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1.
BMC Cancer ; 24(1): 163, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302933

RESUMO

BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.


Assuntos
Antígenos de Superfície , Carcinoma de Células Renais , Glutamato Carboxipeptidase II , Neoplasias Renais , Lutécio , Radioisótopos , Compostos Radiofarmacêuticos , Humanos , Masculino , Carcinoma de Células Renais/radioterapia , Carcinoma de Células Renais/tratamento farmacológico , Dipeptídeos/efeitos adversos , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/efeitos adversos , Lutécio/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Radioisótopos/efeitos adversos , Radioisótopos/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral , Feminino , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos Multicêntricos como Assunto , Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/antagonistas & inibidores , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico
2.
Bioconjug Chem ; 29(3): 795-803, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29283548

RESUMO

In the field of cancer immunotherapy, an original approach consists of using granulocyte colony-stimulating factor (G-CSF) to target and activate neutrophils, cells of the innate immune system. G-CSF is a leukocyte stimulating molecule which is commonly used in cancer patients to prevent or reduce neutropenia. We focused herein on developing a G-CSF nanocarrier which could increase the in vivo circulation time of this cytokine, keeping it active for targeting the spleen, an important reservoir of neutrophils. G-CSF-functionalized silica and gold nanoparticles were developed. Silica nanoparticles of 50 nm diameter were functionalized by a solid phase synthesis approach. The technology enabled us to incorporate multiple functionalities on the surface such as a PEG as hydrophilic polymer, DTPA as 111In chelating agent and G-CSF. The gold nanocarrier consisted of nanoparticles of 2-3 nm diameter elaborated with DTPA groups on the surface and functionalized with G-CSF. We studied the particle biodistribution in mice with special attention to organs involved in the immune system. The two nanocarriers with similar functionalization of surface showed different pathways in mice, probably due to their difference in size. Considering the biodistribution after G-CSF functionalization, we confirmed that the protein was capable of modifying the pharmacokinetics by increasing the nanocarrier concentration in the spleen, a reservoir of G-CSF receptor expressing cells.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacocinética , Portadores de Fármacos/química , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Nanopartículas/química , Adjuvantes Imunológicos/química , Animais , Sistemas de Liberação de Medicamentos , Ouro/química , Fator Estimulador de Colônias de Granulócitos/química , Camundongos , Nanopartículas/ultraestrutura , Dióxido de Silício/química , Baço/imunologia , Distribuição Tecidual
3.
Bioconjug Chem ; 29(3): 804-812, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29283559

RESUMO

The purpose of immuno-modulation is to increase or restore the action of immunocompetent cells against tumors with or without the use of monoclonal antibodies. The innate immune system is a key player in various pathological situations, but cells of this system appear to be inhibited or insufficiently active in malignancy or severe infectious diseases. The present study was designed to investigate therapeutic value of nanoparticles (NPs) coupled with bioactive hematopoietic growth factors acting on the innate immune system. The use of nanoparticles (NPs) allowing multimodal detection and multifunctional grafting are currently of great interest for theranostic purposes. In the present work, we have evaluated the impact of the number of granulocyte-colony stimulating factor (G-CSF) grafted on the surface on the NPs on the biodistribution in mice thanks to indium 111 radiolabeling. Furthermore, we have investigated whether grafted G-CSF NPs could stimulate the immune innate system and enhance the therapeutic efficacy of the monoclonal antibody rituximab in mice bearing human lymphoma xenografts. Following intravenous (i.v.) administration of NP-DTPA and NP-DTPA/G-CSF-X high levels of radioactivity were observed in the liver. Furthermore, spleen uptake was correlated with the number of G-CSF molecules grafted on the surface of the NPs. Combining NP-DTPA/G-CSF-34 with rituximab strongly reduced RL tumor growth compared to rituximab alone or in combination with conventional G-CSF + rituximab. The use of highly loaded G-CSF NPs as immune adjuvants could enhance the antitumor activity of therapeutic monoclonal antibodies by amplifying tumor cell destruction by innate immune cells.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Linfoma/tratamento farmacológico , Nanopartículas/química , Rituximab/administração & dosagem , Adjuvantes Imunológicos/farmacocinética , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sinergismo Farmacológico , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Linfoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Rituximab/farmacocinética , Rituximab/farmacologia , Rituximab/uso terapêutico , Dióxido de Silício/química , Distribuição Tecidual
4.
BMC Cancer ; 18(1): 646, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884132

RESUMO

BACKGROUND: Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. METHODS: Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90Y-OTSA-101 for radionuclide therapy. RESULTS: From January 2012 to June 2015, 20 pts. (median age 43 years [21-67]) with advanced SS were enrolled. Even though 111In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. CONCLUSIONS: Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. TRIAL REGISTRATION: The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Receptores Frizzled/antagonistas & inibidores , Radioimunoterapia/métodos , Sarcoma Sinovial/radioterapia , Radioisótopos de Ítrio/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Tecidual , Adulto Jovem , Radioisótopos de Ítrio/farmacologia
5.
Nanomedicine ; 11(1): 247-57, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24983891

RESUMO

Gadolinium based nanoparticles (GBNs, diameter 2.9±0.2nm), have promising biodistribution properties for theranostic use in-vivo. We aimed at demonstrating the radiosensitizing effect of these GBNs in experimental radioresistant human head and neck squamous cell carcinoma (SQ20B, FaDu and Cal33 cell lines). Combining 0.6mM GBNs with 250kV photon irradiation significantly decreased SQ20B cell survival, associated with an increase in non-reparable DNA double-strand breaks, the shortening of G2/M phase blockage, and the inhibition of cell proliferation, each contributing to the commitment of late apoptosis. Similarly, radiation resistance was overcome for SQ20B stem-like cells, as well as for FaDu and Cal33 cell lines. Using a SQ20B tumor-bearing mouse model, combination of GBNs with 10Gy irradiation significantly delayed tumor growth with an increase in late apoptosis and a decrease in cell proliferation. These results suggest that GBNs could be envisioned as adjuvant to radiotherapy for HNSCC tumors.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Gadolínio/química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Nanopartículas/química , Radiossensibilizantes/química , Animais , Apoptose , Carcinoma de Células Escamosas/patologia , Caspase 2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Dano ao DNA , Feminino , Citometria de Fluxo , Neoplasias de Cabeça e Pescoço/patologia , Histonas/química , Humanos , Camundongos , Camundongos Nus , Microscopia Confocal , Microscopia de Fluorescência , Nanomedicina , Radioterapia
7.
Nanomedicine ; 10(8): 1887-95, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24972007

RESUMO

This work takes place in the "cartilage targeting strategy", consisting in using the quaternary ammonium (QA) function as a vector to proteoglycans (PGs) of extracellular matrix (ECM). The objective was to demonstrate that QA could address gadolinium based small rigid platforms (SRP) to PG-rich tumors. SRP were functionalized with QA, radiolabeled with (111)Indium and evaluated for biodistribution in vivo, respectively to non functionalized SRP, in two experimental models: (i) the HEMCSS human xenograft model; (ii) the Swarm rat chondrosarcoma (SRC) orthotopic model. The contribution of cellular uptake to tumoral accumulation of nano-objects was also determined from in vitro binding. In the SRC model expressing a highly and homogeneously distributed PG content, tumor accumulation and retention of SRP@QA were increased by 40% as compared to non-functionalized SRP. When considering the radiosensitizing potential of gadolinium based SRP, these results provide hopes for the radiobiological approach of highly resistant tumor such as chondrosarcoma. FROM THE CLINICAL EDITOR: In this study, gadolinium-based complexing DOTA-surfaced small polysiloxane nanoparticles were functionalized with quaternary ammonium derivatives that target the extracellular matrix of chondrosarcoma. The authors demonstrate in a rat model that the use of these constructs results in a 40% increase of tumor accumulation and retention compared to non-functionalized (and otherwise same) platforms. Similar approaches would be welcome additions to the clinical armamentarium addressing chondrosarcoma.


Assuntos
Compostos de Amônio/química , Condrossarcoma/metabolismo , Nanopartículas/química , Compostos de Amônio/uso terapêutico , Animais , Linhagem Celular Tumoral , Condrossarcoma/tratamento farmacológico , Matriz Extracelular , Gadolínio/química , Humanos , Masculino , Nanopartículas/metabolismo , Ratos , Ratos Sprague-Dawley , Siloxanas/química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Clin Nucl Med ; 49(3): 283-284, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38306382

RESUMO

ABSTRACT: Here, we report the case of a 35-year-old woman who performed PET/CT 18F-FDG as an initial workup for HER2+ right breast invasive ductal carcinoma. Examination revealed multifocal breast involvement with homolateral lymph node involvement. Contralateral axillary adenopathy and diffuse splenic and osteomedullary hypermetabolism were also observed, suggesting associated lymphoma in the absence of a recent COVID-19 vaccination. Cytopuncture was discussed and finally postponed after the patient was found to have recently received a pneumococcal vaccination.


Assuntos
Neoplasias da Mama , COVID-19 , Feminino , Humanos , Adulto , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Vacinas contra COVID-19 , Compostos Radiofarmacêuticos , Metástase Linfática/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Neoplasias da Mama/patologia , Vacinação
9.
Clin Nucl Med ; 49(7): 655-658, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38689436

RESUMO

ABSTRACT: We report the cases of 4 patients treated for recurrent meningiomas of various grades. Pretreatment 68 Ga-DOTATOC PET/CT was performed prior to screening for vectorized internal radiotherapy with 177 Lu-DOTATATE or prior external radiotherapy to aid contouring. None of these patients had sufficient uptake to be eligible for 177 Lu-DOTATATE or reliable contouring. Most recurrences were grades II and III, suggesting a loss of physiological somatostatin receptor overexpression in these tumors. Therefore, the benefit of treatment with 177 Lu-DOTATATE in the current indication is questionable. In the absence of a validated systemic treatment, and considering a few case reports, treatment with 177 Lu-PSMA could be investigated as an additional vectorized internal radiotherapy option.


Assuntos
Meningioma , Octreotida , Compostos Organometálicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Meningioma/diagnóstico por imagem , Meningioma/radioterapia , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Feminino , Pessoa de Meia-Idade , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/radioterapia , Idoso , Recidiva , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/radioterapia
10.
Clin Nucl Med ; 49(8): 779-780, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38861410

RESUMO

ABSTRACT: We report the case of a patient followed up for squamous cell carcinoma of the buccal floor with lymph node involvement. The initial staging PET/CT revealed bone foci that were not definitively pathological in the context of a regional collateral circulation secondary to a defibrillator. A new monitoring examination, conducted due to the rapid local progression, revealed a dissociated evolution of the bone uptake adjacent to the collateral circulation, some confirming false-positives, but one indicating a real metastasis. This case illustrates that bone uptakes without morphological lesions adjacent to a collateral circulation are not easily interpretable.


Assuntos
Circulação Colateral , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Reações Falso-Positivas , Masculino , Neoplasias Ósseas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Pessoa de Meia-Idade , Idoso
11.
Clin Nucl Med ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38915157

RESUMO

ABSTRACT: Collateral circulation is often secondary to a regional thrombosis. This phenomenon can lead to the detection of misleading bone lesions on imaging and is a well-known source of false-positives. Here, we present 2 different tracers PET/CT images, 18F-FDG and 18F-choline, with collateral circulation but without obvious thrombosis. Both cases displayed bone uptake, which mimicked metastasis. However, clinical follow-up ruled out metastasis and revealed false-positive bone lesions related to collateral circulation, even in the lack of acute or chronic underlying thrombotic processes.

12.
Clin Nucl Med ; 49(1): 66-68, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37976520

RESUMO

ABSTRACT: We present a case of a 48-year-old woman who had previously undergone surgical resection for bladder paraganglioma. An 18 F-FDOPA PET/CT scan performed for suspected colorectal paraganglioma showed intense colorectal uptake associated with adenopathy. Histological examination did not support the presence of a neuroendocrine tumor but instead confirmed the presence of moderately differentiated colorectal adenocarcinoma. Colorectal adenocarcinoma belongs to the list of nonneuroendocrine false-positive tumors that can be detected using 18 F-FDOPA. Therefore, a morphological analysis is important. Thus, 18 F-FDOPA may be a marker for the aggressiveness of colorectal adenocarcinoma.


Assuntos
Adenocarcinoma , Neoplasias das Glândulas Suprarrenais , Neoplasias Colorretais , Tumores Neuroendócrinos , Paraganglioma , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Di-Hidroxifenilalanina , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Paraganglioma/patologia , Neoplasias Colorretais/diagnóstico por imagem , Adenocarcinoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons
13.
Clin Nucl Med ; 49(8): 764-766, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38689443

RESUMO

ABSTRACT: We report the case of a 25-year-old man who was undergoing follow-up for neurofibromatosis type 1. The man underwent 68 Ga-DOTATOC PET/CT for a suspected well-differentiated duodenal neuroendocrine tumor. This examination did not reveal any significant uptake, whereas complementary 18 F-FDG PET/CT showed moderate 18 F-FDG uptake in the primary tumor as well as the adenopathy. Histology, a well-differentiated duodenal neuroendocrine tumor was confirmed, consistent with the diagnosis of somatostatinoma. Although rare, this well-differentiated neuroendocrine tumor should be kept in mind as a possible source of false-negative somatostatin receptor PET/CT findings.


Assuntos
Octreotida , Compostos Organometálicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Somatostatinoma , Humanos , Masculino , Adulto , Octreotida/análogos & derivados , Somatostatinoma/diagnóstico por imagem , Reações Falso-Negativas , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia
14.
Clin Nucl Med ; 49(6): 584-586, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38630998

RESUMO

ABSTRACT: A 69-year-old man diagnosed with progressive bone metastatic castration-resistant prostate adenocarcinoma and concurrent alcoholic cirrhosis with multiple hepatocellular carcinoma (HCC) nodules was referred to our nuclear medicine service for 177 Lu-PSMA-617 therapy. The patient's pretreatment screening using 68 Ga-PSMA-11 PET/CT revealed high prostate-specific membrane antigen expression in both prostatic and HCC lesions. The patient underwent 2 doses of 177 Lu-PSMA-617. Subsequent imaging assessments with 68 Ga-PSMA-11 PET/CT and hepatic MRI indicated progressive HCC nodules, while showing a partial response in prostatic bone metastases. Positive clinical and biological responses were observed only in prostatic disease, but not in HCC nodules.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Lutécio , Humanos , Masculino , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/diagnóstico por imagem , Idoso , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/diagnóstico por imagem , Radioisótopos/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico
15.
EJNMMI Radiopharm Chem ; 9(1): 28, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564046

RESUMO

BACKGROUND: (S)-[18F]FETrp is a promising PET radiotracer for imaging IDO1 activity, one of the main enzymes involved in the tryptophan metabolism that plays a key role in several diseases including cancers. To date, the radiosynthesis of this tryptophan analogue remains highly challenging due to partial racemization occurring during the nucleophilic radiofluorination step. This work aims to develop a short, epimerization-free and efficient automated procedure of (S)-[18F]FETrp from a corresponding enantiopure tosylate precursor. RESULTS: Enantiomerically pure (S)- and (R)-FETrp references as well as tosylate precursors (S)- and (R)-3 were obtained from corresponding Na-Boc-(L and D)-tryptophan in 2 and 4 steps, respectively. Manual optimisation of the radiolabelling conditions resulted in > 90% radiochemical conversion with more than 99% enantiomeric purity. Based on these results, the (S)-[18F]FETrp radiosynthesis was fully automated on a SynChrom R&D EVOI module to produce the radiotracer in 55.2 ± 7.5% radiochemical yield, 99.9% radiochemical purity, 99.1 ± 0.5% enantiomeric excess, and molar activity of 53.2 ± 9.3 GBq/µmol (n = 3). CONCLUSIONS: To avoid racemisation and complicated purification processes, currently encountered for the radiosynthesis of (S)-[18F]FETrp, we report herein significant improvements, including a versatile synthesis of enantiomerically pure tosylate precursor and reference compound and a convenient one-pot two-step automated procedure for the radiosynthesis of (S)-[18F]FETrp. This optimised and robust production method could facilitate further investigations of this relevant PET radiotracer for imaging IDO1 activity.

16.
Adv Healthc Mater ; 13(16): e2303280, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38445812

RESUMO

Conventional therapies for inflammatory bowel diseases are mainly based on systemic treatments which cause side effects and toxicity over long-term administration. Nanoparticles appear as a valid alternative to allow a preferential accumulation in inflamed tissues following oral administration while reducing systemic drug exposure. To increase their residence time in the inflamed intestine, the nanoparticles are here associated with a hydrogel matrix. A bioadhesive peptide-based hydrogel is mixed with nanoemulsions, creating a hybrid lipid-polymer nanocomposite. Mucopenetrating nanoemulsions of 100 nm are embedded in a scaffold constituted of the self-assembling peptide hydrogel product PuraStat. The nanocomposite is fully characterized to study the impact of lipid particles in the hydrogel structure. Rheological measurements and circular dichroism analyses are performed to investigate the system's microstructure and physical properties. Biodistribution studies demonstrate that the nanocomposite acts as a depot in the stomach and facilitates the slow release of the nanoemulsions in the intestine. Efficacy studies upon oral administration of the drug-loaded system show the improvement of the disease score in a mouse model of intestinal inflammation.


Assuntos
Hidrogéis , Peptídeos , Animais , Hidrogéis/química , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Camundongos , Sistemas de Liberação de Medicamentos/métodos , Distribuição Tecidual , Nanopartículas/química , Inflamação/tratamento farmacológico , Administração Oral , Nanocompostos/química , Doenças Inflamatórias Intestinais/tratamento farmacológico , Intestinos/efeitos dos fármacos
17.
Biomater Adv ; 161: 213881, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38749213

RESUMO

Nanoparticle's success as drug delivery systems for cancer treatment has been achieved through passive targeting mechanisms. However, tumor heterogeneity and rapid drug clearance limit the treatment efficacy. Improved outcomes and selective drug release can be achieved by grafting ligands at the surface of nanocarriers that bind molecules overexpressed in the tumor microenvironment (TME). In this work, we developed a docetaxel-loaded nanoemulsions (NEs) binding an anti-netrin-1 monoclonal antibody (NP137) to selectively target the netrin-1 protein overexpressed in many different tumors. The goal is to refine a combined approach utilizing NP137 and docetaxel as an improved tumor-targeting chemotherapeutic agent for addressing triple-negative breast cancer (TNBC). Several factors have been considered for the optimization of the active targeted drug delivery system via the click-chemistry conjugation, as the impact of PEGylated surfactant that stabilize the NEs shell on conjugation efficiency, cytocompatibility with EMT6 cell line and colloidal stability over time of NEs. Results showed that a 660 Da PEG chain length contributed to NEs colloidal stability and had no impact on cell viability or on the antibody binding ability for its ligand after surface conjugation. Moreover, docetaxel was encapsulated into the oily core of NEs, with an encapsulation efficiency of 70 %. To validate our treatment strategy in vivo, the 4T1 murine breast cancer model was used. As a result, the comparison of active-targeted and non-targeted NEs revealed that only active-targeted NE could decrease the tumor growth rate.


Assuntos
Docetaxel , Nanopartículas , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Animais , Feminino , Nanopartículas/química , Linhagem Celular Tumoral , Camundongos , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Docetaxel/administração & dosagem , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico
18.
Adv Mater ; 36(13): e2308738, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38105299

RESUMO

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA-/EMA-approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two-component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation.


Assuntos
Anticorpos Monoclonais , Quitosana , Humanos , Camundongos , Animais , Anticorpos Monoclonais/farmacocinética , Hidrogéis , Preparações de Ação Retardada , Injeções Subcutâneas
19.
Eur Urol Oncol ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38664139

RESUMO

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

20.
Clin Nucl Med ; 48(2): 203-205, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36607372

RESUMO

ABSTRACT: We report the case of an 81-year-old man presenting with peritoneal carcinosis secondary to a metastatic castrate-resistant prostate cancer addressed for 177Lu-PSMA-1 therapy. During the second cycle, a diffuse uptake in his left forearm was observed on the 1-hour postinjection scintigraphy, typical for an accidental intra-arterial injection. Less than 24 hours postinjection, a full removal of the intra-arterial injection was observed in the man, without any pain or symptoms. Moreover, the man demonstrated an 85% PSA reduction and a CT OR following the RECIST 1.1 criteria after 3 cycles.


Assuntos
Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Idoso de 80 Anos ou mais , Injeções Intra-Arteriais , Dipeptídeos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Heterocíclicos com 1 Anel , Resultado do Tratamento
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