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Indocyanine Green Liposomes for Diagnosis and Therapeutic Monitoring of Cerebral Malaria.

ABSTRACT: Cerebral malaria (CM) is a major cause of death of Plasmodium falciparum infection. Misdiagnosis of CM often leads to treatment delay and mortality. Conventional brain imaging technologies are rarely applicable in endemic areas. Here we address the unmet need for a simple, non-invasive imaging methodology for early diagnosis of CM. This study presents the diagnostic and therapeutic monitoring using liposomes containing the FDA-approved fluorescent dye indocyanine green (ICG) in a CM murine model. Increased emission intensity of liposomal ICG was demonstrated in comparison with free ICG. The Liposomal ICG's emission was greater in the brains of the infected mice compared to naïve mice and drug treated mice (where CM was prevented). Histological analyses suggest that the accumulation of liposomal ICG in the cerebral vasculature is due to extensive uptake mediated by activated phagocytes. Overall, liposomal ICG offers a valuable diagnostic tool and a biomarker for effectiveness of CM treatment, as well as other diseases that involve inflammation and blood vessel occlusion.

SUBMITTER: Portnoy E

PROVIDER: S-EPMC4729766 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Indocyanine Green Liposomes for Diagnosis and Therapeutic Monitoring of Cerebral Malaria.

Portnoy Emma E Vakruk Natalia N Bishara Ameer A Shmuel Miriam M Magdassi Shlomo S Golenser Jacob J Eyal Sara S

Theranostics 20160101 2

Cerebral malaria (CM) is a major cause of death of Plasmodium falciparum infection. Misdiagnosis of CM often leads to treatment delay and mortality. Conventional brain imaging technologies are rarely applicable in endemic areas. Here we address the unmet need for a simple, non-invasive imaging methodology for early diagnosis of CM. This study presents the diagnostic and therapeutic monitoring using liposomes containing the FDA-approved fluorescent dye indocyanine green (ICG) in a CM murine model ...[more]

PMID: 26877776

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Project description:BackgroundPhotodynamic therapy (PDT) involves the administration of a photosensitizing agent and irradiation of light at an excitation wavelength that damages tumor cells without causing significant damage to normal tissue. We developed indocyanine green (ICG)-modified liposomes in which paclitaxel (PTX) was encapsulated (ICG-Lipo-PTX). ICG-Lipo-PTX accumulates specifically in tumors due to the characteristics of the liposomes. The thermal and photodynamic effects of ICG and the local release of PTX by irradiation are expected to induce not only antitumor effects but also cancer immunity. In this study, we investigated the antitumor effects of ICG-Lipo-PTX in breast cancer.MethodsThe antitumor effects of ICG-Lipo-PTX were examined in xenograft model mice subcutaneously implanted with KPL-1 human breast cancer cells. ICG-Lipo-PTX, ICG-Lipo, or saline was administered intraperitoneally, and the fluorescence intensity was measured with a fluorescence imaging system (IVIS). Intratumor temperature, tumor volume, and necrotic area of tumor tissue were also compared. Next, we investigated the induction of cancer immunity in an allogeneic transplantation model in which BALB-MC mouse breast cancer cells were transplanted subcutaneously in the bilateral inguinal region. ICG-Lipo-PTX was administered intraperitoneally, and PDT was performed on only one side. The fluorescence intensity measured by IVIS and the bilateral tumor volumes were compared. Cytokine secretory capacity was also evaluated by ELISPOT assay using splenocytes.ResultsIn the xenograft model, the fluorescence intensity and temperature during PDT were significantly higher with ICG-Lipo-PTX and ICG-Lipo in tumor areas than in nontumor areas. The fluorescence intensity in the tumor area was reduced to the same level as that in the nonirradiated area after two times of irradiation. Tumor growth was significantly reduced and the percentage of necrotic area in the tumor was higher after PDT in the ICG-Lipo-PTX group than in the other groups. In the allograft model, tumor growth on day 14 in the ICG-Lipo-PTX group was significantly suppressed not only on the PDT side but also on the non-PDT side. In addition, the secretion of interferon-γ and interleukin-2 was enhanced, whereas that of interleukin-10 was suppressed, in the ICG-Lipo-PTX group.ConclusionThe PDT therapy with ICG-Lipo-PTX may be an effective treatment for breast cancer.

Project description:BackgroundEfficient cancer therapy is sought not only for primary tumor treatment but also for the prevention of metastatic cancer growth. Immunotherapy has been shown to prevent cancer metastasis by inducing antigen-specific immune responses. Indocyanine green (ICG) has a peak spectral absorption at about 800 nm, which makes it a photothermal reagent for direct treatment of solid tumors by photothermal therapy (PTT). Since PTT alone cannot fully induce antigen-specific immune response for prevention of cancer metastasis, the combination of PTT and immunotherapy has been developed as a new strategy of cancer treatment.MethodsThermal responsive liposomes (TRL) were synthesized by incorporating ICG into the lipid bilayer and encapsulating the water-soluble immune stimulatory molecule polyinosinic:polycytidylic acid (poly I:C) in the hydrophilic core. The poly I:C- and ICG-containing TRLs (piTRLs) were analyzed according to size, and their photothermal effect was evaluated following laser irradiation at 808 nm. Moreover, the temperature-dependent release of poly I:C was also measured. For cancer therapy, CT-26 (carcinoma) and B16 (melanoma) cells were subcutaneously inoculated to build the 1st transplanted tumor in BALB/c and C57BL/6 mice, respectively. These mice received a 2nd transplantation with the same cancer cells by intravenous inoculation, for evaluation of the anti-metastatic effects of the liposomes after PTT.ResultsNear-infrared (NIR) laser irradiation increased the temperature of piTRLs and effectively released poly I:C from the liposomes. The increased temperature induced a photothermal effect, which promoted cancer cell apoptosis and dissolution of the 1st transplanted tumor. Moreover, the released poly I:C from the piTRL induced activation of dendritic cells (DCs) in tumor draining lymph node (tdLN). Cancer cell apoptosis and DC-activation-mediated cancer antigen-specific immune responses further prevented growth of lung metastatic cancer developed following intravenous transplantation of cancer cells.ConclusionThese results demonstrated the potential usage of a piTRL with laser irradiation for immuno-photothermal therapy against various types of cancer and their metastases.

Project description:There have been few anatomical structure segmentation studies using deep learning. Numbers of training and ground truth images applied were small and the accuracies of which were low or inconsistent. For a surgical video anatomy analysis, various obstacles, including a variable fast-changing view, large deformations, occlusions, low illumination, and inadequate focus occur. In addition, it is difficult and costly to obtain a large and accurate dataset on operational video anatomical structures, including arteries. In this study, we investigated cerebral artery segmentation using an automatic ground-truth generation method. Indocyanine green (ICG) fluorescence intraoperative cerebral videoangiography was used to create a ground-truth dataset mainly for cerebral arteries and partly for cerebral blood vessels, including veins. Four different neural network models were trained using the dataset and compared. Before augmentation, 35,975 training images and 11,266 validation images were used. After augmentation, 260,499 training and 90,129 validation images were used. A Dice score of 79% for cerebral artery segmentation was achieved using the DeepLabv3+ model trained using an automatically generated dataset. Strict validation in different patient groups was conducted. Arteries were also discerned from the veins using the ICG videoangiography phase. We achieved fair accuracy, which demonstrated the appropriateness of the methodology. This study proved the feasibility of operating field view of the cerebral artery segmentation using deep learning, and the effectiveness of the automatic blood vessel ground truth generation method using ICG fluorescence videoangiography. Using this method, computer vision can discern blood vessels and arteries from veins in a neurosurgical microscope field of view. Thus, this technique is essential for neurosurgical field vessel anatomy-based navigation. In addition, surgical assistance, safety, and autonomous surgery neurorobotics that can detect or manipulate cerebral vessels would require computer vision to identify blood vessels and arteries.

Dataset Information

Indocyanine Green Liposomes for Diagnosis and Therapeutic Monitoring of Cerebral Malaria.

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Indocyanine Green Liposomes for Diagnosis and Therapeutic Monitoring of Cerebral Malaria.

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