초록 ▼

￭ 의료용 방사성동위원소 ⁶⁴Cu에 대한 안정적인 공급 체계 구축
- ⁶⁴Cu 생산의 자동화와 함께 표준화시스템을 구축하였고, 매생산시마다 100mCi 이상을 생산하고 있음.

- 총 8,200mCi 이상을 생산하여 국내 연구자들에게 공급함.

- 최근에는 새로운 타겟장치을 개발하여 효율적인 생산시스템을 향상

￭ 의료용 방사성동위원소 ⁸⁶Y의 생산 및 정제기술 연구
- 2013년도에 국내 최초로 양전자방출 진단용

￭ 의료용 방사성동위원소 ⁶⁴Cu에 대한 안정적인 공급 체계 구축
- ⁶⁴Cu 생산의 자동화와 함께 표준화시스템을 구축하였고, 매생산시마다 100mCi 이상을 생산하고 있음.

- 총 8,200mCi 이상을 생산하여 국내 연구자들에게 공급함.

- 최근에는 새로운 타겟장치을 개발하여 효율적인 생산시스템을 향상

￭ 의료용 방사성동위원소 ⁸⁶Y의 생산 및 정제기술 연구
- 2013년도에 국내 최초로 양전자방출 진단용 방사성동위원소인 ⁸⁶Y에 대한 생산 기술력을 확보(시간당 약 4mCi)

￭ 의료용 방사성동위원소 ⁸⁹Zr의 생산 및 정제기술 연구
- 국내 최초로 ⁸⁹Zr의 생산기술 확보(시간당 약 7.5mCi)
- 고순도의 ⁸⁹Zr을 획득하기 위해 1회용 컬럼을 개발함.
- 또한 국내 최초로 ⁸⁹Zr의 PET 영상법 개발 및 소동물영상 촬영에도 성공

￭ 의료용 방사성동위원소 ¹²⁴I에 대한 안정적인 공급체계 구축
- 핵반응, 표적장치 개선 및 신규 정제장치의 제작으로 월평균 2회 생산가능
- 총 1,624.7mCi을 생산하여 국내 연구자들에게 공급함.

￭ 종양 저산소현상 진단용 small molecule 방사성의약품 개발
- [⁶⁴Cu]ATSM 제조, 기준 및 시험방법을 확립하고 식약처로부터 마이크로도즈 임상시험에 대한 승인을 획득하여 임상시험 진행중.

￭ 항체 방사성의약품의 개발(5종의 임상후보물질 도출)
- 합성 validation system 확립하였고, 후보물질들에 대한 최적화를 진행 중임.
- 1단계에서 우수한 임상후보물질들로 총 5종의 항체 방사성의약품의 도출

￭ 금속성 방사성동위원소를 위한 킬레이터의 개발
- 금속성 동위원소를 위한 BFC 개발 및 in-vivo validation을 수행함.

￭ 종양표적형 펩타이드 방사성의약품의 개발
- 종양 신생혈관을 표적하는 RGD 기반의 5종 후보물질을 개발 및 도출
- Intra cellular target을 지향하는 peptide 방사성의약품의 개발 및 전임상 검증을 실시하였으며, 비금속성 방사성동위원소인 ¹²⁴I를 표지한 peptide 방사성의약품의 개발 및 전임상 비교 검증 연구를 수행함.

￭ 금속성 방사성핵종을 표지한 직접세포표지법을 이용한 세포추적법 개발
- 직접 세포 표지법의 개발과 안착능 영상평가를 수행

￭ 나노입자 플랫폼 기반 종양 진단 방사성 다중영상프로브 개발
- 스트렙트아비딘-바이오틴 기반 혈관내피세포성장인자 및 혈관신생 억제 펩타이드는 PET과 광학 영상에서 U87MG 종양 마우스의 종양에 높은 섭취를 보였음.

- 테트락-리포솜은 혈관신생 억제제인 테트락에 의하여 종양에 높은 섭취를 보였음.
- ADIBO기를 도입한 메조포러스실리카겔 나노입자를 마우스에 먼저 주사한 후 24시간 후에 방사성 아지도 화합물을 주사하여 생체 내 클릭반응 유도로 종양 섭취를 높임.

- 금속산화물에 혈관신생억제제인 RGD 펩타이드를 접합하여 종양 타겟팅에 성공

￭ 종양진단 관련 다중영상프로브 개발
- ⁶⁴Cu-표지 다중영상프로브를 이용하여 마우스 슬와림프절의 PET/광학영상에 성공

￭ ⁴⁴Ti 생산표적 개발
- Ti-44의 생산을 위한 Sc 표적의 최적에너지와 표적 두께를 선정하였고, 저전류에서의 시험생산을 위한 실험표적 및 헬륨 냉각시스템을 설계

- 장시간 조사와 높은 생성량을 확보하기 위하여 자동화된 표적시스템을 설계/제작함.

- Au 코팅으로 양성자빔 조사 과정에서 발생하는 Sc의 불안정성을 효과적으로 억제함.

￭ ⁴⁴Ti/Sc 분리용 흡착제 개발
- ⁴⁴Ti/Sc 제조기의 동위원소 흡착물질을 개발하기 위하여 10 mol% Al-W포함된 다공성 타이타노-실리케이트와 α,β-인산금속으로 타이타늄과 스칸듐을 합성 성공함.

￭ ⁴⁴Sc 활용 방사성의약품 개발
- ⁴⁴Ti/Sc 제조기에서 용출되는 ⁴⁴Sc를 이용한 표지화합물을 개발함.

(출처 : 요약서 3p)

Abstract ▼

IV. Results of the Research

1. Development of production and collection technology for diagnositic metallic positron emission radioisotopes

A. Building of stable support system for ⁶⁴Cu
▪ For production of ⁶⁴Cu, we used (p,n) nuclear reaction and used duralumi

IV. Results of the Research

1. Development of production and collection technology for diagnositic metallic positron emission radioisotopes

A. Building of stable support system for ⁶⁴Cu
▪ For production of ⁶⁴Cu, we used (p,n) nuclear reaction and used duralumin and Ta foils as beam degraders in order to reduce beam energy. Because it is really difficult to control beam energy due to old cyclotron.

▪ Recently, we produce ⁶⁴Cu more than three times in a month and have been supporting to domestic researchers. We obtained the production license in 2012 and this document give us the information for radiochemical quality. We made the standardization of production and designed the separation equipment by semi automation, so the method of production and its application were successfully established.

▪ Production has increased steadily and we produced three times in a month and obtained more than 100 mCi, each time. The productivity five-fold in just two years. And till April 2014, we have already supported ⁶⁴Cu more than 8,200 mCi to domestic researchers. So we have contributed to the strengthening national research and more than 3,800 million won are earned for importing effect.

▪ Recently, the study for building more efficient production system is performed by using new target device. New target device is the specialized target system for our MC-50 cyclotron. It was designed to proceed nuclear reaction more efficiently and to maximize the cooling effect during the beam irradiation.

▪ The successful development of ⁶⁴Cu-based radiopharmaceuticals is highly dependent on the proper choice of bifunctional chelator as well as targeting biomolecules. We synthesized TE2A in efficient way, and found that TE2A makes much more stable Cu complex compare with DOTA and TETA.

B. Study of production and collection technology for ⁸⁶Y
▪ In 2013, we had secured the production technology of ⁸⁶Y for the first time in Korea. For production of ⁸⁶Y, we used (p,n) nuclear reaction by using Sr carbonate and production was carried out research as a way of making powder based on disc type target.

▪ And currently, we can get the ⁸⁶Y by 4 mCi per hour. In the near future, we have plan to produce ⁸⁶Y according to research schedule and will support to domestic researchers.

C. Study of production and collection technology for ⁸⁹Zr
▪ ⁸⁹Zr has long physical half-life and this allow the use of ⁸⁹Zr in PET applications with monoclonal antibodies, which posses long biological half-lives up to several days. We developed production technology of ⁸⁹Zr in 2012.

▪ For production of ⁸⁹Zr, we used (p,n) nuclear reaction by using natural yttrium foil. The productivity increased 37 times compared to the previous year. And currently, we can get the ⁸⁹Zr by 10 mCi per hour.

▪ We designed and manufactured disposable column for purification, and developed the high purity refining process. After beam irradiation, we confirmed ⁸⁹Zr was obtained purely from the MCA analysis.

▪ We have carried out experiment by the synthesis of ⁸⁹Zr labelled-herceptin, and from the result, ⁸⁹Zr from the KIRAMS formed stable complexes with antibody and was confirmed the possibility as diagnostic radiopharmaceuticals. Shortly, we have plan to produce ⁸⁹Zr according to research schedule and will support to domestic researchers.

D. Building of stable support system for ¹²⁴I
▪ For production of ¹²⁴I, we used (p,2n) nuclear reaction by using 125TeO2. Recently, we produce twice a month and have been supporting to domestic researchers. The production and supply have increased steadily each year and we are gradually observing improvement in our quality.

▪ Especially, the productivity four-fold in just two year. And till April 2014, we have already supported ¹²⁴I more than 1,600 mCi to domestic researchers. So we have contributed to the strengthening national research and more than 690 million won are earned for importing effect.

E. Development of chelators forming ultra stable ⁶⁴Cu complexes
▪ Even though Cu-64 shows attractive decay mode (both beta+ and beta-), current widely used chelators such as DOTA and TETA loose free Cu(II) ions in vivo due to non-optimized stability of their Cu complexes. Therefore, new chelators showing high in vivo stability are highly needed.

▪ During last three years, new three chelators (MM-TE2A, DM-TE2A, PCB-TE2A) were developed. Three chelators were radiolabeled in quantitative radiolabeling yield using optimized labeling conditions. Furthermore, the radiolabeled chelators showed ultra high in vivo stability in animal model experiments.

▪ New bifunctional chelator based on TE2A was developed. It showed excellent conjugation ability with antibody and its ⁶⁴Cu-labeled antibody conjugate detected tumor clearly in tumor animal models.

2. Development of Metallic Radioisotope Labeled Probe for Tumor Diagnosis

A. Development of radiopharmaceutical like small molecule for diagnostic of tumor hypoxia
▪ Established ⁶⁴Cu-ATSM CMC, Non-clinical data for clinical trials approved secure
▪ Approved microdose clinical trials(2013. 12. 05)

B. Development of antibody radiopharmaceuticals
▪ Builded synthetic validation system (cell saturation binding test, immuno-reacticity test, conjugation level test)

▪ Candidate for clinical application optimization (⁶⁴Cu-DOTA-Trastuzumab, ⁸⁹Zr-DFO-Trastumumab, ⁶⁴Cu-DOTA-Bevacizumab, ⁸⁶Y-DTPA-Rituximab, ⁶⁴Cu-DOTA-Cetuximab)

▪ Established clinical application of the first candidate CMC, Acquire non-clinical datas, Approved clinical trial

C. Development of peptide radiopharmaceuticals
▪ Development of [⁶⁴Cu]GlucosaNODAGA-c(RGDfk)₂ and its analogues by RGD-based for angiogenesis tumor targeted

▪ Established clinical application of the first candidate CMC, Acquire non-clinical datas, Approved clinical trial

▪ Development of Intra cellular target-oriented peptide radiopharmaceuticals and preclinical validation

▪ Development of non-metallic RI labeled peptide radiopharmaceuticals and preclinical validation

D. Development of direct cell labeling and cell tracking method using metallic RI labeled radiopharmaceuticals
▪ Development of direct cell labeling and evaluation of imaging performance

E. Development of chelate
▪ Development of bifunctional chelators for metallic RI and in-vivo validation

3. Development of multimodality imaging probes using radiometal

A. Development of tumor targeting multimodality imaging probes using nanoparticle platforms
▪ Streptavidin-biotin based vascular endothelial growth factor and antiangiogenic peptide showed high and specific tumor uptakes in U87MG tumor mice using both PET and optical imaging (3.4 ~ 4.2% ID/g @20 h)

▪ Tetrac-liposomes had high tumor uptake due to conjugation of tetrac, an angiogenesis inhibitor (⁶⁴Cu/tetrac-liposomes: ⁶⁴Cu-liposomes = 4.86:1)

▪ Mesoporous silica nanoparticles conjugated with ADIBO group were injected into mice, and after 24 h, radioactive azido compound was injected into the same mice, inducing in situ click reaction which increases tumor uptake (pretargeting)

▪ Metal oxide nanoparticles attached with RGD peptide were also successfully synthesized. Therefore, multimodality imaging probes developed in this research were shown to have potential for tumor imaging.

B. A multimodality imaging probe related to tumor diagnosis, ⁶⁴Cu-labeled probe was synthesized and evaluated: increased signals were monitored in popliteal lymph nodes of mice in PET/optical imaging.

4. Development of ⁴⁴Ti/Sc Generator and its utilizations

A. Target development for ⁴⁴Ti production and production of ⁴⁴Ti
▪ Ti-44 production using Sc-45 stable isotope was performed in two ways, the development of target system and the improvement of stability of Sc-45.

▪ Optimum energy and thickness of Sc target were selected for the production of Ti-44, and a test target and helium cooling system were designed for the test production with low beam current.

B. Development of column material and extraction system for ⁴⁴Ti/Sc separation
▪ 10 mol% Al-W-incorporated mesoporous titano-silicates and α,β-metal (Zr and Ti) phosphates their absorption characterizations of titanium and scandium were synthesized.

▪ Characterizations of Metal oxide was observed X-ray diffraction, SEM-EDX, TEM, zeta-potential and hydration size.

C. Development of ⁴⁴Sc labelled radiopharmaceutical
▪ Characterizations of [⁴⁵Sc]DOTA-peptide observed nomal-phase Thin Layer Chromatography, High Performance Liquid Chromatography, ¹H-Nuclear Magnetic Resonance spectroscopy.

▪ The labeling efficiency was determined by thin layer chromatography (TLC) using silica gel plates.

(출처 : SUMMARY 15p)

목차 Contents

• 표지 ... 1
• 제 출 문 ... 2
• 보고서 요약서 ... 3
• 요 약 문 ... 5
• S U M M A R Y ... 12
• C O N T E N T S ... 21
• 목차 ... 22
• 그림목차 ... 23
• 표목차 ... 27
• 제 1장 연구개발과제의 개요 ... 29
• 제 1절 연구개발의 필요성 ... 29
• 제 2절 기술의 중요성 ... 32
• 제 3절 경제적·사회적 의미 및 필요성 ... 33
• 제 2장 국내외 기술개발 현황 ... 35
• 제 1절 세계적 수준 ... 35
• 제 2절 국내 수준 ... 42
• 제3장 연구개발수행 내용 및 결과 ... 45
• 제 1절 이론적, 실험적 접근방법 ... 45
• 제 2절 연구 내용 및 결과 ... 51
• 제 4장 목표 달성도 및 관련 분야에의 기여도 ... 122
• 제 1절 목표 달성도 ... 122
• 제 2절 관련 분야의 기여도 ... 127
• 제 5장 연구개발결과의 활용계획 ... 130
• 제 1절 기술적 측면 ... 130
• 제 2절 의료 산업적 측면 ... 133
• 제 3절 추가 연구의 필요성 ... 135
• 제 6장 연구개발과정에서 수집한 해외과학기술정보 ... 137
• 제 1절 최신기술 동향분석 ... 137
• 제 2절 관련 학회/연구소 소개 및 연구동향 분석 ... 142
• 제 7장 참고문헌 ... 147
• 끝페이지 ... 156