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Kafe 바로가기주관연구기관 | 인하대학교 InHa University |
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연구책임자 | 김철희 |
참여연구자 | 오은택 , 곽종영 , 이해준 |
보고서유형 | 1단계보고서 |
발행국가 | 대한민국 |
언어 | 한국어 |
발행년월 | 2017-12 |
과제시작연도 | 2016 |
주관부처 | 과학기술정보통신부 Ministry of Science and ICT |
등록번호 | TRKO201900027245 |
과제고유번호 | 1711045317 |
사업명 | 원자력연구기반확충사업 |
DB 구축일자 | 2020-09-19 |
키워드 | 방사선 치료.방사선 민감도.종양조직환경.암혈관내피세포.세포간 상호반응.세포 표지 인자.Theranostics 플랫폼.종양혈관칩.3D 배양.Radiotherapy.Radiosensitivity.Tumor microenvironment.Cancer endothelial cell.Cross talk.Cell surface marker.Theranostic platform.3D vascular chip.3D culture. |
종양조직환경을 선택적으로 타겟팅하는 신개념 바이오-나노 기술을 이용하여 방사선 치료 효능 증진과 지적재산권 확보를 통한 산업화 기술개발 및 전문인력 양성을 최종목표로 함. 이를 위해
• 방사선 치료 시 정상 및 저산소환경에서 암혈관내피세포 및 종양조직환경 (cancer niche) 세포간 상호반응체계를 규명하고 발굴된 인자들을 표적하는 약제를 탐색하여 암세포의 방사선 민감도 증진 효과를 연구함.
• 방사선 치료 효능 증진과 예후 판별을 위해 종양조직환경 세포 및 물질을 타겟팅하는 theranostic 플랫폼 제조 기술을
종양조직환경을 선택적으로 타겟팅하는 신개념 바이오-나노 기술을 이용하여 방사선 치료 효능 증진과 지적재산권 확보를 통한 산업화 기술개발 및 전문인력 양성을 최종목표로 함. 이를 위해
• 방사선 치료 시 정상 및 저산소환경에서 암혈관내피세포 및 종양조직환경 (cancer niche) 세포간 상호반응체계를 규명하고 발굴된 인자들을 표적하는 약제를 탐색하여 암세포의 방사선 민감도 증진 효과를 연구함.
• 방사선 치료 효능 증진과 예후 판별을 위해 종양조직환경 세포 및 물질을 타겟팅하는 theranostic 플랫폼 제조 기술을 개발함.
• 동물모델 시스템을 대체 할 수 있는 저비용, 고효율의 방사선생물학 및 방사선 치료연구에 특화된 종양조직환경 3D 생체모사 배양시스템을 개발함.
• 기초-임상 중개연구를 통한 연구결과의 유효성 평가를 수행함.
본 센터의 최종목표를 달성하기 위해 해당단계에서는 각 세부과제별로 다음과 같이 연구를 수행함.
제 1세부과제: 종양조직환경 세포 표적 방사선 민감도 조절 연구 (in vitro, in vivo)
• 암혈관내피세포의 방사선 민감도 조절인자들의 발굴 (유방암, 대장암 유래).
• 방사선에 의한 암혈관내피세포와 종양조직환경 세포간의 상호반응 방사선 치료 저항성 조절인자들을 발굴
• 암혈관내피세포 특이적 세포 표지 인자 및 ECM 등의 발현 변화 분석
• 나노전달체 및 3D 생체모사 배양시스템의 효능 평가
제 2세부과제: 종양조직환경 타겟팅 theranostic 플랫폼 제조 기술 개발
• 암혈관내피세포의 optical 이미징을 위한 타겟팅 CRGDC 펩타이드 개발
• 암혈관내피세포의 이미징 및 선택적 약물전달을 위한 mesoporous 나노전달체 개발
• 종양 특이적 환경을 타겟팅하는 theranostic mesoporous 나노전달체 개발
제 3세부과제: 3D 종양혈관칩 수준에서 암혈관내피세포의 방사선 민감도 측정 기술 개발
• 혈관내피세포와 암세포의 3D 공배양 시스템 구축과 3D 에세이칩에서 방사선 민감도 측정 기술 개발
• 혈관내피세포층을 구성하는 구획과 종양조직 환경을 구성하는 구획에서 혈관내피세포의 암혈관내피세포로의 3D 배양조건을 확립하고 방사선 민감도를 측정하는 기술 개발
제 4세부과제: 종양 및 종양조직환경에 대한 방사선 민감도 평가 동물모델 연구 (in vivo)
• 종양 및 종양조직환경의 방사선 민감도 평가 동물모델 구축
• 방사선 조사 방법에 따른 종양 및 종양조직환경의 방사선 민감도 연구
• 종양 및 종양조직환경의 방사선 민감도 조절인자에 대한 in vivo 검증
• 종양조직환경 조절에 의한 방사선 민감도와 암치료 효율의 평가
(출처 : 보고서 요약서 3p)
Ⅳ. Results
Research group 1
□ Study of the target molecules and their mechanisms for the control of the radiosensitivity of cancer endothelial cells
• Target molecules and their mechanisms for the radiosensitivity of cancer endothelial cells under normoxia and hypoxia were identified and va
Ⅳ. Results
Research group 1
□ Study of the target molecules and their mechanisms for the control of the radiosensitivity of cancer endothelial cells
• Target molecules and their mechanisms for the radiosensitivity of cancer endothelial cells under normoxia and hypoxia were identified and validated.
□ Elucidation of the radiation-induced interactive communication between cancer endothelial cells and cancer niche cells
• The target molecules and their mechanisms for the radiation-induced interactive communication between cancer endothelial cells and cancer niche cells under normoxia and hypoxia were identified and validated.
□ Study of the cell surface markers and ECM to control the radiosensitivity of cancer endothelial cells
• The cell surface markers and ECM to control the radiosensitivity of cancer endothelial cells under normoxia and hypoxia were identified and validated.
□ Use of nanoparticles for delivering drugs and 3D culture systems to cancer niche cells
• The anticancer drugs to be conjugated with multifunctional nanoparticles which are designed to target cancer niche cells were identified.
• Effectiveness of 3D culture systems to cancer niche cells was evaluated.
Research group 2
□ Development of theranostic mesoporous nanoparticles using peptide gatekeepers with responsiveness to unique bioreductase upregulated in various tumor cells.
□ Development of targeting CRGDC peptide for optical imaging of tumor endothelial cells.
□ Development of mesoporous nanoparticles with targeting-gatekeeping dual functional CNGRC/CRGDC peptides for enhanced radiotherapy of tumor endothelial cells.
□ Verification of enhanced therapeutic effect of mesoporous nanoparticles with targeting-gatekeeping dual functional CNGRC/CRGDC peptides for enhanced radiotherapy of tumor endothelial cells.
□ Development of targeted drug delivery system using mesoporous nanoparticles with stimuli-responsiveness to NQO1 upregulated in hypoxic tumor cells.
□ Verification of enhanced therapeutic effect of targeted drug delivery system using mesoporous nanoparticles with stimuli-responsiveness to NQO1 upregulated in hypoxic tumor cells.
□ Development of mesoporous nanoparticles with targeting-gatekeeping dual functional A6 peptides for enhanced radiotherapy of tumor endothelial cells
□ Development of mesoporous nanoparticles for enhanced tumor therapeutic effect via increased endosomal escape capability.
□ Verification of controlled drug release of stimuli-responsive mesoporous nanoparticles according to the generation of the surface dendron units.
Research group 3
□ In-direct co-culture of endothelial cells and cancer cells in PCL nanofiber scaffold
• 3D culture of endothelial cells in PCL nanofiber scaffold
• Morphological changes of endothelial cells after co-culture of the cells and cancer cells in two-layer system of PCL nanofiber scaffold
• Effects of hypoxia-inducing CoCl2 on the proliferation of cancer cells in 3D culture
• Effects of CoCl2 on the morphological changes of endothelial cells cultured alone and cultured with cancer cells
• 3D migration assay of endothelial cells to cancer cells in PCL nanofiber-based two-layer system
• Increased secretion of VEGF by CoCl2-treated cancer cells in 3D culture conditions
• Effects of radiation on the secretion of VEGF by CoCl2-treated cancer cells in 3D culture conditions
□ 3D indirect co-culture of endothelial and cancer cells in transparent PVA nanofiber scaffold
• Production of PVA nanofibers for cell culture scaffold
• Optical and fluorescent microscopic observation of cell morphology in transparent nanofiber membrane
• Observation of stained cells co-cultured cells in both sides of PVA membrane
• Adhesion and tight junction formation of endothelial cells on PVA nanofiber membrane
• Proliferation of endothelial cells in PVA nanofiber membrane
• 3D migration assay of endothelial cells to co-cultured cancer cells in opposite side of PVA nanofiber membrane
□ Indirect 3D co-culture of endothelial and cancer cells in fucoidan-PCL nanofiber scaffold
• Production of Fucoidan-PCL by electrospinning
• Increased adhesion of endothelial cells to Fucoidan-PCL
• Proliferation and nitric oxide generation by endothelial cells cultured in Fucoidan-PCL
□ 3D culture of endothelial cells on Fucoidan-blended PVA nanofiber membrane
• Production and anlysis of Fucoidan-PVA nanofibers
• Increased adhesion of endothelial cells to Fucoidan-PVA nanofiber membrane
□ Decellulared nanofibers for 3D culture of endothelial cells
• PCL/PVA-decellular nanofibers from fibroblast culture in PCL/PVA nanofibers and culture of endothelial cells on the scaffold
□ Development of wall chamber consisting of electrospun nanofibers
• Production of wall chamber with nanofiber alone
• 3D migration assay of endothelial cells to cancer cells in wall chamber
□ Culture of endothelial cells derived from tumor tissue of implanted cancer cells
Research group 4
□ Construction of various tumor models
• Establishes allogeneic and xenograft tumor models for the assessment of radiation sensitivity.
• Establishes of orthotopic tumor model.
□ Study of dose-specific radiation reactivity in in vivo tumor models
• At 4, 8, 12, and 16 Gy single irradiation, higher tumor growth inhibition was observed at higher doses, which correlated with tumor vascular density.
• 10 Gy or more radiation suppressed tumor growth and vascular density
□ Radiological response analysis of tumor vessels after irradiation
• When irradiated with 10 Gy or less (8 Gy), tumor vascular cells decrease until 3 days after irradiation and then increase again after 5 days.
• The number of vascular endothelial cells in the tumor decreased after 10 Gy (16 Gy) irradiation but increased after 7 days.
□ Establishment of low-dose and high-dose irradiation conditions in cancer model and analysis of tumor response
• Single irradiation (4, 8, 12, 16 Gy) and fractionated irradiation (2 Gy x 4, 2 Gy x 6, 2 Gy x 8) were conducted in the mouse lung cancer allograft tumor model and confirm the therapeutic response to the tumor.
• 16 Gy single irradiation showed the highest tumor suppression effect, but the tumor growth rapidly increased after 7 days.
□ Analysis of changes in tumor tissue environment in the irradiation method above 4 conditions
• 16 Gy shows the lowest hypoxic environment under single exposure conditions.
• The density of tumor vascular endothelial cells and the area of b lood vessel to total tumor area tend to decrease in proportion to the total radiation dose
• The distribution of tumor macrophages in tumors tends to increase as radiation dose increases.
□ Analysis of change of tumor tissue cell by hypoxia
• In normal oxygen saturation, tumor cells and vascular endothelial cells are highly sensitive to radiation, but the sensitivity of vascular endothelial cells to high dose radiation is low in hypoxic environments.
(출처 : SUMMARY 13p)
과제명(ProjectTitle) : | - |
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연구책임자(Manager) : | - |
과제기간(DetailSeriesProject) : | - |
총연구비 (DetailSeriesProject) : | - |
키워드(keyword) : | - |
과제수행기간(LeadAgency) : | - |
연구목표(Goal) : | - |
연구내용(Abstract) : | - |
기대효과(Effect) : | - |
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