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1.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-34361080

RESUMEN

Photoimmunotherapy (PIT) is an upcoming potential cancer treatment modality, the effect of which is improved in combination with chemotherapy. PIT causes a super-enhanced permeability and retention (SUPR) effect. Here, we quantitatively evaluated the SUPR effect using radiolabeled drugs of varying molecular weights (18F-5FU, 111In-DTPA, 99mTc-HSA-D, and 111In-IgG) to determine the appropriate drug size. PIT was conducted with an indocyanine green-labeled anti-HER2 antibody and an 808 nm laser irradiation. Mice were subcutaneously inoculated with HER2-positive cells in both hindlimbs. The tumor on one side was treated with PIT, and the contralateral side was not treated. The differences between tumor accumulations were evaluated using positron emission tomography or single-photon emission computed tomography. Imaging studies found increased tumor accumulation of agents after PIT. PIT-treated tumors showed significantly increased uptake of 18F-5FU (p < 0.001) and 99mTc-HSA-D (p < 0.001). A tendency toward increased accumulation of 111In-DTPA and 111In-IgG was observed. These findings suggest that some low- and medium-molecular-weight agents are promising candidates for combined PIT, as are macromolecules; hence, administration after PIT could enhance their efficacy. Our findings encourage further preclinical and clinical studies to develop a combination therapy of PIT with conventional anticancer drugs.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Sistemas de Liberación de Medicamentos , Inmunoterapia/métodos , Neoplasias/terapia , Fototerapia/métodos , Cintigrafía/métodos , Animales , Apoptosis , Proliferación Celular , Terapia Combinada , Humanos , Verde de Indocianina/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Neoplasias/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Clin Cancer Res ; 26(23): 6230-6241, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32933998

RESUMEN

PURPOSE: Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αVß3 integrin (αVß3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αVß3-positive OCPM mouse models, we studied the theranostic potential of an αVß3-specific radiopeptide, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment. EXPERIMENTAL DESIGN: αVß3-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. 64Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies. RESULTS: Intraperitoneal administration was an efficient route for targeting 64Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of 64Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. 64Cu-RaftRGD-based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2-17.2 mm). 64Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity. CONCLUSIONS: Collectively, these results demonstrate the all-in-one potential of 64Cu-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing αVß3- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.


Asunto(s)
Complejos de Coordinación/farmacología , Radioisótopos de Cobre/farmacología , Neoplasias Ováricas/prevención & control , Péptidos Cíclicos/farmacología , Neoplasias Peritoneales/prevención & control , Radiofármacos/farmacología , Animales , Apoptosis , Proliferación Celular , Complejos de Coordinación/química , Radioisótopos de Cobre/química , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Péptidos Cíclicos/química , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/secundario , Radiofármacos/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Nucl Med ; 60(10): 1437-1443, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30850497

RESUMEN

Pancreatic cancer (PC) has a very poor prognosis. Surgery is the primary treatment for patients with resectable PC; however, local recurrence, hepatic metastasis, and peritoneal dissemination often occur even after extensive surgery. Adjuvant chemotherapy, typically with gemcitabine, has been used clinically but with only a modest survival benefit. To achieve a better outcome, we investigated the efficacy of 64Cu-intraperitoneal radioimmunotherapy (ipRIT) with 64Cu-labeled antiepidermal growth factor receptor antibody cetuximab as an adjuvant treatment after PC surgery using an orthotopic xenografted mouse model. Methods: The efficacy of adjuvant 64Cu-ipRIT was investigated in a human PC mouse model harboring orthotopic xenografts of xPA-1-DC cells. To reproduce the clinical situation, PC xenografts were surgically resected when pancreatic tumors were readily visible but not metastatic tumors. Increasing doses of 64Cu-cetuximab were intraperitoneally injected, and the mice were monitored for toxicity to determine the safe therapeutic dose. For adjuvant 64Cu-ipRIT, the day after tumor resection, the mice were intraperitoneally administered 22.2 MBq of 64Cu-PCTA-cetuximab and the survival was compared with that in surgery-only controls. For comparison, adjuvant chemotherapy with gemcitabine was also examined using the same model. Results: The mouse model not only developed primary tumors in the pancreas but also subsequently reproduced local recurrence, hepatic metastasis, and peritoneal dissemination after surgery, which is similar to the manifestations that occur with human PC. Adjuvant 64Cu-ipRIT with 64Cu-labeled cetuximab after surgery effectively suppressed local recurrence, hepatic metastasis, and peritoneal dissemination in this model. Significant improvement of the survival with minimal toxicity was achieved by adjuvant 64Cu-ipRIT compared with that in control mice that underwent surgery only. Adjuvant chemotherapy with gemcitabine nominally prolonged the survival, but the effect was not statistically significant. Conclusion:64Cu-ipRIT with cetuximab can be an effective adjuvant therapy after PC surgery.


Asunto(s)
Radioisótopos de Cobre/farmacología , Inyecciones Intraperitoneales , Neoplasias Pancreáticas/radioterapia , Radioterapia Adyuvante , Animales , Línea Celular Tumoral , Cetuximab/farmacología , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Modelos Animales de Enfermedad , Receptores ErbB/química , Femenino , Células HCT116 , Humanos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundario , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Trasplante de Neoplasias , Radioinmunoterapia , Resultado del Tratamiento , Gemcitabina , Neoplasias Pancreáticas
4.
Oncotarget ; 9(48): 28935-28950, 2018 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-29989003

RESUMEN

Peritoneal dissemination is a common cause of death from gastrointestinal cancers and is difficult to treat using current therapeutic options, particularly late-phase disease. Here, we investigated the feasibility of integrated therapy using 64Cu-intraperitoneal radioimmunotherapy (ipRIT), alone or in combination with positron emission tomography (PET)-guided surgery using a theranostic agent (64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab) to treat early- and late-phase peritoneal dissemination in mouse models. In this study, we utilized the OpenPET system, which has open space for conducting surgery while monitoring objects at high resolution in real time, as a novel approach to make PET-guided surgery feasible. 64Cu-ipRIT with cetuximab inhibited tumor growth and prolonged survival with little toxicity in mice with early-phase peritoneal dissemination of small lesions. For late-phase peritoneal dissemination, a combination of 64Cu-ipRIT for down-staging and subsequent OpenPET-guided surgery for resecting large tumor masses effectively prolonged survival. OpenPET clearly detected tumors (≥3 mm in size) behind other organs in the peritoneal cavity and was useful for confirming the presence or absence of residual tumors during an operation. These findings suggest that integrated 64Cu therapy can serve as a novel treatment strategy for peritoneal dissemination.

5.
World J Gastroenterol ; 24(48): 5491-5504, 2018 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-30622378

RESUMEN

AIM: To investigate near-infrared photoimmunotherapeutic effect mediated by an anti-tissue factor (TF) antibody conjugated to indocyanine green (ICG) in a pancreatic cancer model. METHODS: Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that utilizes an antibody-photosensitizer conjugate administration, followed by NIR light exposure. Anti-TF antibody 1849-ICG conjugate was synthesized by labeling of rat IgG2b anti-TF monoclonal antibody 1849 (anti-TF 1849) to a NIR photosensitizer, ICG. The expression levels of TF in two human pancreatic cancer cell lines were examined by western blotting. Specific binding of the 1849-ICG to TF-expressing BxPC-3 cells was examined by fluorescence microscopy. NIR-PIT-induced cell death was determined by cell viability imaging assay. In vivo longitudinal fluorescence imaging was used to explore the accumulation of 1849-ICG conjugate in xenograft tumors. To examine the effect of NIR-PIT, tumor-bearing mice were separated into 5 groups: (1) 100 µg of 1849-ICG i.v. administration followed by NIR light exposure (50 J/cm2) on two consecutive days (Days 1 and 2); (2) NIR light exposure (50 J/cm2) only on two consecutive days (Days 1 and 2); (3) 100 µg of 1849-ICG i.v. administration; (4) 100 µg of unlabeled anti-TF 1849 i.v. administration; and (5) the untreated control. Semiweekly tumor volume measurements, accompanied with histological and immunohistochemical (IHC) analyses of tumors, were performed 3 d after the 2nd irradiation with NIR light to monitor the effect of treatments. RESULTS: High TF expression in BxPC-3 cells was observed via western blot analysis, concordant with the observed preferential binding with intracellular localization of 1849-ICG via fluorescence microscopy. NIR-PIT-induced cell death was observed by performing cell viability imaging assay. In contrast to the other test groups, tumor growth was significantly inhibited by NIR-PIT with a statistically significant difference in relative tumor volumes for 27 d after the treatment start date [2.83 ± 0.38 (NIR-PIT) vs 5.42 ± 1.61 (Untreated), vs 4.90 ± 0.87 (NIR), vs 4.28 ± 1.87 (1849-ICG), vs 4.35 ± 1.42 (anti-TF 1849), at Day 27, P < 0.05]. Tumors that received NIR-PIT showed evidence of necrotic cell death-associated features upon hematoxylin-eosin staining accompanied by a decrease in Ki-67-positive cells (a cell proliferation marker) by IHC examination. CONCLUSION: The TF-targeted NIR-PIT with the 1849-ICG conjugate can potentially open a new platform for treatment of TF-expressing pancreatic cancer.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodos , Neoplasias Pancreáticas/terapia , Fototerapia/métodos , Tromboplastina/inmunología , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Línea Celular Tumoral , Terapia Combinada/métodos , Humanos , Inmunoconjugados/química , Inmunoconjugados/inmunología , Inmunoconjugados/uso terapéutico , Verde de Indocianina/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/inmunología , Fármacos Fotosensibilizantes/química , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
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