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Small Molecule Ligands and Antibody Drug Conjugates for Potential Application in Targeted Cancer Therapy and PET Imaging
Title
Small Molecule Ligands and Antibody Drug Conjugates for Potential Application in Targeted Cancer Therapy and PET Imaging
Creator
Ren, Siyuan
Date
2020
Description
Cancer has been a deadly disease threatening humans. Traditional treatment methods such as chemotherapy with non-specific targeting may cause...
Show moreCancer has been a deadly disease threatening humans. Traditional treatment methods such as chemotherapy with non-specific targeting may cause severe side effects to normal cells and tissues. Novel and better methods for treatment and imaging of cancer has been eagerly sought. We wanted to develop new small molecule inhibitors and antibody drug conjugates for targeted cancer therapy and imaging. Theranostic conjugates combining therapeutic entity and imaging agent are useful in treatment and diagnosis of cancer. We designed a theranostic conjugate containing iron chelating anti-tumor agent and optical imaging probe. Novel iron chelator CAB-NE3TA displayed significant anti-proliferation activity against several cancer cell lines and was conjugated to targeting antibody panitumumab (PAN). The therapeutic conjugate exhibited excellent anti-tumor efficacy and targeting ability to EGFR overexpressed on cancer cells such as skin cancer (A431). The theranostic conjugate CAB-NE3TA-PAN loaded with a near IR fluorescent dye provided promising anti-tumor efficacy and optical imaging in tumor-bearing mice. Tetrahydroisoquinoline (THIQ) analogues were synthesized and evaluated for cytotoxicity against different cancer cell lines. Our in vitro studies showed that the THIQ analogues exhibited anti-proliferative activities against multiple cancer cell lines. Cytotoxicity study revealed that anti-tumor activity of THIQ analogues are structure-dependent. Binding affinity between THIQ analogues and a potential target Tdp1 was determined. Positron emission tomography (PET) has been used in diagnosis of cancer. In this study, small molecules and chelators with potential donor groups were evaluated systematically for complexation with 89Zr for PET imaging. New ligands with different donors were evaluated for radiolabeling efficiency and complex stability with 89Zr. The theranostic conjugate (CAB-NE3TA-PAN-IR800) and small molecule THIQs and 89Zr-chelators showed encouraging results for potential applications in for therapy and imaging of cancer.
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ELECTROSPUN SILKWORM SILK FIBROIN - INDOCYANINE GREEN BIOCOMPOSITE FIBERS: FABRICATION, CHARACTERIZATION AND APPLICATION TOWARDS HEMORRHAGE CONTROL
Title
ELECTROSPUN SILKWORM SILK FIBROIN - INDOCYANINE GREEN BIOCOMPOSITE FIBERS: FABRICATION, CHARACTERIZATION AND APPLICATION TOWARDS HEMORRHAGE CONTROL
Creator
Siddiqua, Ayesha
Date
2022
Description
Silk fibroin (SF), a structural protein found in the Bombyx mori cocoons has gained attention in several biomedical applications as tissue...
Show moreSilk fibroin (SF), a structural protein found in the Bombyx mori cocoons has gained attention in several biomedical applications as tissue engineering scaffolds and wound dressings owing to its properties such as biocompatibility, water vapor permeability and biodegradability. Indocyanine Green (ICG) is an FDA approved tricarbocyanine dye used in medical diagnostics due to its unique photothermal and fluorescent properties. Electrospinning is a highly efficient, easy, and inexpensive technique used to generate nanometer to micrometer thick fibers. In this study, SF and ICG were co-spun to generate flexible microfibers with high surface area to volume ratios. Pure silk, SF-ICG (0.1%) and SF-ICG (0.4%) were chosen for the purpose of this study. Since, as-spun fibers are unstable in aqueous solutions, post treatment methods were explored to enhance the durability of the fibers and to minimize ICG leaching. It was found that ethanol vapor treatment (EVT) not only induced β-sheet formation in SF but also improved the SF-ICG interaction thereby reducing ICG leaching from the composite fibers. Ethanol vapor treated SF-ICG fibers showed less ICG leaching than liquid ethanol treated (LET) SF-ICG fibers indicating the efficacy of the EVT. The increase in SF solution viscosity with ICG concentration suggested a strong silk-ICG interaction which was further confirmed by DSC. The 1h water uptake and the three-day mass loss experiments indicated that the fibers are stable and highly absorbent material. Heat evolution was evaluated by measuring the temperature change in water of a fixed volume after irradiation with a 500 mW, 808 nm diode laser. The heat evolved by the flat fiber scaffolds was higher than the 3D fiber balls, indicating improved light penetration in the former. Pure silk produced negligible heat and it was used as a control. With 14.9 W/cm2 irradiation, the post-treated SF-ICG (0.4%) 3D fibrous ball of 2-3 mg dry weight, solidified a drop of bovine blood in 40 s. In contrast, a single layer fiber matrix required 3 min. to achieve the same clotting effect. Fibers folded into flat scaffolds were able to solidify a blood drop in 25 s. Pure silk fibers in all the cases showed negligible change after irradiation. The results suggest that a larger contact area of fibers is desirable for faster blood clotting, and EVT prompted better ICG retention in SF fibers. Based on the above results, SF-ICG (0.4%) fibers were utilized in a device developed to mimic blood flowing at a rate of 0.5 mL/h through a damaged blood vessel. It was found that irradiation of SF-ICG locally placed at the “damage” region effectively stopped “bleeding” whereas irradiated pure silk was unable to control the blood flow, which demonstrated the success of our SF-ICG fibers towards hemorrhage control.
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