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1.
Life (Basel) ; 11(2)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670777

RESUMO

"Theranostics," a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, "Lactosome" nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the "89Zr-labeled CPP and TPP-loaded Lactosome particles" and future directions based on important milestones and recent developments in this platform.

2.
Atherosclerosis ; 311: 1-12, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32911376

RESUMO

BACKGROUND AND AIMS: Dysregulated lipid metabolism has emerged as one of the major risk factors of atherosclerosis. Presently, there is a consensus that oxidized LDL (oxLDL) promotes development of atherosclerosis and downstream chronic inflammatory responses. Due to the dynamic metabolic disposition of lipoprotein, conventional approach to purify bioactive lipids for subsequent comprehensive analysis has proven to be inadequate for elucidation of the oxidized lipids species accountable for pathophysiology of atherosclerotic lesions. Herein, we aimed to utilize a novel mass microscopic imaging technology, coupled with mass spectrometry (MS) to characterize oxidized lipids in atherosclerotic lesions. METHODS: We attempted to use MALDI-TOF-MS and iMScope to identify selected oxidized lipid targets and visualize their respective localizations in study models of atherosclerosis. RESULTS: Based on the MS analysis, detection of 7-K under positive ionization through product ion peak at m/z 383 [M + H-H2O] indicated the distinctive presence of targeted lipid within Cu2+-oxLDL and Cu2+-oxLDL loaded macrophage-like J774A.1 cells, along with other cholesterol oxidation products. Moreover, the application of two-dimensional iMScope has successfully visualized the localization of lipids in aortic atherosclerotic plaques of the Watanabe heritable hyperlipidemic (WHHL) rabbit. Distinctive lipid distribution profiles were observed in atherosclerotic lesions of different sizes, especially the localizations of lysoPCs in atherosclerotic plaques. CONCLUSIONS: Taken together, we believe that both MALDI-TOF-MS and iMScope metabolomics technology may offer a novel proposition for future pathophysiological studies of lipid metabolism in atherosclerosis.


Assuntos
Aterosclerose , Placa Aterosclerótica , Animais , Lipídeos , Lipoproteínas LDL , Espectrometria de Massas , Metabolômica , Coelhos
3.
Sci Rep ; 10(1): 9765, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555349

RESUMO

Photothermal therapy (PTT) using a photo-absorbent in the near-infrared (NIR) region is an effective methodology for local cancer treatment. Before PTT using a NIR absorbent is executed, the operator generally determines the two parameters of fluence rate and irradiation time. However, even if the irradiation parameters are unchanged, the therapeutic effect of PTT is often different for individual tumors. Hence, we examined the therapeutic effect of PTT using a NIR absorbent (ICG lactosome) while changing two parameters (fluence rate and irradiation time) in various combinations. As a result, there was no robust correlation between those parameters and the therapeutic effect. Compared to those parameters, we found that a more reliable determinant was maintenance of the tumor temperature above 43 °C during NIR irradiation. To reconfirm the significance of the determinant, we developed a new system that can regulate the temperature at the NIR irradiation site at a constant level. By using the new system, we verified the treatment outcomes for tumors in which the NIR absorbent had accumulated. All of the tumors that had been kept at 43 °C during NIR irradiation were cured, while none of the tumors that had been kept at a temperature below 41 °C were cured. In conclusion, PTT using a NIR absorbent with thermal dosimetry is a highly reliable treatment for cancer.


Assuntos
Neoplasias do Colo/terapia , Hipertermia Induzida/métodos , Raios Infravermelhos , Nanopartículas/administração & dosagem , Fototerapia/métodos , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/patologia , Terapia Combinada , Feminino , Humanos , Verde de Indocianina/química , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Oncotarget ; 10(54): 5622-5631, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31608138

RESUMO

BACKGROUND: The diagnostic use and therapeutic effect of near infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) was investigated for gallbladder cancer using indocyanine green (ICG)-lactosomes. RESULTS: PDT was toxic for NOZ cells treated with ICG-lactosomes. Fluorescence intensity in the tumor region of mice administered ICG-lactosomes, but not ICG alone, was higher than the healthy contralateral region ≥24 hours after injection. PDT exerted immediate and continuous phototoxic effects in NOZ implanted mice injected with ICG-lactosomes. Enhanced antitumor effects were observed in the twice irradiated group compared with the once irradiated group. METHOD: ICG or ICG-lactosomes were added to the human gallbladder cancer cell line NOZ followed by PDT and cell viability was measured. Mass spectrometry of ICG and ICG-lactosomes was performed after PDT. ICG or ICG-lactosomes were intravenously administered to BALB/c nude mice implanted subcutaneously with NOZ cells and fluorescence was evaluated by NIF imaging. Implanted tumors underwent PDT and antitumor effects were analyzed after performing irradiation once or twice in ICG-lactosome groups. CONCLUSIONS: ICG-lactosomes accumulated in xenograft tumors and PDT had an antitumor effect on these malignant tumors. NIF imaging with ICG-lactosomes and PDT may be useful diagnostic and/or therapeutic agents for gallbladder cancer.

5.
Photodiagnosis Photodyn Ther ; 26: 436-441, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31054334

RESUMO

Indocyanine green lactosome (ICG-lactosome) is an attractive new-generation agent for photodynamic therapy (PDT) that is characterized by a near-infrared excitation wavelength and high stability in the bloodstream. Fluorescence imaging has been used to examine its pharmacokinetics in vivo, but no depth-resolved information can be obtained with this method. In this study, we applied photoacoustic (PA) imaging to visualize the depth distribution of ICG-lactosome in a mouse subcutaneous tumor model. With this method, the depth distribution of blood vessels can also be visualized, enabling detection of vascular shutdown effects due to PDT. We performed PA imaging of both the distributions of ICG-lactosome and blood vessels in a tumor before and after PDT, and we found that PA signals originating from ICG-lactosome were greatly increased at 18 h after drug injection but rapidly decreased after PDT. These results indicate efficient accumulation of ICG-lactosome and rapid photobleaching due to the PDT reaction in the tumor, respectively. After PDT, PA amplitudes of hemoglobin were significantly decreased, being attributable to vascular shutdown effects. These results show the usefulness of PA imaging for monitoring not only photosensitizer accumulation and bleaching but also vascular responses in PDT with ICG-lactosome. This method can be applied to the diagnosis of many types of PDT processes.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Verde de Indocianina/farmacologia , Técnicas Fotoacústicas , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Modelos Animais de Doenças , Feminino , Verde de Indocianina/farmacocinética , Camundongos , Camundongos Nus , Fármacos Fotossensibilizantes/farmacocinética
6.
Nanomaterials (Basel) ; 8(2)2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-29385027

RESUMO

Polymeric micelle of the A3B-type lactosome comprising (poly(sarcosine))3-b-poly(l-lactic acid) was labeled with 111In. The 111In-labeled A3B-type lactosome was administered to the model mice bearing meningeal dissemination and bone metastasis at mandible. With single-photon emission computed tomography (SPECT) imaging, the meningeal dissemination was identified successfully by 111In-labeled A3B-type lactosome, which was superior to 201TlCl in regard of the imaging contrast. The 111In-labeled A3B-type lactosome was also potential in imaging selectively of bone metastasis at mandible, whilst a nonspecific imaging of the whole bone was obtained by the SPECT imaging using 99mTc-HMDP. The polymeric micelle of the A3B-type lactosome was therefore found to be effective as a vehicle of 111In to be targeted to meningeal dissemination and bone metastasis.

7.
PLoS One ; 12(8): e0183527, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28859104

RESUMO

BACKGROUND: Anticancer agents and operating procedures have been developed for hepatocellular carcinoma (HCC) patients, but their prognosis remains poor. It is necessary to develop novel diagnostic and therapeutic strategies for HCC to improve its prognosis. Lactosome is a core-shell-type polymeric micelle, and enclosing labeling or anticancer agents into this micelle enables drug delivery. In this study, we investigated the diagnostic and therapeutic efficacies of indocyanine green (ICG)-loaded lactosome for near-infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) for HCC. METHODS: The human HCC cell line HuH-7 was treated with ICG or ICG-lactosome, followed by PDT, and the cell viabilities were measured (in vitro PDT efficiency). For NIF imaging, HuH-7 cells were subcutaneously transplanted into BALB/c nude mice, followed by intravenous administration of ICG or ICG-lactosome. The transplanted animals were treated with PDT, and the antineoplastic effects were analyzed (in vivo PDT efficiency). RESULTS: PDT had toxic effects on HuH-7 cells treated with ICG-lactosome, but not ICG alone. NIF imaging revealed that the fluorescence of tumor areas in ICG-lactosome-treated animals was higher than that of contralateral regions at 24 h after injection and thereafter. PDT exerted immediate and continuous phototoxic effects in the transplanted mice treated with ICG-lactosome. CONCLUSIONS: Our results demonstrate that ICG-lactosome accumulated in xenograft tumors, and that PDT had antineoplastic effects on these malignant implants. NIF imaging and PDT with ICG-lactosome could be useful diagnostic and/or therapeutic strategies for HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Verde de Indocianina/administração & dosagem , Neoplasias Hepáticas/terapia , Fotoquimioterapia , Animais , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Camundongos , Imagem Óptica , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Sci Technol Adv Mater ; 17(1): 245-252, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27877876

RESUMO

Polymeric micelles that are composed of synthetic polymers are generally size controllable and can be easily modified for various applications. Lactosomes (A3B-type) are biodegradable polymeric micelles composed of an amphipathic polymer, including three poly(sarcosine) blocks and a poly(l-lactic acid) block. Lactosomes accumulate in tumors in vivo through the enhanced permeability and retention (EPR) effect, even on frequently administering them. However, lactosomes cannot be efficiently internalized by cells. To improve cellular uptake of lactosomes, cell-penetrating peptide (CPP)-modified lactosomes were prepared. Seven CPPs (including EB1 and Pep1) were used, and most of them improved the cellular uptake efficiency of lactosomes. In particular, EB1- and Pep1-modified lactosomes were efficiently internalized by cells. In addition, by using CPP-modified and photosensitizer-loaded lactosomes, we demonstrated the photoinduced killing of mammalian cells, including human cancer cells. Accumulation of the EB1-modified lactosomes in NCI-N87 tumors was shown by in vivo imaging. Thus, this study demonstrated that the CPP-modified lactosome is a promising drug carrier.

9.
PLoS One ; 11(7): e0159303, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27410684

RESUMO

In the field of positron emission tomography (PET) radiochemistry, compact microreactors provide reliable and reproducible synthesis methods that reduce the use of expensive precursors for radiolabeling and make effective use of the limited space in a hot cell. To develop more compact microreactors for radiosynthesis of 18F-labeled compounds required for the multistep procedure, we attempted radiosynthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) via a three-step procedure using a microreactor. We examined individual steps for [18F]SFB using a batch reactor and microreactor and developed a new continuous-flow synthetic method with a single microfluidic chip to achieve rapid and efficient radiosynthesis of [18F]SFB. In the synthesis of [18F]SFB using this continuous-flow method, the three-step reaction was successfully completed within 6.5 min and the radiochemical yield was 64 ± 2% (n = 5). In addition, it was shown that the quality of [18F]SFB synthesized on this method was equal to that synthesized by conventional methods using a batch reactor in the radiolabeling of bovine serum albumin with [18F]SFB.


Assuntos
Benzoatos/síntese química , Radioisótopos de Flúor/química , Microfluídica/métodos , Tomografia por Emissão de Pósitrons/métodos , Succinimidas/síntese química , Benzoatos/química , Marcação por Isótopo/métodos , Radioquímica/métodos , Compostos Radiofarmacêuticos/química , Succinimidas/química
10.
Mod Rheumatol ; 26(6): 885-890, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27141810

RESUMO

OBJECTIVES: The early diagnosis and treatment of rheumatoid arthritis (RA) is important to reduce joint destruction. Many of the current imaging techniques have disadvantages, such as the need for contrast agents and interpretation by specialists. Fluorescence imaging is an emerging technique that overcomes some of these problems. The aim of this study was to determine whether near-infrared (NIR) fluorescence imaging of indocyanine green (ICG)-lactosomes can detect joint inflammation in a mouse model of RA. METHODS: Control and arthritic SKG/Jcl mice were injected with ICG alone or ICG-lactosomes and examined by NIR fluorescence imaging. Arthritis severity was assessed macroscopically and histopathologically. RESULTS: ICG fluorescence was detected in the liver soon after injection and then decreased over the next several hours. ICG was not detected in the joints of control or arthritic mice. In contrast, ICG-lactosomes remained in mice for at least 48 h and accumulated specifically at inflamed joints. ICG-lactosome fluorescence was higher in arthritic versus normal joints at all times examined and was maximal at 24 h after injection. CONCLUSIONS: NIR fluorescence imaging of ICG-lactosomes detects arthritic joints in a mouse model of RA. ICG-lactosomes may preferentially localize to inflamed joints via enhanced permeability and retention.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Imagem Óptica/métodos , Animais , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/farmacocinética , Verde de Indocianina/administração & dosagem , Verde de Indocianina/farmacocinética , Camundongos , Micelas
11.
Cancer Imaging ; 16: 6, 2016 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-27052371

RESUMO

BACKGROUND: We hypothesized that indocyanine green (ICG) fluorescence patterns using Clairvivo OPT in resected liver specimens could confirm hepatocellular carcinoma (HCC) better than earlier commercial imaging systems. This preclinical trial evaluated the effectiveness of fluorescence imaging as an intraoperative cancer navigation tool. METHODS: ICG fluorescence images of resected specimens from 190 patients with HCC were classified into two groups according to whether high fluorescence was seen in the HCC (high cancerous [HC] group) or in the surrounding liver tissue (high surrounding [HS] group). The HC and HS groups were sub-classified into whole and partial types and whole and ring types, respectively. RESULTS: The HC group had significantly higher prevalence of esophageal or gastric varices, and worse liver function than patients in the HS group. The HC group also had a higher percentage of limited resection cases than did the HS group. Cirrhotic liver histology was significantly more common in the HC group than in the HS group. Multivariate analysis revealed that the HC group was a predictive factor for cirrhosis in HCC patients. Among the HC patients, a higher percentage of well-differentiated HCC cases were seen in the partial-type subgroup than in the whole-type subgroup (23/48 (48 %) vs. 7/68 (10 %)). In the HS group, the ring-type subgroup had a higher percentage of poorly differentiated HCC cases than did the whole-type subgroup (6/37 (16 %) vs. 0/37 (0 %)). CONCLUSION: Tumor differentiation and fibrosis in the non-cancerous liver parenchyma could affect ICG fluorescence imaging in HCC. ICG fluorescence imaging may be a good indication for fibrosis stage. In future, we will try to evaluate fluorescence imaging with ICG for intraoperative cancer navigation in HCC, using a portable near-infrared fluorescence imaging system.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Corantes , Verde de Indocianina , Neoplasias Hepáticas/diagnóstico , Imagem Óptica/métodos , Administração Intravenosa , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Corantes/administração & dosagem , Varizes Esofágicas e Gástricas/diagnóstico , Varizes Esofágicas e Gástricas/patologia , Feminino , Hepatectomia/métodos , Humanos , Verde de Indocianina/administração & dosagem , Raios Infravermelhos , Cuidados Intraoperatórios , Lasers Semicondutores , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Microscopia de Fluorescência/instrumentação , Pessoa de Meia-Idade , Imagem Óptica/instrumentação , Estudos Retrospectivos , Fatores Sexuais
12.
Acta Med Okayama ; 70(1): 13-24, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26899605

RESUMO

Intact ß2-glycoprotein I (iß2GPI) is a glycoprotein that regulates coagulation and fibrinolysis. Nicked ß2GPI (nß2GPI) possesses an angiogenic property at a relatively low concentration, and an antiangiogenic property at a high concentration. Here we investigated the functions of ßi 2GPI and nß2GPI in vascular endothelial growth factor (VEGF)-A-induced endothelial cell proliferation and tube formation. We used noninvasive PET imaging to analyze the in vivo distribution of intravenously injected ß2GPI variants in tumor lesions in mice. iß2GPI was incubated with plasmin to obtain nß2GPI, and its N-terminal sequence was analyzed. nß2GPI had at least one other cleavage site upstream of the ß2GPI's domain V, whereas the former plasmin-cleavage site locates between K317 and T318. Both of intact and nicked ß2GPI significantly inhibited the VEGF-A-induced cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs). PET imaging visualized considerably distributed intensities of all tested ß2GPI variants in tumor lesions of pancreatic tumor cell-xenografts. These results indicate that ß2GPI may be physiologically and pathophysiologically important in the regulation of not only coagulation and fibrinolysis, but also angiogenesis.


Assuntos
Inibidores da Angiogênese/metabolismo , Neovascularização Patológica/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , beta 2-Glicoproteína I/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Camundongos , Neoplasias Pancreáticas/metabolismo , Tomografia por Emissão de Pósitrons , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Chem Pharm Bull (Tokyo) ; 63(9): 737-40, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26329868

RESUMO

A new radiolabeling method using a microreactor was developed for the rapid synthesis of [(11)C]raclopride. A chip bearing a Y-shaped mixing junction with a 200 µm (width)×20 µm (depth)×250 mm (length) flow channel was designed, and the efficiency of O-[11C]methylation was evaluated. Dimethyl sulfoxide solutions containing the O-desmethyl precursor or [11C]CH3I were introduced into separate injection ports by infusion syringes, and the radiochemical yields were measured under various conditions. The decay-corrected radiochemical yield of microreactor-derived [11C]raclopride reached 12% in 20 s at 25 °C, which was observed to increase with increasing temperature. In contrast, batch synthesis at 25 °C produced a yield of 5%: this indicates that this device could effectively achieve O-[11C]methylation in a shorter period of time. The microreactor technique may facilitate simple and efficient routine production of 11C-labeled compounds via O-[11C]methylation with [11C]CH3I.


Assuntos
Hidrocarbonetos Iodados/química , Técnicas Analíticas Microfluídicas , Racloprida/síntese química , Radioisótopos de Carbono , Metilação , Técnicas Analíticas Microfluídicas/instrumentação , Racloprida/química
14.
Ann Surg Oncol ; 22 Suppl 3: S923-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25986868

RESUMO

BACKGROUND: Preoperative and intraoperative diagnoses of lymph node (LN) metastasis in patients with gastric cancer is essential to determine the extent of LN dissection in order to establish individualized treatment strategies. We investigated the theranostic value of a newly developed drug delivery system employing nanoparticles loaded with the indocyanine green (ICG) derivative ICG-loaded lactosome (ICGm) using a murine draining LN metastasis model of gastric cancer. METHODS: In the experimental draining LN metastasis model of human gastric cancer, the right hind footpads of nude mice were injected with cancer cells. Three weeks later, either ICGm or ICG solution was injected through the tail vein. Forty-eight hours after the administration of a photosensitizer, in vivo and ex vivo imaging and photodynamic therapy (PDT) were performed, and size of the LNs was measured. RESULTS: In vivo imaging revealed metastatic LNs in the ICGm-treated mice but not in the ICG-treated mice. PDT using ICGm induced apoptosis and significantly inhibited the growth of metastatic LNs. CONCLUSIONS: ICGm presents a novel theranostic nanodevice for LN metastasis of gastric cancer.


Assuntos
Adenocarcinoma/secundário , Apoptose , Linfonodos/patologia , Nanopartículas/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Neoplasias Gástricas/patologia , Nanomedicina Teranóstica , Adenocarcinoma/metabolismo , Adenocarcinoma/prevenção & controle , Animais , Proliferação de Células , Corantes/metabolismo , Sistemas de Liberação de Medicamentos , Fluorescência , Humanos , Verde de Indocianina/metabolismo , Ácido Láctico/administração & dosagem , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/prevenção & controle , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Sci ; 105(12): 1626-30, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25287817

RESUMO

Although there have been multiple advances in the development of novel anticancer agents and operative procedures, prognosis of patients with advanced gastric cancer remains poor, especially in patients with peritoneal metastasis. In this study, we established nanoparticles loaded with indocyanine green (ICG) derivatives: ICG loaded lactosomes (ICGm) and investigated the diagnostic and therapeutic value of photodynamic therapy (PDT) using ICGm for experimental peritoneal dissemination of gastric cancer. Experimental peritoneal disseminated xenografts of human gastric cancer were established in nude mice. Three weeks after intraperitoneal injection of the cancer cells, either ICGm (ICGm-treated mice) or ICG solution (ICG-treated mice) was injected through the tail vein. Forty-eight hours after injection of the photosensitizer, in vivo and ex vivo imaging was carried out. For PDT, 48 h after injection of the photosensitizer, other mice were irradiated through the abdominal wall, and the body weight and survival rate were monitored. In vivo imaging revealed that peritoneal tumors were visualized through the abdominal wall in ICGm-treated mice, whereas only non-specific fluorescence was observed in ICG-treated mice. The PDT reduced the total weight of the disseminated nodules and significantly improved weight loss and survival rate in ICGm-treated mice. In conclusion, ICGm can be used as a novel diagnostic and therapeutic nanodevice in peritoneal dissemination of gastric cancer.


Assuntos
Verde de Indocianina/administração & dosagem , Nanopartículas/química , Cavidade Peritoneal/lesões , Fármacos Fotossensibilizantes/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Verde de Indocianina/química , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Neoplasias Experimentais , Especificidade de Órgãos , Cavidade Peritoneal/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Neoplasias Gástricas/patologia , Neoplasias Gástricas/ultraestrutura , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
16.
ACS Med Chem Lett ; 5(8): 873-7, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25147606

RESUMO

Lactosome is a polymeric micelle composed of amphiphilic polydepsipeptide, poly(sarcosine)64-block-poly(l-lactic acid)30 (AB-type), which accumulates in solid tumors through the enhanced permeability and retention (EPR) effect. However, lactosome on multiple administrations changed its pharmacokinetics from accumulation in tumors to liver due to the production of antilactosome IgM, which was triggered by the first administration. This phenomenon is called the accelerated blood clearance (ABC). In order to reduce the production of antilactosome IgM, a novel nanoparticle composed of (poly(sarcosine)23)3-block-poly(l-lactic acid)30 (A3B-type) was prepared. The A3B-type lactosome at the second administration showed an in vivo disposition similar to that at the first administration due to suppression of antibody production. This study involving the AB- and A3B-type lactosomes, with variation of conditions, revealed that the high local density of poly(sarcosine) chains of the A3B-type lactosome should relate to the prevention of a polymeric micelle from interacting B-cell receptors.

17.
J Pept Sci ; 20(7): 570-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24863398

RESUMO

Nanoparticles are expected to be applicable for the theranostics as a carrier of the diagnostic and therapeutic agents. Lactosome is a polymeric micelle composed of amphiphilic polydepsipeptide, poly(sarcosine)64-block-poly(L-lactic acid)30, which was found to accumulate in solid tumors through the enhanced permeability and retention effect. However, lactosome was captured by liver on the second administration to a mouse. This phenomenon is called as the accelerated blood clearance phenomenon. On the other hand, peptide-nanosheet composed of amphiphilic polypeptide, poly(sarcosine)60-block-(L-Leu-Aib)6, where the poly(L-lactic acid) block in lactosome was replaced with the (L-Leu-Aib)6 block, abolished the accelerated blood clearance phenomenon. The ELISA and in vivo near-infrared fluorescence imaging revealed that peptide-nanosheets did not activate the immune system despite the same hydrophilic block being used. The high surface density of poly(sarcosine) chains on the peptide-nanosheet may be one of the causes of the suppressive immune response.


Assuntos
Imunossupressores/química , Nanoestruturas/química , Peptídeos/química , Sarcosina/análogos & derivados , Animais , Linhagem Celular Tumoral , Humanos , Imunoglobulina M/metabolismo , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Peptídeos/farmacocinética , Peptídeos/farmacologia , Sarcosina/química , Sarcosina/farmacocinética , Sarcosina/farmacologia
18.
Cancer Sci ; 105(8): 1056-62, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24863849

RESUMO

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a protease activating MMP-2 that mediates cleavage of extracellular matrix components and plays pivotal roles in tumor migration, invasion and metastasis. Because in vivo noninvasive imaging of MT1-MMP would be useful for tumor diagnosis, we developed a novel near-infrared (NIR) fluorescence probe that can be activated following interaction with MT1-MMP in vivo. MT1-hIC7L is an activatable fluorescence probe comprised of anti-MT1-MMP monoclonal antibodies conjugated to self-assembling polymer micelles that encapsulate NIR dyes (IC7-1, λem : 858 nm) at concentrations sufficient to cause fluorescence self-quenching. In aqueous buffer, MT1-hIC7L fluorescence was suppressed to background levels and increased approximately 35.5-fold in the presence of detergent. Cellular uptake experiments revealed that in MT1-MMP positive C6 glioma cells, MT1-hIC7L showed significantly higher fluorescence that increased with time as compared to hIC7L, a negative control probe lacking the anti-MT1-MMP monoclonal antibody. In MT1-MMP negative MCF-7 breast adenocarcinoma cells, both MT1-hIC7L and hIC7L showed no obvious fluorescence. In addition, the fluorescence intensity of C6 cells treated with MT1-hIC7L was suppressed by pre-treatment with an MT1-MMP endocytosis inhibitor (P < 0.05). In vivo optical imaging using probes intravenously administered to tumor-bearing mice showed that MT1-hIC7L specifically visualized C6 tumors (tumor-to-background ratios: 3.8 ± 0.3 [MT1-hIC7L] vs 3.1 ± 0.2 [hIC7L] 48 h after administration, P < 0.05), while the probes showed similarly low fluorescence in MCF-7 tumors. Together, these results show that MT1-hIC7L would be a potential activatable NIR probe for specifically detecting MT1-MMP-expressing tumors.


Assuntos
Metaloproteinase 14 da Matriz/análise , Neoplasias/metabolismo , Imagem Óptica/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Fluorescência , Xenoenxertos , Camundongos , Neoplasias/diagnóstico , Ratos
19.
Nanomedicine ; 10(1): 187-95, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23811292

RESUMO

Near-infrared (NIR: 800-1000 nm) fluorescent probes, which activate their fluorescence following interaction with functional biomolecules, are desirable for noninvasive and sensitive tumor diagnosis due to minimal tissue interference. Focusing on bioavailability and applicability, we developed a probe with a self-assembling polymer micelle, a lactosome, encapsulating various quantities of NIR dye (IC7-1). We also conjugated anti-HER2 single chain antibodies to the lactosome surface and examined the probe's capacity to detect HER2 in cells and in vivo. Micelles encapsulating 20mol% IC7-1 (hIC7L) showed 30-fold higher fluorescence (λem: 858 nm) after micelle denaturation compared to aqueous buffer. Furthermore, antibody modification allowed specific activation of the probe (HER2-hIC7L) following internalization by HER2-positive cells, with the probe concentrating in lysosomes. HER2-hIC7L intravenously administered to mice clearly and specifically visualized HER2-positive tumors by in vivo optical imaging. These results indicate that HER2-hIC7L is a potential activatable NIR probe for sensitive tumor diagnosis. FROM THE CLINICAL EDITOR: Near-infrared probes that activate their fluorescence following interaction with specific biomolecules are desirable for noninvasive and sensitive tumor detection due to minimal tissue interference. This team of authors developed a probe termed hIC7L and demonstrate its potential in HER2 tumor diagnosis.


Assuntos
Anticorpos Monoclonais , Neoplasias da Mama/genética , Receptor ErbB-2/isolamento & purificação , Animais , Anticorpos Monoclonais/imunologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes , Humanos , Camundongos , Micelas , Microscopia de Fluorescência , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Espectroscopia de Luz Próxima ao Infravermelho
20.
Langmuir ; 30(2): 669-74, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24372167

RESUMO

Amphiphilic polydepsipeptides having a hydrophobic poly(L-lactic acid) block and varying numbers of a hydrophilic poly(sarcosine) block ranging from 1 to 3, AB-, A2B-, and A3B-type, were prepared and studied on their molecular assemblies. The morphologies were found to be polymeric micelles for the AB- and the A3B-type polydepsipeptides, but worm-like micelles for the A2B-type polydepsipeptide. The hydrodynamic diameter of the A3B-type polydepsipeptide (22 nm) became smaller than the AB-type polydepsipeptide (34 nm). The polymeric micelle sizes composed of the AB-type polydepsipeptide were adjustable up to ca. 100 nm with incorporation of poly(L-lactic acid) into the hydrophobic core. On the other hand, with varying mixing ratio of the AB-type and A3B-type polydepsipeptides, the hydrodynamic diameters were tunable to become smaller sizes with a precise control in the range from 22 to 34 nm. The polydispersity indices of the polymeric micelles were less than 0.1, indicating that we can obtain the homogeneous polymeric micelles with diameters in the range from 20 to 100 nm under a precise control.


Assuntos
Nanoestruturas/química , Peptídeos/química , Tensoativos/química , Hidrodinâmica , Micelas , Tamanho da Partícula , Peptídeos/síntese química , Propriedades de Superfície , Tensoativos/síntese química
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