carbocyanines and Triple-Negative-Breast-Neoplasms

Abnormally high levels of class I histone deacetylases (HDACs) are associated with triple-negative breast cancer (TNBC) proliferation, malignant transformation, and poor prognosis of patients. Herein, we report a near-infrared imaging probe for TNBC detection via visualizing class I HDACs. Conjugating Cy5.5 to a cyclic depsipeptide inhibitor, we obtained the probe (

Topics: Animals; Biomarkers, Tumor; Carbocyanines; Cell Line, Tumor; Depsipeptides; Epigenesis, Genetic; Female; Fluorometry; Gene Expression Regulation, Neoplastic; Heterografts; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lung Neoplasms; Mice, Nude; Triple Negative Breast Neoplasms; Vorinostat

A novel chemical-based orthogonal bioconjugation strategy to produce tri-functionalized nanoparticles (NPs) an chemotherapy drug, doxorubicin (DOX), a near-infrared cyanine dye (Cy7) and CRGDK homing peptide, a peptide specifically binds to neuropilin-1 (Nrp-1) overexpressed on triple negative breast cancer (TNBC) cells, has been validated. These theranostic NPs have been evaluated in vitro and in vivo using an orthotopic xenotransplant mouse model using TNBC cells. In vitro assays show that theranostic NPs improve the therapeutic index in comparison with free DOX. Remarkably, in vivo studies showed preferred location of theranostic NPs in the tumor area reducing the volume at the same level than free DOX while presenting lower side effects. This multifunctionalized theranostic nanodevice based on orthogonal conjugation strategies could be a good candidate for the treatment and monitoring of Nrp-1 overexpressing tumors. Moreover, this versatile nanodevice can be easily adapted to treat and monitor different cancer types by adapting the conjugation strategy.

Topics: Animals; Carbocyanines; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Female; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Nanoparticles; Neoplasm Proteins; Neuropilin-1; Peptides; Theranostic Nanomedicine; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

The development of effective targeted therapies for triple negative breast cancer (TNBC) remains a challenge. This targeted drug delivery system used a near-infrared fluorescence dye cyanine 5.5 (Cy5.5) and an ICAM-1 antibody on thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs). The ICAM-1 antibody and cyanine 5.5-engineered PMOs (PMO-Cy5.5-ICAM) offer excellent in vivo and in vitro biocompatibility. The PMO-Cy5.5-ICAM shows a loading capacity up to 400 mg/g of doxorubicin (DOX). The drug release profile of the DOX-loaded targeted delivery system (DOX@PMO-Cy5.5-ICAM) is pH-sensitive. Confocal microscopy showed that the PMO-Cy5.5-ICAM efficiently targets and enters TNBC cells. In in vivo experiments, the DOX@PMO-Cy5.5-ICAM accumulates more in TNBCs than in the control groups and exhibits better therapeutic effects on TNBC; thus, it is a promising treatment strategy for TNBC.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies; Carbocyanines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Screening Assays, Antitumor; Female; Humans; Intercellular Adhesion Molecule-1; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Organosilicon Compounds; Particle Size; Porosity; Structure-Activity Relationship; Surface Properties; Triple Negative Breast Neoplasms

The development of early, accurate diagnostic strategies for triple-negative breast cancer (TNBC) remains a significant challenge. Intercellular adhesion molecule-1 (ICAM-1) overexpressed in human TNBC cells is a potential molecular target and biomarker for diagnosis. In this study, small-molecule probe (denoted as γ3-Cy5.5) constructed with a short 17-mer linear peptide (γ3) and near-infrared fluorescence (NIRF) dye cyanine 5.5 (Cy5.5) was used to detect the expression of ICAM-1 in vitro and in vivo, and to diagnose TNBC via NIRF imaging.. Western blotting and flow cytometric analysis were used for the detection of ICAM-1 expression in MDA-MB-231 and MCF-7 cells. The cytotoxicity of the small-molecule probe γ3-Cy5.5 was detected using the CCK8 assay. The in vitro targeting of the small-molecule probe γ3-Cy5.5 was verified via flow cytometry and a laser scanning confocal microscope. Finally, the targeting of small-molecule probe in vivo and ex vivo was observed by NIRF imaging.. Western blotting and flow cytometry demonstrate that ICAM-1 was highly expressed in the MDA-MB-231 TNBC cell line. Laser confocal microscopy and flow cytometry results show that TNBC cells have an increased cellular uptake of γ3-Cy5.5 compared to the control probe γ3S-Cy5.5. With in vivo NIRF, a significantly higher Cy5.5 signal appeared in the tumors of mice administered γ3-Cy5.5 than those treated with γ3S-Cy5.5. The target-to-background ratio observed on the NIRF images was significantly higher in the γ3-Cy5.5 group (10.2, 13.6) compared with the γ3S-Cy5.5 group (4.4, 4.0) at 1 and 2 h, respectively.. This is the first report of the use of ICAM-1-specific small-molecule probe for in vivo NIRF optical imaging of TNBC. This method provides a noninvasive and specific strategy for the early diagnosis of TNBC.

Topics: Animals; Carbocyanines; Cell Line, Tumor; Intercellular Adhesion Molecule-1; Mice, Inbred BALB C; Mice, Nude; Molecular Probes; Optical Imaging; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Histone deacetylases (HDACs) are overexpressed in various cancers. In vivo imaging to measure the expression and functions of HDACs in tumor plays an important role for tumor diagnosis and HDAC-targeted therapy evaluation. The development of stable and highly sensitive HDAC targeting probe is highly desirable. Near-infrared (NIR) fluorescence optical imaging is a powerful technology for visualizing disease at the molecular level in vivo with high sensitivity and no ionizing radiation. We report here the design, synthesis, and bioactivity evaluation of LBH589-Cy5.5 for in vivo NIR fluorescence imaging of HDACs. The IC50 value of the resulting NIR probe to HDACs was determined to be 9.6 nM. In vitro fluorescence microscopic studies using a triple-negative breast cancer cell line, MDA-MB-231, established the binding specificity of LBH589-Cy5.5 to HDACs. An in vivo imaging study performed in MDA-MB-231 tumor xenografts demonstrated accumulation of the probe in tumor with good contrast from 2 h to 48 h postinjection. Furthermore, the fluorescent signal of LBH589-Cy5.5 in tumor was successfully blocked by coinjection of nonfluorescent LBH589 with the probe. In a following therapy evaluation study, the administration of SAHA, a clinically used HDAC inhibitor, decreased LBH589-Cy5.5 accumulation in tumor, demonstrating the potential application of LBH589-Cy5.5 for evaluating therapeutic response of HDAC inhibitors in cancer treatment.

Topics: Animals; Carbocyanines; Cell Line, Tumor; Diagnostic Imaging; Female; Fluorescent Dyes; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Mice; Mice, Nude; Spectroscopy, Near-Infrared; Triple Negative Breast Neoplasms