S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
Improved Drug Targeting to Liver Tumors Following Intra-arterial Delivery Using SPIO and Iodized Oil: Preclinical Study in a Rabbit Model
간암의 간동맥화학요법에서 초상자성 산화철 나노입자를 이용한 약물 전달 효율 향상: 토끼 모델을 이용한 전임상 연구
- Lee, In Joon
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과 영상의학전공, 2015. 8. 정진욱.
- Introduction: Superparamagnetic iron oxide (SPIO) is a type of magnetic nanoparticle (MNP) that has been developed for the purpose of clinical diagnostic and therapeutic techniques. The aim of this experimental study was to evaluate the biodistribution and the therapeutic efficacy of a drug delivery system composed of SPIO and iodized oil (IO) to improve selective intra-arterial (IA) drug delivery to liver tumors.
Materials and Methods: A rabbit VX2 liver tumor model was used in this study. This study was comprised of two parts
the part 1 was for the image-based biodistribution analysis of SPIO after delivery, and the part 2 was for the evaluation of drug delivery efficiency and therapeutic effect to the tumor. First of all, 99mTc labeled SPIO (99mTc-SPIO) and SPIO loaded with doxorubicin (DOX-SPIO) were synthesized. For the part 1, 99mTc-SPIO was administrated by using three different methods
intra-venous delivery of 99mTc-SPIO (group I, n = 3), IA delivery of 99mTc-SPIO (group II, n = 4), and IA delivery of 99mTc-SPIO and IO mixture (group III, n = 4). Sequential acquisition of gamma scintigraphy and SPECT/CT was immediately performed until 180 min after the delivery. After that, MRI and pathological specimens were acquired to confirm the deposit of SPIO in the tumor. For the part 2, IA delivery was performed by using four different agents
only doxorubicin (group A, n=3), doxorubicin and IO mixture (group B, n=3), DOX-SPIO (group C, n=4), and DOX-SPIO and IO mixture (group D, n=5). To evaluate pharmacokinetics, the serum doxorubicin concentration was measured at 0, 5, 30, 60, 120, and 180 minutes after delivery. To assess the distribution of the SPIO, MRI was performed at 1 day and 7 days after the IA delivery. Finally, pathological specimens were acquired to measure the intratumoral doxorubicin concentration and tumor viability.
Results: In the part 1, the tumor uptake on gamma scintigraphy and SPECT/CT was ranged from the highest to lowest values according to the order of group III, II, and I at all time points up to 180 minutes, which was well correlated with the trend of signal decrease of the tumor on MRI. The relative tumor-normal liver parenchyma uptake ratios on SPECT/CT were 0.83 for group I, 2.74 for group II, and 8.01 for group III. The relative tumor-back muscle signal intensity ratios on MRI were 1.06 for group I, 0.75 for group II, and 0.39 for group III. On the CT images, the high attenuated lesions in tumor representing IO deposition were easily detected in all animals only in groups III. In the part 2, groups C and D exhibited signal decreases of the tumor at days 1 and 7 post-delivery. The peak serum concentrations decreased according the order group A, B, C, and D. Group D exhibited the lowest serum doxorubicin concentration at all time points up to 180 minutes after the delivery, suggesting minimal passage of doxorubicin into the systemic circulation. The intratumoral doxorubicin concentrations were 25.3 ng/g for group A, 142.0 ng/g for group B, 309.4 ng/g for group C, and 679.6 ng/g for group D. The proportion of viable tumor cells were 84.3% for group A, 5.7% for group B, 17.0% for group C, and 0.1% for group D.
Conclusions: The drug delivery system developed using SPIO and IO resulted in efficient drug targeting and good therapeutic response when it was used for IA delivery to liver cancer. The promising results of this study warrant further investigation of this potential clinical treatment of advanced liver cancer.