서지주요정보
Indocyanine green-loaded pulmonary surfactant-based nanoparticles for near-infrared fluorescent detection of lung metastasis via inhalation delivery = 폐전이암 근적외선 형광탐색을 위한 흡입전달용 폐계면활성제 기반 인도시아닌 그린 나노입자 개발
서명 / 저자 Indocyanine green-loaded pulmonary surfactant-based nanoparticles for near-infrared fluorescent detection of lung metastasis via inhalation delivery = 폐전이암 근적외선 형광탐색을 위한 흡입전달용 폐계면활성제 기반 인도시아닌 그린 나노입자 개발 / Daeho Jung.
발행사항 [대전 : 한국과학기술원, 2018].
Online Access 원문보기 원문인쇄

소장정보

등록번호

8033047

소장위치/청구기호

학술문화관(문화관)B1층 보존서고

MBIS 18020

휴대폰 전송

도서상태

이용가능(대출불가)

사유안내

반납예정일

리뷰정보

초록정보

Lung cancer is one of the deadliest types of cancers worldwide, possessing a high number of patients and death rate. The first and foremost treatment to such diagnosed lung cancers is surgical removal, where physical excisions of the lung cancer tissues are performed. In such basic surgical treatments, minimizing the accidental removal of the healthy lung tissue is critical, as it is the major factor in affecting the patient’s life quality post-surgery. Thus, an imaging system that can distinguish the tumor tissues from normal lung tissues with high accuracy and precision is in need of development. Currently, various near-infrared fluorescent materials are being used to distinguishing certain tissues in biological systems. In particular, Indocyanine Green, a fluorescent with its emission spectrum near 780nm, is an FDA-approved material with high biosafety. By loading such fluorescent material onto a nanoparticle based on pulmonary surfactant, a commercially available material naturally abundant within the lungs, clinical safety may be maximized. Inhalation delivery of these nanoparticles showed specific delivery to only the lungs, thereby decreasing possible toxicity in other major organs. Such delivered particles have been confirmed to be able to distinguish lung cancer nodules from healthy lung tissue with highly efficient negative imaging, mainly because of the physical barriers of the tumor nodules and the decreased ratio of macrophages in the nodules, which is the major type of cell that exhibit uptaking ability towards nanoparticles. Furthermore, the fact that such fluorescent nanoparticles distinguish tumor regions from healthy tissues more efficiently than other small-molecule fluorescent materials have been confirmed, yielding the potential to decrease the general dosage of the fluorescent material in use, possibly decreasing the toxicity while increasing the economic efficiency of the imaging system. In short, this study allows ICG to behave as a nanoparticle by loading it onto a liposome-form nanoparticle based on a bio-safe material, the pulmonary surfactant. Via inhalation of this newly synthesized Surf-ICG nanoparticles, an accurate and effective detection of the lung cancer nodules from the background-existing healthy lung tissues can be met.

폐암은 전 세계적으로 많은 빈도수와 높은 치사율을 보유하고 잇는 질병이다. 가장 기본적인 치료법으로는 폐암을 정확하게 물리적으로 제거하는 수술이다. 이러한 기본적인 수술 중 가장 중요한 것은 실수로 정상폐조직을 자르는 것을 최소화하는 것이며, 실제로 환자의 삶의 질을 좌우하는 가장 근본적인 요소이다. 때문에, 폐암과 정상폐조직을 구분화 할 수 있는 탐색 시스템이 절실하다. 이를 위해 최근 근적외선 형광들이 각광받고 있는데, 이 중 인도시아닌 그린은 780nm 구간에서 빛을 발광하며, FDA의 승인을 받은, 안전성이 매우 높은 물질이다. 이러한 근적외선 형광을 폐 내부에 자연적으로 존재하는 폐계면활성제라는 물질을 기반으로 한 나노입자에 탑재한다면, 임상 안전성이 보장된 이미징 나노입자가 형성된다. 이러한 나노입자를 호흡기법으로 전달하여, 특이적으로 폐에 축적 시킨다. 본 연구에서는 이렇게 전달 된 Surf-ICG라는 나노입자가, 폐암 주변에 존재하는 물리적 장벽과 정상폐조직에 많이 분포되어 있는 대식세포의 영향에 따라 음성 영상화를 통해 폐암 탐색이 가능한 것을 확인했다. 또한, 본 탐색 기법은 수술 도중에 쓰일 수 있음으로 물리적 제거를 할 시에 가이드 역할을 할 수 있는 탐색 시스템이다. 더 나아가, 기존 small-molecule기반 형광물질에 비해 보다 효율적으로 탐색이 가능하다.

서지기타정보

서지기타정보
청구기호 {MBIS 18020
형태사항 42 p. : 삽화 ; 30 cm
언어 영어
일반주기 저자명의 한글표기 : 정대호
지도교수의 영문표기 : Jiho Park
지도교수의 한글표기 : 박지호
Including Appendix
학위논문 학위논문(석사) - 한국과학기술원 : 바이오및뇌공학과,
서지주기 References : p. 39-40
QR CODE

책소개

전체보기

목차

전체보기

이 주제의 인기대출도서

The general structure the lungs of the metastatic lung cancer model in mouse. The cancer nodules exhibita physical barrierdue to the density ofthe metastatic lung cancer cells, and a low number of macrophages as compared to the healthy lung tissue with proper alveolar space intact.

The abundant nature of alveolar macrophages in the alveolar regions of thelungs5). Alveolarmacrophages are abundantin thelungs and havemultiplefunctions to keep the lungs working properly. Some functions include immune defense, inflammation contml and nharocutosis.ffnotentiallv harmful materials

The application ofNIR fluorescencein clinical imagingofg) vessels in the limbs, andh) lymphatic systems near the neck of patients7, Clear contrast of different structures and tissues within the region may be helpful for doctors in their treatment to

Imaging of the tumor within a mouse model, pre- and post- intravenous injection of NIR fluorescence. Emission near 800nm exhibit a clear contrast between tumorand healthy tissue.

The general absorption spectrum of the blood and the biological tissues.

Typesof existing fluorescent nanoparticles used for biologicalimaging9) Such nanoparticles are more stablein terms oftheiropticproperties, as opposed to small molecule fluorescence.

Left: the absorbance and the emission spectrum of the ICG. Right: The emission intensity ofthe ICGin the Shortwave Infrared (SW-IR) region oflight11)

Types of some existing fluorescent materials being used for biological imaging. Note that ICG is known for its biosafety, via the approval from the FDA.

Typical pulmonary surfactant composition13) Note that various Surfactant Proteins are embedded in a rich combination oflipids.

The main function ofthe pulmonary surfactant: to maintain the surface tension ofthe alveolar space and the cells surroundingit10,

The composition of Surfacten, Curosurf, in comparison to naturally occuring pulmonary surfactant. Most of their compositions, including the types of Surfactant Proteins (SPs), are very similar in comparison.

Steps in synthesizing Surf-ICG, a pulmonary surfactant-based nanoparticleloaded with ICG. The hydrophobic regions ofICG are expected to anchor themselves into the bilayer of the surfactant nanoparticle. Such Surf-ICG nanoparticles will have certain properties, such as increased biosafety and retention, appropriate for a more efficientlung cancer nodule imaging.

A nebulizer used for mouse models and for patient treatment15). Usually,

Existing nanoparticles delivered via inhalation, and their advantages.

The general scheme of this research. In alung cancer patient, Surf-ICG nanoparticle will be able to negatively image the locations of the cancer nodules effectively.

,5.Compositions ofthe mimetic liposome, and various molar ratios ofSurf- ICGsynthesis. Left: the typesofphospholipids that make up the Mimetic Liposome, a conventional type ofliposome mimicking the Surf-ICG, excluding the Surfactant Proteins. Right: The various molar ratios of surfactant:ICG considered when optimizing Surf:ICG's ideal molar ratio. Mimetic liposomes were used as a control compariso

The size andzeta potentials ofvarious kinds ofSurf-ICG and Mim-ICG.

Different ICG encapsulation rates for each Surf-ICG synthesized with different Surf:ICG molar ratios post-dialysis. Via Stewart Assay protocol, up to the molar ratio of 250:8 of Surf:ICG, similar amounts of ICG were loaded onto the pulmonary surfactant nanoparticle. However, since around 250:16, less percentage of totalICG added were actually loaded onto each nanoparticle, meaning that250:8 marked

The final molar ratio oftheSurf:ICG,after calculations considering the encapsulation rateofICG onto each Surf:ICG,compared to theideal ratioin which 100% ofICG added are all loaded. All experiments were performed post-dialysis of onob nononorhiol.

TEM image of the Surf-ICG. Scale baron the bottom leftindicate 200nm in size. General sizes were found to be raning from 200~400nm.

Inhalation does not alter the sizes ofnanoparticles. The difference in sizes ofthe pulmonary surfactant-based nanoparticle, when compared toa conventional liposome (mimetic), post-inhalation process. Little to no change in sizes were observed for both cases, indicating that indeed Surf-ICG behaves similar to a conventional liposome in that the size or the nanoparticle's structure does not getalter

10% FBS-Stability Test of Surf-ICG, when compared to a conventional liposome loaded with ICG. All nanoparticles were finalized in synthesis with dialysis. The trend shown by the graphs indicate that up to almost 24 hours, Surf-ICG seems to

Co-cultured 4T1 metastatic breast cancer cells and Raw246.7 macrophages, treated with Surf-ICG. Cells are marked with DAPI staining (blue), and 4T1 are marked by the expression of GFP signal (green). Surf-ICG nanoparticles are markedbythe lipophilic dye DiI (red). In general, Surf-ICG localized and were taken upby the macrophages, andnottheregionsin which dense 4T1 confluency were present. This sh

Harvested major organs for biodistribution of Surf-ICG. Right: Harvested major organs from a healthy mouse, inhaled with Surf-ICG. Left: NIR- emission measurement, precisely at 800nm for ICG signals of inhaled Surf-ICG. Two figures are ofidentical organs, from the same mouse.

The biodistribution offree ICG, notloaded onto any nanoparticle. Mice were sacrificed and major organs were harvested each at1,3,6, 12, and 24 hours, and signal intensities ofICG were takenin all ofthe majororgans, viaLi-Corimaging system.

The biodistribution of Surf-ICG. Mice were sacrificed and major organs were harvested eachat1,3,6,12, and 24hours, and signal intensities ofICG weretaken in all ofthe majororgans, via Li-Corimaging system.

Comparison ofICG signal intensity between a healthy mouse's lungS inhaled with freeICG and with Surf-ICG. Mice were sacrificed at·1,3,6,12, and24 hours post-inhalation. Generally, Surf-ICG seems to retain in the lungformuchlonger, when compared to freeICG.

Negative imaging of the lung cancer nodules using inhaled Surf-ICG. NIR fluorescence imaging of4T1 metastatic lung cancer models in mice, precisely measured at 800nm emission, post-inhalation of Surf-ICG. Cancer nodules within the lungs are outlined by the yellow-dotted lines. The NIR fluorescence reveals that much of Surf-ICG's 800nm-emission intensities were found in the normal lung tissues, and

Surf-ICG has better imaging ability than conventional free ICG.

Long-term imaging ability of the Surf-ICG. TBR value comparison of Free ICG, Surf-ICG, and Mim-ICG sized at 400nm, 6hours post-inhalation. Even after 6 hours, ICG in the form of nanoparticles possess high contrast and precise imaging of the nodules. However, because Free ICGs are cleared out faster than Surf-ICG, less contrast is exhibitedbythe small molecule ICG.

Macrophage co-localize with Surf-ICG in vivo. Confocal images ofa cryosection of a lung tissue in a 4T1 metastatic lung cancer model in mice, post- inhalation of the Surf-ICG. After sacrificing the mice models, thelungs were harvested 6hourspost-inhalation, and were frozenin OCT solutions priorto 10mm sectioning of the tissues. Confocal imagesrevealthat, atleast partially, the macrophages stained