc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N-hydroxysuccinimide (NHS)-ester coupling. LogD values were measured and PSMA-specificity of these ligands was determined in LS174T-PSMA cells. Tumor targeting was evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies. Results: SPAAC chemistry increased lipophilicity of the ligands (range LogD: -2.4 to -4.4). In vivo, SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 hours after injection, enabling clear visualization using µSPECT/CT and fluorescence imaging. Overall, no significant differences between the SPAAC chemistry ligands and their NHS-based counterparts were found (2 h p.i., p > 0.05), while 111In-labeled ligands outperformed the 99mTc ligands. Conclusion: Here we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. Use of click-chemistry in PSMA ligand development opens up the opportunity for fast, efficient and versatile conjugations of multiple imaging moieties and/or drugs.

scholarly journals Novel vinyl-modified RGD conjugated silica nanoparticles based on photo click chemistry for in vivo prostate cancer targeted fluorescence imaging

RSC Advances ◽  
2019 ◽  
Vol 9 (44) ◽  
pp. 25318-25325
Author(s):  
Hanrui Li ◽  
Ke Li ◽  
Qi Zeng ◽  
Yun Zeng ◽  
Dan Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Click Chemistry ◽  
Silica Nanoparticles ◽  
Fluorescence Imaging ◽  
Tumor Targeting ◽  
Diagnosis And Treatment ◽  
Targeting Ability

Photo click chemistry has been used to prepare RGD conjugated silica nanoprobe (SiO2@T1-RGDk NPs) that exhibits excellent tumor targeting ability and negligible toxicity which enables them to be used for the diagnosis and treatment of cancer.

scholarly journals Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer

2022 ◽  
Author(s):  
Yvonne H. W. Derks ◽  
Sanne A. M. van Lith ◽  
Helene I. V. Amatdjais-Groenen ◽  
Lieke W. M. Wouters ◽  
Annemarie Kip ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Fluorescence Imaging ◽  
Multimodal Imaging ◽  
Tumor Targeting ◽  
First Generation ◽  
Solid Phase ◽  
Binding Motif ◽  
High Affinity ◽  
Biodistribution Studies

Abstract  Introduction The first generation ligands for prostate-specific membrane antigen (PSMA)–targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled PSMA ligands by crucial modification of existing PSMA ligand backbone structures (PSMA-1007/PSMA-617) for multimodal imaging and targeted PDT of PCa. Methods Various new PSMA ligands were synthesized using solid-phase chemistry and provided with a DOTA chelator for 111In labeling and the fluorophore/photosensitizer IRDye700DX. The performance of three new dual-labeled ligands was compared with a previously published first-generation ligand (PSMA-N064) and a control ligand with an incomplete PSMA-binding motif. PSMA specificity, affinity, and PDT efficacy of these ligands were determined in LS174T-PSMA cells and control LS174T wildtype cells. Tumor targeting properties were evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies after dissection. Results In order to synthesize the new dual-labeled ligands, we modified the PSMA peptide linker by substitution of a glutamic acid into a lysine residue, providing a handle for conjugation of multiple functional moieties. Ligand optimization showed that the new backbone structure leads to high-affinity PSMA ligands (all IC50 < 50 nM). Moreover, ligand-mediated PDT led to a PSMA-specific decrease in cell viability in vitro (P < 0.001). Linker modification significantly improved tumor targeting compared to the previously developed PSMA-N064 ligand (≥ 20 ± 3%ID/g vs 14 ± 2%ID/g, P < 0.01) and enabled specific visualization of PMSA-positive tumors using both radionuclide and fluorescence imaging in mice. Conclusion The new high-affinity dual-labeled PSMA-targeting ligands with optimized backbone compositions showed increased tumor targeting and enabled multimodal image-guided PCa surgery combined with targeted photodynamic therapy.

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

2019 ◽  
Vol 18 (9) ◽  
pp. 1289-1294 ◽  
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.

scholarly journals Humanization, Radiolabeling and Biodistribution Studies of an IgG1-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications

2021 ◽  
Vol 14 (12) ◽  
pp. 1251
Author(s):  
Joanna Strand ◽  
Kjell Sjöström ◽  
Urpo J. Lamminmaki ◽  
Oskar Vilhelmsson Timmermand ◽  
Sven-Erik Strand ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Binding ◽  
Hek293 Cells ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biodistribution Studies ◽  
Indium 111 ◽  
Hormone Refractory ◽  
Theranostic Applications

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications.

scholarly journals A Novel TMTP1-modified Theranostic Nanoplatform for Targeted in Vivo NIR-II Fluorescence Imaging-guided Chemotherapy of Cervical Cancer

2021 ◽  
Author(s):  
Alifu Nuernisha ◽  
Rong Ma ◽  
Lijun Zhu ◽  
Zhong Du ◽  
Shuang Chen ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Blood Vessels ◽  
Fluorescence Imaging ◽  
Spatial Resolution ◽  
Self Assembly ◽  
Tumor Targeting ◽  
High Sensitivity ◽  
High Definition ◽  
Targeting Ability

Abstract BackgroundNear-infrared II (NIR-II, 900-1700 nm) fluorescence bioimaging with advantages of good biosafety, excellent spatial resolution, high sensitivity and contrast, has attracted great attentions in biomedical research fields. However, most nanoprobes used for NIR-II fluorescence imaging have poor tumor-targeting ability and therapeutic efficiency. To overcome these limitations, a novel NIR-II-emissive theranostic nanoplatform for imaging and treatment of cervical cancer was designed and prepared. The NIR-II-emissive dye IR-783 and chemotherapy drug doxorubicin (DOX) were encapsulated into liposomes, and the tumor-targeting peptide TMTP1 was conjugated to the surface of the liposomes to form IR-783-DOX-TMTP1 nanoparticles (NPs) via self-assembly methods.ResultsThe IR-783-DOX-TMTP1 NPs showed strong NIR-II emission, excellent biocompatibility, a long lifetime, and low toxicity. Further, high-definition NIR-II fluorescence microscopy images of ear blood vessels and intratumor blood vessels were obtained from IR-783-DOX-TMTP1 NPs-stained mice with high spatial resolution under 808 nm laser excitation. Moreover, IR-783-DOX-TMTP1 NPs showed strong tumor targeting ability and high efficiently chemotherapeutic character towards cervical tumors. ConclusionsThe novel targeting and NIR-II-emissive IR-783-DOX-TMTP1 NPs have potential in diagnosis and therapy for cervical cancer.

scholarly journals Synthesis of Fluorescent Polythiophene Dots

2018 ◽  
Vol 2018 ◽  
pp. 1-7
Author(s):  
Zhen Liu ◽  
Alaa Nahhas ◽  
Li Liu ◽  
Earl Ada ◽  
Xinyu Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hydrazine Hydrate ◽  
Cancer Cells ◽  
Real Time ◽  
Fluorescence Imaging ◽  
Chemical Oxidation ◽  
Prostate Cancer Cells ◽  
One Step ◽  
Live Mouse

Ring-functionalized semiconducting polythiophene dots (Pdots) were synthesized rapidly and in one step by the hydrazine hydrate reduction of doped parent polythiophene, obtained by conventional chemical oxidation of thiophene monomer by FeCl3 in anhydrous acetonitrile. Dispersions of these Pdots display robust (pseudo) solvatochromism and solvatofluorism. Polythiophene Pdots exhibit significant cytotoxicity towards prostate cancer cells (expected) although when injected subcutaneously in vivo in live mouse, no toxicity is observed for 24 days when monitored in real time using fluorescence imaging.

Tumor targeting of functionalized lipid nanoparticles: Assessment by in vivo fluorescence imaging

2010 ◽  
Vol 75 (2) ◽  
pp. 137-147 ◽  
Author(s):  
Mathieu Goutayer ◽  
Sandrine Dufort ◽  
Véronique Josserand ◽  
Audrey Royère ◽  
Emilie Heinrich ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Tumor Targeting ◽  
Lipid Nanoparticles ◽  
In Vivo Fluorescence ◽  
In Vivo Fluorescence Imaging

scholarly journals Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1371 ◽  
Author(s):  
Bogdan Mitran ◽  
Zohreh Varasteh ◽  
Ayman Abouzayed ◽  
Sara S. Rinne ◽  
Emmi Puuvuori ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Diagnostic Imaging ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Binding Specificity ◽  
Tumor Uptake ◽  
Biodistribution Data ◽  
Positron Emission ◽  
Ic50 Values

Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging of PCa. The heterodimer NOTA-DUPA-RM26 was produced by manual solid-phase peptide synthesis. NOTA-DUPA-RM26 was labeled with 111In and 68Ga, with yields >98%, and demonstrated a high stability and binding specificity to PSMA and GRPR. IC50 values for natIn-NOTA-DUPA-RM26 were 4 ± 1 nM towards GRPR and 824 ± 230 nM towards PSMA. An in vivo binding specificity 1 h pi of 111In-NOTA-DUPA-RM26 in PC3-PIP-xenografted mice demonstrated partially blockable tumor uptake when co-injected with an excess of PSMA- or GRPR-targeting agents. Simultaneous co-injection of both agents induced pronounced blocking. The biodistribution of 111In-NOTA-DUPA-RM26 and 68Ga-NOTA-DUPA-RM26 revealed fast activity clearance from the blood and normal organs via the kidneys. Tumor uptake exceeded normal organ uptake for both analogs 1 h pi. 68Ga-NOTA-DUPA-RM26 had a significantly lower tumor uptake (8 ± 2%ID/g) compared to 111In-NOTA-DUPA-RM26 (12 ± 2%ID/g) 1 h pi. Tumor-to-organ ratios increased 3 h pi, but decreased 24 h pi, for 111In-NOTA-DUPA-RM26. MicroPET/CT and microSPECT/CT scans confirmed biodistribution data, suggesting that 68Ga-NOTA-DUPA-RM26 and 111In-NOTA-DUPA-RM26 are suitable candidates for the imaging of GRPR and PSMA expression in PCa shortly after administration.

scholarly journals Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin 177Lu-PP-F11N

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2629
Author(s):  
Nathalie M. Grob ◽  
Roger Schibli ◽  
Martin Béhé ◽  
Thomas L. Mindt
Keyword(s):  
Tumor Targeting ◽  
Amide Bond ◽  
Amide Bonds ◽  
Structural Modifications ◽  
The Past ◽  
Cell Internalization ◽  
Biodistribution Studies ◽  
Metabolic Degradation

The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with 177Lu3+, and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT/CT imaging). NMGs with triazoles inserted between the amino acids DGlu10-Ala11 and/or Tyr12-Gly13 showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms.

Sign in / Sign up

Export Citation Format

Share Document