Visualization of Breast Cancer for Diagnosis using Nanoparticles Ye-Eun Kang 2017.04.18 Functional Soft Nanomaterials Lab. Supervised by Prof. Seung Yun Yang

Breast Cancer  Early diagnosis is very important! Breast Cancer - Cancer that develops from breast tissue - Most commonly develops in cells from the lining of milk ducts and the lobules that supply the ducts with milk - Risk factors : Being female, obesity, lack of physical exercise, drinking alcohol, older age, family history, etc. Incidence Rate Mortality Rate Survival Rate(2001~2012 수술환자 대상) 한국유방암학회 2016 중앙암등록본부 2016 통계청 2016 If detected early, breast cancer is curable  Early diagnosis is very important!

Diagnosis methods for breast cancer Breast Self Examination - Anyone can do it easily at no cost Radiological diagnosis - Use electromagnetic wave and ultrasonic wave to generate images - Mammography, CT scan, MRI scan, and ultrasonography CT cancer MRI cancer normal PCR (Polymerase Chain Reaction) - Amplify certain regions of DNA using polymerase chain reaction - Be used for DNA sequencing, analyzing the functionality of genes, and diagnosing hereditary cases of breast cancer Immunochemistry - A method by which cancer cells are detected in the body by antigen-antibody reaction - Staining technique used to identify cancer cells in a tissue sample

Biomarker-specific ligand Materials for breast cancer diagnosis Materials for breast cancer diagnosis Concept Biomarker An indicator that can detect changes in the body (health or disease state) by using proteins, DNA, RNA, and metabolites Substances that are specifically expressed in breast cancer cells Gene (BRCA1/2, PALB2, BRIP1) Receptor (HER2, ER, PR) MicroRNA (Let-7a, MiR-21) Biomarker-specific ligand A substance that specifically binds to a biomarker Allow drugs or imaging agents to specifically target breast cancer Antibodies, nucleic acid, peptides that complementary bind to breast cancer biomarkers Imaging agent Material that visualizes the size (volume) and location of breast cancer cell (tissue) Allows to monitor the diagnosis or progress of the cancer Contrast agent (Iodine ion compound, gadolinium ion compound) Fluorescent substance (Fluorescein)

Fluorescent substance Imaging agent for breast cancer diagnosis Conventional imaging agent for diagnosis Contrast agent Fluorescent substance - A substance that increases the contrast of tissue to more accurately distinguish normal and lesion tissues - Through oral or intravenous administration Ex. Iodine ion compound – for CT scan Gadolinium ion compound – for MRI scan - A substance that can re-emit light upon light excitation(UV or visible light) - Used to label and track cells in fluorescence microscopy applications Ex. Fluorescein(green) and its derivatives CT MRI breast cancer cell(green), estrogen receptor α(red) - non-contrast + contrast normal blood vessels brain tumor  When used in vivo, it can sometimes cause side effects  Fluorescence intensity decreases with time (photobleaching)  Exhibit narrow absorption spectra and broad emission spectra  Can cause side effects such as vomiting, anaphylactoid reaction, and, in the worst case, death  Short imaging time T. Fehm et al., Breast cancer research, 10, R76 (2008)

Nanoparticles as imaging agents for breast cancer diagnosis

Nanoparticles enable efficient and accurate diagnosis Why are nanoparticles used as imaging agent for breast cancer diagnosis? Nanoparticles - Nano-scaled(1 – 100 nm) materials  unique interaction with biological systems at molecular level - Have a very large surface area relative to their volume  have various physicochemical properties (such as strength, conductivity, catalytic activity, optical properties, magnetic properties, etc.)  various molecules can attached to the nanoparticle surface (targeting ligands – peptide, nucleotide, antibody, etc.) Nanoparticles enable efficient and accurate diagnosis

Fluorescent substance Nanoparticles for breast cancer diagnosis Contrast agent Gold nanoparticles (AuNPs) for CT scan Superparamagnetic iron oxide nanoparticles (SPIONs) for MRI scan Fluorescent substance Quantum dots (QDs) for in-vivo, in-vitro bioimaging

Gold nanoparticles for CT contrast agents Gold nanoparticles (AuNPs) - Unique electronic, magnetic, optical and catalytic properties  tunable by changing the size, shape, surface chemistry, or aggregation state. - Have biocompatibility (bio-inert) - Gold absorb more X-ray energy than iodine  gold-based CT agents can show high-resolution image than conventional iodine-based CT agents

Gold nanoparticles for CT contrast agents aorta Hematoma region before 5 min 1 h 2 h 4 h 12 h After 24 h of incubation

Superparamagnetic iron oxide nanoparticles for MRI contrast agents Superparamagnetic iron oxide nanoparticles (SPIONs) - Has magnetic properties only in the presence of an external magnetic field.

Superparamagnetic iron oxide nanoparticles for MRI contrast agents

Quantum dots for visualization of cancer cell Quantum dots (QDs) - Semiconductor fluorescent nanoparticles - Have photo-stability  emit fluorescent light over a long time without photobleaching - Emission spectrum, fluorescence property depends on size - Exhibit broad absorption spectra and narrow emission spectra  possible to label multiple molecular targets simultaneously Quantum size effect Quantum dots for in-vivo cancer targeting and imaging

Quantum dots for visualization of cancer cell In vitro In vivo 0.6 nmol 6 h circulatin 0.6 nmol 24 h circulatin 0.4 nmol 2 h circulatin 0.4 nmol 2 h circulatin

Quantum dots for visualization of cancer cell In vivo 0.6 nmol 6 h circulatin 0.6 nmol 24 h circulatin 0.4 nmol 2 h circulatin

Conclusion Early diagnosis is important because breast cancer can be treated at early detection Conventional imaging agents for breast cancer diagnosis can cause side effects and are relatively inefficient Nanoparticles have been developed as imaging agents that overcome the drawbacks of conventional imaging agents for breast cancer diagnosis

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