• Biomolecules & Therapeutics
• /
• 제5권3호
• /
• pp.233-238
• /
• 1997

The distribution and excretion of radioactivity were examined after intraportal administration of sup 166/Ho-chitosan complex at a dose of 1 mcitg (10 mg chitosan/kg) to rats. Whole body macroautoluminographs showed that the radioactivity after an administration was concentrated in liver and perfused primarily to organs including kidney, spleen, and bone marrow, then to muscle and brain. Similar profiles were observed from 2 hr to 168 hr after the administration. The relative percentage of radioactivity in bone and spinal column increased with time, suggesting that free $^{166}$ Ho, released from chitosan complex deposited in the liver, selectively binds to these tissues. $^{166}$ Ho-chitosan complex administered intraportally was excreted less than 4% through urine (2.7$\pm$0.8%) and feces (0.65 $\pm$ 0.4%) up to seven days. These results demonstrate that the radio-activity of $_{166}$ Ho-chitusan complex when administered intraportally, mainly localizes in liver without affec-ting other tissues and organs. Considering the short half life of $^{166}$ Ho and the localization to the liver, $^{166}$ Ho-chitosan complex might be a useful agent in the treatment of hepatic carcinoma.

• 대한핵의학회지
• /
• 제31권4호
• /
• pp.433-439
• /
• 1997

낭성뇌종양은 낭 내부에 베타선을 방출하는 방사성동위원소를 주입하여 낭 내부 및 낭벽에 존재하는 암세포에 일정량의 방사선 에너지를 전달함으로써 그 치료 효과를 기대할 수 있다. 본 연구에서는 $^{166}Ho$-chitosan 복합체를 낭성뇌종양 치료에 이용하고자 할 때 낭의 크기와 주입되는 방사능의 변화에 따라 낭벽에 전달되는 방사선 흡수선량이 어떻게 변화하는가를 평가하고자 한다. 구형의 종양성 낭 모델에 대하여 Monte Carlo code인 EGS4를 이용하여 $^{166}Ho$ 베타선의 에너지 전달 현상에 대한 모사계산을 수행한다. 종양성 낭 내부에 주입된 $^{166}Ho$-chitosan 복합체의 낭내 분포는 낭 내부액과 섞여있거나 낭벽 표면에 부착되는 두 가지 경우를 고려한다. 방사선 조사의 표적 영역으로서, 낭벽의 표면으로부터 매 1mm 깊이의 체적을 설정하여 4mm 깊이까지 고려한다. 직경이 각 1cm, 2cm, 그리고 3cm 인 종양성낭을 평가 대상으로 설정한다. 직경이 3cm인 종양성 낭에 10mCi의 $^{166}Ho$-chitosan 복합체가 주입되어 낭 내부에 균일하게 분포하였다고 가정하였을 경우에 1mm 두께의 낭벽에 전달되는 방사선 흡수선량은 매 1mm 깊이의 낭벽 체적에서 각각 40.06Gy, 14.96Gy, 5.315Gy, 1.660Gy으로 계산되었다. 한편, 낭 내부에 주입된 10mCi의 $^{166}Ho$-chitosan 복합체가 낭벽에 균일하게 분포하였다고 가정하였을 경우에는 매 1mm 두께의 낭벽 체적에 전달되는 방사선 흡수선량이 601.7Gy, 188.7Gy, 73.87Gy, 27.80Gy로 평가되었다. 낭 내부에 주입된 $^{166}Ho$-chitosan 복합체가 낭벽에 부착될 가능성이 있음이 한 임상 적용 예에서 시사된 바, 정확한 $^{166}Ho$-chitosan 복합체의 낭 내부벽 부착률을 확인함으로써 낭벽에 대한 흡수선량을 예시하고 이를 근거로 주입할 $^{166}Ho$-chitosan 복합체의 양을 결정해야 할 것이다.

• 대한핵의학회지
• /
• 제30권3호
• /
• pp.351-360
• /
• 1996

새로운 내부 방사선 치료용(Internal radiotherapy) $^{166}Ho$-CHICO와 CHIMA를 개발하고자 한다. $^{166}Ho$-CHICO 형성에 pH, 반응시간, chitosan 농도, $^{166}Ho$의 양 등의 영향을 실험하고, 형성된 $^{166}Ho$-CHICO로부터 $^{166}Ho$-CHIMA를 제조하여 $^{166}Ho$-CHICO와 CHIMA의 체내외 안정성 검사 등의 실험을 수행하였다. $^{166}Ho$-CHICO 형성시 최적의 조건은 pH 3.0에서 0.75% 이상의 chitosan 용액과, chitosan 무게에 대해 최대 20%까지는 $^{166}Ho$이 정량적으로 착물을 형성하였고, $^{166}Ho$-CHICO를 알칼리 처리하여 $^{166}Ho$ CHIMA를 제조하였다. 그리고 $^{166}Ho$-CHICO와 CHIMA는 체내외에서 매우 안정하였다. $^{166}Ho$-CHICO와 CHIMA는 매우 이상적인 carrier로서의 특성을 지닌 천연의 chitosan에 $^{166}Ho$을 쉽게 정량적으로 표지할 수 있고, 높은 체내외 안정성으로 미루어보아 내부 방사선 치료용 제제로서의 이용 가능성이 매우 높으며, 앞으로 충분한 동물실험을 거치면 신규 내부 방사선 치료제로서 새로운 장을 열 수 있을 것이다.

• 대한핵의학회지
• /
• 제32권1호
• /
• pp.99-108
• /
• 1998

Intraperitoneal administration of radioisotopes is suggested to treat the metastatic ovarian cancer in the peritoneal cavity. Administering beta-emitting radioisotopes into the peritoneal cavity allows the maximum energy delivery to the cancerous cells of the peritoneal wall surface while sparing the normal cells located in deep site of the peritoneal wall. In this study, dose estimates of the peritoneal wall are provided to be used for prescribing the amount of $^{166}Ho$-chitosan complex administered. The $^{166}Ho$-chitosan complex diffused in the peritoneal fluid may attach to the peritoneal wall surface. The attachment fraction of $^{166}Ho$-chitosan complex to the peritoneal wall surface is obtained by simulating the ascites with Fischer rats. Both volume source in the peritoneal fluid and the surface source over the peritoneal wall surface are counted for the contribution to the peritoneal wall dose. The Monte Carlo code EGS4 is used to simulate the energy transfer of the beta particles emitted from $^{166}Ho$. A plane geometrical model of semi-infinite volume describes the peritoneal cavity and the peritoneal wall. A semi-infinite plane of $10{\mu}m$ in thickness at every 1 mm of depth in the peritoneal wall is taken as the target in dose estimation. Greater than 98 percents of attachment fraction has been observed from the experiments with Fischer rats. Given $1.3{\mu}Ci/cm^2$ and $2.4{\mu}Ci/ml$ of uniform activity density, absorbed dose is 123 Gy, 8.59 Gy, 3.00 Gy, 1.03 Gy, and .327 Gy at 0 mm, 1 mm, 2 mm, 3 mm, and 4 mm in depth to the peritoneal wall, respectively.

• 대한핵의학회:학술대회논문집
• /
• 대한핵의학회 1999년도 제38차 춘계학술대회
• /
• pp.200-204
• /
• 1999

Rheumatoid arthritis (RA) is o chronic inflammatory disease of joints with proliferation of synovial epithelial tissue. Therapeutic approach of the RA consists of pharmacological and surgical interventions. Synovectomy is indicated in patients with progressive inflammatory signs and symptoms intractable to medical treatment including local intracavitary steroid injection. Recently, local injection of radionuclides which emit high energy beta rays are labeled with chemical compounds such as $^{90}Y,\;^{165}Dy-ferric$ hydroxide macroaggregate and have been introduced as an alternative therapeutic modality to surgical synovectomy. Holmium-166 is one of beta emitter and Ho-166-chitosan complex was developed for radiation synovectomy. Preclinical trial is on-going at our hospital using Ho-166-chitosan. The procedure and methods of preclinical trial are discussed.

• 대한골관절종양학회지
• /
• 제9권2호
• /
• pp.190-199
• /
• 2003

목적: Holmium-166은 류마티스성 관절염 및 간암 치료에서 이미 임상적으로 사용이 보고된 방사성 동위원소이다. 본 연구는 holmium-166-chitosan 복합체를 외과적으로 생체에 투입하여 임상에 적용 가능한 방법을 연구하고, 투여량과 기간, 투여 부위에 따른 조직학적 반응 정도를 정성 및 정량 분석하여 임상적용의 기초로 활용하는 것이다. 재료 및 방법: Absorbable gelatin sponge에 액체상태의 holmium-166-chitosan 복합체를 50 ${\mu}l}$ 도포하여 고형제로 만들었다. 최종 삽입전에 caliberator로 측정한 방사선량은 약 1.5 mCi였다. Wistar종 흰쥐에 외과적 시술을 통하여 대퇴근육 내부와, 그리고 대퇴골에 접하게 holmium-166-chitosan 복합체가 부착된 gelatin sponge를 삽입 후 봉합하였다. 대퇴 근육내와 대퇴골에 투여한 후 2주, 4주, 6주에 육안 및 현미경 소견하에서 조직 괴사의 깊이, 조직 변화의 양상, 삽입된 gelatin sponge의 변화 등을 관찰하였다. 결과: 2주후의 현미경 소견상 holmium-166과의 접촉면에서는 정상 근육세포의 모양을 찾아 볼 수 없을 만큼 심한 괴사 소견을 보였고 근육세포의 퇴화 및 재생, 근육간 부종, 염증세포의 침윤 소견을 보였으며 유발된 괴사의 깊이는 평균 3.3 mm 였다. 대퇴골에서는 holmium-166과의 접촉면에 있는 골피질은 골소강내 골세포의 소실이 관찰되었고 골수강내의 골수 세포도 파괴되고 섬유화 또는 염증성 반응을 보였다. 괴사의 깊이는 평균 2.9 mm 였다. 4주 때 근육에서는 석회화와 보다 심해진 섬유화 소견이 추가 되었고 괴사의 깊이는 평균 3.3 mm 였다. 골조직에서도 골수강의 섬유화가 더 증가되었고 괴사의 깊이는 평균 3.3 mm였다. 경과 관찰 6주 군에는 연부 조직의 위축과 섬유화의 증가, 육아조직의 형성, 염증 소견의 소실 등이 관찰되었다. 결론: Holmium-166-chitosan 복합체를 생체 흡수 가능한 gelatin sponge에 부착시킨 후 실험동물에 삽입한 결과, 실험동물의 사망을 유발하지도 않았으며 상처의 괴사, 염증, 감염 등의 부작용이 전혀 없어, 생체에 외과적 적용이 가능하였다. 유발된 조직 괴사의 범위는 약 3 mm로 미리 예측한 정도에 근접하는 것으로 악성종양 치료에 임상적 적용이 가능할 것으로 생각한다.

• Biomolecules & Therapeutics
• /
• 제5권1호
• /
• pp.100-105
• /
• 1997

DW-166HC ($^{166}$Holmium-chitosan) is a complex of $^{166}$Ho, $\beta$- and $\gamma$-ray emitter, and chitosan, a polymer of glucosamine, with radiotherapeutic potential. The current study was performed to determine the acute toxicities of $^{165}$Ho-chitosan in mice by two different routes of administration. The both sex mice were given a single intravenous bolus injection of $^{165}$Ho-chitosan complex at doses of 12, 10, 6, 5 and 4 mg/kg or subcutaneous administration at doses of 600, 500, 400 and 300 mg/kg. Chitosan was dosed to control animals as 16 and 800 mg/kg, intravenously and subcutaneously, respectively. The doses of $_{165}$Ho-chitosan complex were expressed as $_{165}$holmium nitrate pentahydrate and the ratio of $^{165}$Ho$(NO_3)_3$).$5H_2O$ to chitosan was 3/4 Severe convulsion and respiratory failure were followed by death within 10 min after intravenous dosing. Transient unilateral hindlimb hypokinesias were found in two mice of 5 mg/kg dosing group during the study period. No abnormalities were observed during the necropsy of survived animals in intravenous dosing group. Only one male animal was found dead in 500 mg/kg subcutaneously dosed group. Alopecia with or without cutaneous ulcer were found in most mice including control animals. During necropsy, omental adhesion was observed in all dose ranges and enlarged spleen was found in several animals including control group. It is suggested that the acute intravenous >).$LD_{50}s$ for male and female mice were 4.90 and 6.03 mg/kg, respectively. The lowest lethal dose in male was 500 mg/kg by subcutaneous administration.

• Journal of Korean Neurosurgical Society
• /
• 제29권10호
• /
• pp.1309-1315
• /
• 2000

Objectives : We performed an in vivo experiment to investigate the effect of $^{166}Holmium$ and $^{166}Holmium$-chitosan complex($^{166}Ho$-CHICO) on the normal brain of rats and to determine the sublethal dose of $^{166}Ho$-CHICO. Materials and Methods : $^{166}Ho$ is a beta and gamma ray emitter. $^{166}Ho$-CHICO is a novel radio-pharmaceutical complex with chitosan to facilitate the transport of $^{166}Ho$ obtained from Korea Atomic Energy Research Center(Taejon, Korea). It is in acidic form and becomes gel state at alkaline pH. One hundred and seventy consecutive rats were divided into four groups : $^{166}Ho$ treated(n＝50), $^{166}Ho$-CHICO treated(n＝57), saline treated(n＝5) and chitosan treated(n＝5) groups. $^{166}Ho$ and $^{166}Ho$-CHICO were injected into the rat brain stereotactically with various doses of 0.1mCi/$20{\mu}l$, 0.2mCi/$20{\mu}l$, 0.3mCi/$20{\mu}l$, and 0.4mCi/$20{\mu}l$ using an automated microinjector. Nuclear imaging, histopathological and hematological studies were performed in 10 rats in each group at 1 day, 3days, 7 days, 1 month and 3 months after the injections. Results : An infiltration of inflammatory cells and necrotic changes were noted in $^{166}Ho$ treated group at 1 week after the injection. A wedge-shaped tissue defect due to necrosis, lined with infiltrated glial cells in $^{166}Ho$ treated group and a cystic defect lined with reactive astroglial cells in $^{166}Holmium$-CHICO treated group at 3 months after the injection were observed. $^{166}Ho$ alone without chitosan leaked out and caused necrotic lesion on the cerebral surface but $^{166}Holmium$-CHICO treated group did not show this feature. As the dose of $^{166}Ho$ increased, the mortality rates were also increased. The mortality rate of the $^{166}Holmium$-CHICO group was higher than the $^{166}Ho$ treated group at a dose of 0.4mCi/$20{\mu}l$/300g. There was no detectable radioactivity due to the leakage or extravasation from the injected site of the brain on the scintigraphy performed at 1 hour, 24 hours and 48 hours after the injection. There was also no detectable activity of $^{166}Holmium$-CHICO in other organs including spleen, liver and kidney. Conclusions : $^{166}Ho$-CHICO did not leak out to the critical cortical surface of the brain from the injection site and induced radiation changes of the parenchyma around the injection site without cortical damage. The sublethal dose of $^{166}Ho$-CHICO for the normal brain in rats was determined to be 0.2mCi/$20{\mu}l$/300g.

• 대한방사선협회지
• /
• 제25권1호
• /
• pp.73.2-74
• /
• 1999

• Biomolecules & Therapeutics
• /
• 제5권3호
• /
• pp.278-283
• /
• 1997

DW-166HC ($^{166}$ Holmium ($^{166}$ Ho)-Chitosan complex) is a new radiopharmaceutic anticancer agent with a broad anti-tumoriginec spectrum, especially against human fepatic cancer. DW-166HC was evaluated for the appearance of micronucleus in polychromatic erythrocytes (PCEs) of mouse bone marrow cells after subcutaneous and intravenous single administration. Bone marrow cells were prepared at 24 hr and 48 hr after DW-166HC-I ($^{165}$ Ho-Chitosan complex cold compound) administration and at 24 hr, 72 hr and 2 weeks after DW-166HC ($^{166}$ Ho-Chitosan complex : hot compound) administration. The results showed there was no statistically significant increase of the numbers of PCEs with micronucleus in all DW-166HC-I administered groups compared with a negative control group but there was statistically significant increase of the numbers of PCEs with micronucleus at 24 hr and 72 hr in all DW-166HC administered groups, which was recovered after 2 weeks from the drug administration. The results also showed the ratio of normochromatic erythrocytes (NCEs) to PCEs of all DW-166HC-I administered groups was not significantly different from that of a negative control group but there was significant difference this ratio at 24hr and 72 hr in all DW-166HC administered groups compared with that of negative group, which was also recovered after two weeks from the drug administration. These results suggested that DW-166HC-I may not cause any chromosomal damage but DW-166HC has in vivo mutagenic potential because of its radioactivity.