52 research outputs found
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Development of PSMA Targeted Polymer Nanoparticles to Treat Prostate Cancer By Boron Neutron Capture Therapy Directed Against PSMA
Prostate-specific membrane antigen (PSMA) is a cell surface enzyme highly over expressed in prostate cancer cells that can be employed as a target for prostate cancer imaging and drug delivery. Boron Neutron Capture Therapy (BNCT) is an emerging noninvasive therapeutic modality for treating locally invasive malignant tumors by selective delivery of high boron content to the tumour and then subjecting the tumour to epithermal neutron beam radiation. In this study, we develop carborane encapsulated amphiphilic polymer nanoparticles by conjugating urea based PSMA inhibitors (ACUPA) and 89Zr chelating deferoxamine B (DFB) ligand and have investigated their efficacy to deliver enhanced boron payload to PSMA positive prostate cancer cells with simultaneous positron emission tomography (PET) imaging . Three different carborane encapsulated PLGA-b-PEG nanoparticles (NPs) were formulated with and without the PSMA targeting ligand, out of which two selected formulations; DFB(25)ACUPA(75) NPs and DFB(25) NPs radiolabelled with 89Zr were administered to mice bearing dual PSMA(+) PC3-Pip and PSMA(-) PC3-Flu xenografts. PET imaging and biodistribution studies were performed to demonstrate the in vivo uptake in mice. The NPs showed 2-fold higher uptake in PSMA(+) PC3-Pip tumors to that of PSMA(-) PC3-Flu tumors with a very high tumor/blood ratio of 20. However, no significant influence of the ACUPA ligands were observed. Additionally, the NPs demonstrated fast release of carborane with low delivery of boron to tumors in vivo. Although the in vivo afficacy of those NPs remain limited, a significant progress towards the synthesis, characterization and initial biological evaluation of the polymer nanoparticles is proposed in this report and the results presented could guide the future design of amphiphilic polymer NPs for theranostic applications
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Development of PSMA Targeted Polymer Nanoparticles to Treat Prostate Cancer By Boron Neutron Capture Therapy Directed Against PSMA
Prostate-specific membrane antigen (PSMA) is a cell surface enzyme highly over expressed in prostate cancer cells that can be employed as a target for prostate cancer imaging and drug delivery. Boron Neutron Capture Therapy (BNCT) is an emerging noninvasive therapeutic modality for treating locally invasive malignant tumors by selective delivery of high boron content to the tumour and then subjecting the tumour to epithermal neutron beam radiation. In this study, we develop carborane encapsulated amphiphilic polymer nanoparticles by conjugating urea based PSMA inhibitors (ACUPA) and 89Zr chelating deferoxamine B (DFB) ligand and have investigated their efficacy to deliver enhanced boron payload to PSMA positive prostate cancer cells with simultaneous positron emission tomography (PET) imaging . Three different carborane encapsulated PLGA-b-PEG nanoparticles (NPs) were formulated with and without the PSMA targeting ligand, out of which two selected formulations; DFB(25)ACUPA(75) NPs and DFB(25) NPs radiolabelled with 89Zr were administered to mice bearing dual PSMA(+) PC3-Pip and PSMA(-) PC3-Flu xenografts. PET imaging and biodistribution studies were performed to demonstrate the in vivo uptake in mice. The NPs showed 2-fold higher uptake in PSMA(+) PC3-Pip tumors to that of PSMA(-) PC3-Flu tumors with a very high tumor/blood ratio of 20. However, no significant influence of the ACUPA ligands were observed. Additionally, the NPs demonstrated fast release of carborane with low delivery of boron to tumors in vivo. Although the in vivo afficacy of those NPs remain limited, a significant progress towards the synthesis, characterization and initial biological evaluation of the polymer nanoparticles is proposed in this report and the results presented could guide the future design of amphiphilic polymer NPs for theranostic applications
Prostate-Specific Membrane Antigen Targeted Deep Tumor Penetration of Polymer Nanocarriers.
Tumoral uptake of large-size nanoparticles is mediated by the enhanced permeability and retention (EPR) effect, with variable accumulation and heterogenous tumor tissue penetration depending on the tumor phenotype. The performance of nanocarriers via specific targeting has the potential to improve imaging contrast and therapeutic efficacy in vivo with increased deep tissue penetration. To address this hypothesis, we designed and synthesized prostate cancer-targeting starPEG nanocarriers (40 kDa, 15 nm), [89Zr]PEG-(DFB)3(ACUPA)1 and [89Zr]PEG-(DFB)1(ACUPA)3, with one or three prostate-specific membrane antigen (PSMA)-targeting ACUPA ligands. The in vitro PSMA binding affinity and in vivo pharmacokinetics of the targeted nanocarriers were compared with a nontargeted starPEG, [89Zr]PEG-(DFB)4, in PSMA+ PC3-Pip and PSMA- PC3-Flu cells, and xenografts. Increasing the number of ACUPA ligands improved the in vitro binding affinity of PEG-derived polymers to PC3-Pip cells. While both PSMA-targeted nanocarriers significantly improved tissue penetration in PC3-Pip tumors, the multivalent [89Zr]PEG-(DFB)1(ACUPA)3 showed a remarkably higher PC3-Pip/blood ratio and background clearance. In contrast, the nontargeted [89Zr]PEG-(DFB)4 showed low EPR-mediated accumulation with poor tumor tissue penetration. Overall, ACUPA conjugated targeted starPEGs significantly improve tumor retention with deep tumor tissue penetration in low EPR PC3-Pip xenografts. These data suggest that PSMA targeting with multivalent ACUPA ligands may be a generally applicable strategy to increase nanocarrier delivery to prostate cancer. These targeted multivalent nanocarriers with high tumor binding and low healthy tissue retention could be employed in imaging and therapeutic applications
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Evaluation of 134Ce/134La as a PET Imaging Theranostic Pair for 225Ac α-Radiotherapeutics
225Ac-targeted α-radiotherapy is a promising approach to treating malignancies, including prostate cancer. However, α-emitting isotopes are difficult to image because of low administered activities and a low fraction of suitable γ-emissions. The in vivo generator 134Ce/134La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides 225Ac and 227Th. In this report, we detail efficient radiolabeling methods using the 225Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG4-YS5, for evaluation of their in vivo pharmacokinetic characteristics and comparison to the corresponding 225Ac analogs. Methods: Radiolabeling was performed by mixing DOTA/MACROPA chelates with 134Ce/134La in NH4OAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio-thin-layer chromatography. In vivo biodistributions of 134Ce-DOTA/MACROPA.NH2 complexes were assayed through dynamic small-animal PET/CT imaging and ex vivo biodistribution studies over 1 h in healthy C57BL/6 mice, compared with free 134CeCl3 In vivo, preclinical imaging of 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5 was performed on 22Rv1 tumor-bearing male nu/nu-mice. Ex vivo biodistribution was performed for 134Ce/225Ac-MACROPA-PEG4-YS5 conjugates. Results: 134Ce-MACROPA.NH2 demonstrated near-quantitative labeling with 1:1 ligand-to-metal ratios at room temperature, whereas a 10:1 ligand-to-metal ratio and elevated temperatures were required for DOTA. Rapid urinary excretion and low liver and bone uptake were seen for 134Ce/225Ac-DOTA/MACROPA. NH2 conjugates in comparison to free 134CeCl3 confirmed high in vivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG4-YS5-that the daughter 134La was expelled from the chelate after the decay of parent 134Ce-was confirmed through radio-thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5, displayed tumor uptake in 22Rv1 tumor-bearing mice. The ex vivo biodistribution of 134Ce-MACROPA.NH2, 134Ce-DOTA and 134Ce-MACROPA-PEG4-YS5 corroborated well with the respective 225Ac-conjugates. Conclusion: These results demonstrate the PET imaging potential for 134Ce/134La-labeled small-molecule and antibody agents. The similar 225Ac and 134Ce/134La-chemical and pharmacokinetic characteristics suggest that the 134Ce/134La pair may act as a PET imaging surrogate for 225Ac-based radioligand therapies
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CD46-targeted theranostics for Positron Emission Tomography and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
PurposeMultiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [89Zr]Zr-DFO-YS5 for imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [89Zr]Zr-DFO-YS5 for immunoPET imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models.Experimental designIn vitro saturation binding was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [89Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [225Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity.Results[89Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (Kd = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [89Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [225Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups.ConclusionsOur study showed that the CD46-targeted probe [89Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [225Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation
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Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy.
PurposeRadiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody.Experimental design[225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity.ResultsBiodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line-derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi.Conclusions[225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen-positive and prostate-specific membrane antigen-deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer
Table S12 from CD46-Targeted Theranostics for PET and <sup>225</sup>Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Table S12: [89Zr]Zr-DFO-IgG %IA/Organ in the RPMI8226 subcutaneous xenograft models.</p
Table S21 from CD46-Targeted Theranostics for PET and <sup>225</sup>Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Table S21: [18F]-FDG %IA/g in the ANBL6 subcutaneous xenograft models.</p
Table S29 from CD46-Targeted Theranostics for PET and <sup>225</sup>Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Table S29: [89Zr]Zr-DFO-YS5 %IA/g in the RPMI8266 systemic tumor model.</p
Table S18 from CD46-Targeted Theranostics for PET and <sup>225</sup>Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Table S18: [18F]-FDG %IA/Organ in the MM.1S subcutaneous xenograft model.</p
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