Encapsulated Radiopaque Microcapsules - American Chemical Society

Chapter 27

Evaluation of Poly(dl-lactide) Encapsulated Radiopaque Microcapsules David J. Yang, Li-Ren Kuang, Chun L i , Tony Tsai, Chun-Wei Liu, Walter J. Lin, Wayne Tansey, Sarah Nikiforow, Patricia McCuskey, Zuxing Kan, Kenneth C. Wright, and Sidney Wallace Downloaded by MONASH UNIV on October 29, 2012 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch027

Department of Diagnostic Radiology, M . D. Anderson Cancer Center, The University of Texas, Houston, T X 77030

Poly(d,l-lactide) ( P L A ) microcapsules encapsulated with ethyliopanoate (IOPA E) and ethyldiatrizoate (DZE) were evaluated for their potential use in computed tomography imaging. IOPA Ε was synthesized from iopanoic acid and thionyl chloride, yield 82.4%. DZE was synthesized from diatrizoic acid and ethyliodide, yield 90%. Both compounds were radioiodinated with Na I and encapsulated in P L A microcapsules. In vivo tissue distribution of microcapsule groups and control groups (IOPA Ε and DZE) were evaluated. The percentage of injected dose per liver at 20 min, 2, 5 and 24 hours was 35.19, 20.90, 9.38 and 1.49 for the P L A I-IOPA Ε group; and 46.25, 29.01, 13.19 and 1.27 for the P L A I-DZE group. A significant difference (P iodine content 75 mg I/kg body weight). The rats (N=3/time interval) were k i l l e d at 20 minutes, 2, 5 and 24 hours after injection. The percentage of injected dose in a given organ or weight of tissue was determined by a gamma counter.

Downloaded by MONASH UNIV on October 29, 2012 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch027

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In Vivo Microscopic Examination. The unlabeled P L A - I O P A Ε and P L A - D Z E microcapsules were injected into rats (iv). The in vivo microscope, equipped with a video monitor (Axioplan, Zeiss C o , Germany), was then applied to observe the dynamic circulation of the microcapsules in liver. Results and

Discussion

Chemistry. Both I O P A Ε and D Z E can be easily prepared with a high yield. Using standard solid phase exchange technique, both compounds were labeled i n a reasonable yield. Morphology of P L A Microcapsules. I O P A Ε and D Z E capsules of 0.5-3 μπι were prepared by the process described in the methods section. Figure 4 shows the average particle size of P L A encapsulated D Z E . The particle sizes ranged from 0.5 to 3 μπι i n diameter. Figure 5 shows the S E M examination of P L A - I O P A Ε microcapsules. A l l the capsules prepared had smooth outer surfaces. Stability Test of P L A - I O P A Ε and P L A - D Z E M i c r o c a p s u l e s . Less than 5% radioactivity was detected i n serum after one hour incubation o f both microcapsules. 2 0 - 2 5 % of radioactivity was released in serum after 24 hours incubation of both microcapsules. In Vivo Microscopic O b s e r v a t i o n . The i n vivo m i c r o s c o p i c observation revealed that (1) the microcapsules have uniform shape and little aggregation, (2) the Kupffer cells actively phagocytized P L A - I O P A Ε and P L A - D Z E microcapsules and (3) the microcapsules demonstrated good circulating properties in the liver. In Vivo Biodistribution Studies. The results of tissue distribution studies for I-labeled I O P A Ε groups are shown in Tables I and Π. 131

In Polymeric Delivery Systems; El-Nokaly, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.

Poly(é\-lactide) Encapsulated Radiopaque Microcapsules 377


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F i g u r e 5. Scanning E l e c t r o n M i c r o s c o p i c Observation of I O P A Ε Microcapsules


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Table I. Tissue Distribution of Μ Ο Ρ Α Ε in Rats Organ 20 minutes 2 Hours 5 Hours 24 Hours Blood 1.51 ± 0 . 1 0 ! 1.41 ±0.23 0.99 ± 0.04 0.28 ± 0.12 Lung 1.20 ±0.16 0.64 ± 0.03 0.70 ±0.31 0.13 ± 0.06 Liver 1.62 ±0.18 0.97 ± 0.00 0.73 ± 0.06 0.39 ± 0.13 Spleen 1.89 ± 0.43 0.46 ± 0.01 0.21 ± 0.01 0.12 ± 0.05 Kidney 1.02 ± 0.10 0.61 ± 0.02 0.60 ± 0.33 0.24 ± 0.11 Intestine 2.79 ± 0.29 4.04 ± 0.53 3.66 ± 1.65 1.77 ± 0.80 Bone 0.47 ±0.12 0.27 ± 0.03 0.32 ±0.12 0.04 ± 0.01 Urine 0.34 ± 0.06 2.81 ± 0.40 2.68 ± 0.39 0.77 ± 0.35 ÏData represents the percentage of injected dose per gram of tissue weight (% IND/G). Studies were conducted in three rats per time interval (N=3 / time interval). Downloaded by MONASH UNIV on October 29, 2012 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch027

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Table II. Tissue Distribution of P L A Encapsulated I - I Q P A Ε in Rats Organ 20 minutes 2 Hours 5 Hours 24 Hours Blood 0.23 ± 0.10 0.5$ ± 0.18 0.87 ± 0.06 1.43 ± 0 . 7 1 ! Lung 1.56 ± 0.22 0.11 ± 0.04 0.48 ± 0.04 0.47 ± 0.20 Liver 0.22 ± 0.05 4.13 ±0.33 2.91 ± 0.75 1.61 ± 0.12 Spleen 6.57 ± 0.43 0.28 ± 0.05 3.46 ± 0.90 6.53 ± 0.71 Kidney 0.54 ± 0.03 0.34 ± 0.09 0.19 ± 0.07 0.38 ± 0.02 Intestine 1.56 ± 0.46 0.36 ± 0.01 1.56 ± 0.66 1.06 ± 0.03 Bone 0.23 ± 0.03 0.05 ± 0.01 0.20 ± 0.07 0.16 ± 0.01 Urine 0.87 ± 0.44 1.33 ± 0.35 8.75 ± 2.87 7.76 ± 1.56 *Data represents the % I N D / G (N=3 / time interval). 1 3 1

Tissue distribution for I-labeled D Z E groups are shown in Tables ΠΙ and IV. The liver uptake in P L A - I O P A Ε microcapsule group was higher than I O P A Ε group. Similar results were shown in the P L A - D Z E microcapsule group and the D Z E group. A significant difference (P< 0.05) in percentage of injected dose per gram of liver between microcapsule groups and control groups within 5 hours was observed. The percentage of injected dose per liver at 20 min., 2, 5 and 24 hours for P L A - I O P A Ε and P L A - D Z E microcapsules is shown in Figure 6. 1 Ι-ΙΟΡΑ Ε and I - D Z E were recovered in the intestine and urine at 20 minutes postinjection. The findings suggest that I O P A Ε and D Z E released from P L A microcapsules were excreted through the gastrointestinal tract and kidneys. 131

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Table III. Tissue Distribution of I - D Z E in Rats 20 minutes 2 Hours 5 Hours 24 Hours 0.00 ± 0.00 0.00 ± 0.00 Ô.Ô0 ± 0.00 0.00 ± 0.00 0.13 ±0.09 0.02 ± 0.02 0.00 ± 0.00 0.00 ± 0.00 3.46 ± 0.79 1.86 ± 0.15 0.91 ± 0.17 0.00 ± 0.00 2.30 ± 0.78 0.72 ± 0.27 0.00 ± 0.00 0.08 ± 0.06 0.34 ± 0.04 0.00 ± 0.00 0.23 ± 0.01 0.11 ± 0.04 0.69 ± 0.24 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 1.39 ± 0.59 0.00 ± 0.00 3.36 ± 0.11 2.97 ± 0.77 *Data represents the % I N D / G (N=3 / time interval). 1 3 1

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Table IV. Tissue Distribution of P L A Encapsulated I - D Z E in Rats Organ 20 minutes 2 Hours 5 Hours 24 Hours 0.00 0.02 ± ± 0.00 0.05 ± 0.02 0.00 Blood 0.00 ± 0.00 0.18 ± 0.03 1.29 ± 0.24 2.62 ± 0.35 4.33 ± 0.94 Lung 0.15 ± 0.02 1.52 ± 0.32 3.69 ± 0.18 5.40 ± 0.29 Liver 0.12 ± 0.02 2.19 ± 1.36 7.66 ± 1.22 10.75 ± 2.62 Spleen 0.00 ± 0.00 0.17 ± 0.13 0.34 ± 0.03 0.45 ± 0.03 Kidney 0.00 ± 0.00 0.40 ± 0.07 0.37 ± 0.07 0.50 ± 0.08 Intestine 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 Bone 0.00 ± 0.00 0.00 ± 0.00 0.01 ± 0.01 0.00 ± 0.00 Thyroid 0.47 ± 0.12 3.22 ± 2.90 4.61 ± 0.19 1.43 ± 1.12 Urine *Data represents the % I N D / G (N=3 / time interval). 1 3 1


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PLA-DZE PLA-IOPA Ε DZE IOPA Ε SODIUM DZ

Time (Hours) Figure 6.

Liver Uptake of P L A Encapsulated Radiopaque Microcapsules

Summary Diatrizoate is a water-based ionic contrast agent. Iopanoic acid is an oral radiopaque medium for cholecystography and cholangiography. Approximately 50 percent of the injected dose is excreted within 24 hours and completely in about 5 days (76). Both contrast agents were formulated as microcapsules (0.5-3 μηι) for intravenous injection. U s i n g particulate contrast media for C T enhancement of the liver was reported (6,17,18). However, most studies show that the particles were quickly degraded into water-soluble material and eliminated from the body. B y using microencapsulation techniques, (1) the microcapsules produced sustained release properties in the liver, and (2) the administration route could be changed from oral to iv. Both P L A encapsulated D Z E and I O P A Ε microcapsules produced high uptake in liver compared to the other organs. In vivo microscopic studies demonstrated that both microcapsules were actively taken up by Kupffer cells. Because the Kupffer cells are generally not present in lesions, it is possible to produce a contrast density difference between normal liver tissue and abnormal hepatic focal lesions using the


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microencapsulation technique. The information obtained from this study should provide a basis for using microcapsules to improve detectability of hepatic tumors by CT. Acknowledgements The authors wish to thank Dianne Perez-Onuogu for her excellent help in typing this manuscript. This study is supported by George and Cleo Cook Fund and the John S. Dunn Foundation. Scanning electron microscope facility is supported by N I H Core Grant P30-CA16672.


Literature Cited

1. Bernardino, M.E. In Contrast Media: Biologic effect and Clinical Application; Parver, Z., Ed.; CRC Press: Cleveland, Ohio, 1987, pp 25-39. 2. Burgener, F.A; Hamlin, D.J. Am J Roentgenol 1983, 140, 291-296. 3. Lauteala, L.; Kormano, M.; Violante, M.R. InvestRadiol.1984, 19, 133-141. 4. Seltzer, S.E.; Davis, M.A.; Adams, D.F.; Shulkin, P.M.; Landis, W.J.; Harvon, A. Invest Radiol 1984, 19, 142-151. 5. Violante, M.R.; Fischer, H.W. In Contrast Media: Biologic effect and Clinical Application; Parver, Z., Ed.; CRC Press: Cleveland, Ohio, 1987, pp 89-103. 6. Violante, M.R.; Mare, K.; Fischer, H.W. InvestRadiol.1981, 16, 40-45. 7. Sands, M.S.; Violante, M.R.; Gadeholt, G. InvestRadiol.1987, 22, 408-416. 8. Conti, B.; Pavanetto, F.; Genta, I. J Microencapsulation 1992, 9, 153-166. 9. Bodmeier, R.; McGinity, J.W. Int J Pharm 1988, 43, 179-186. 10. Iwata, M.; McGinity, J.W. J. Microencapsulation 1992, 9, 201-214. 11. Jalil, R.; Nixon, J.R. J. Microencapsulation 1989, 6, 473-484. 12. Krause, H.J.; Schwarz, Α.; Rohdewald, P. Int J Pharm 1985, 27, 145-155. 13. Ogawa, Y.; Yamamoto, M.; Okada, H.; Yashiki, T.; Shimamoto, T. Chem. Pharm. Bull. 1988, 36, 1095-1103. 14. Spenlehauer, G.; Vert, M.; Benoit, J.P; Chabot, F.; Veillard, M. J Controlled Release 1988, 7, 217-229. 15. Wieland, D.M.; Kilbourn, M.R.; Yang, D.J.; Laborde, E.; Gildersleeve, D.L.; Van Dort, M.E.; Pirat, J-L; Ciliax, B.J.; Young, A.B. Int J Appl Radiat Isot 1988, 39, 1219-1225. 16. Mcevoy, G.K. AHES Drug Information; American Society of Hospital Pharmacists, Inc.: Bethesda, MD, 1992; pp 1440-1454. 17. Fischer, H.W. Invest Radiol, 1990, 25, 52-56. 18. Violante, M.R; Dean, P.B. Radiology, 1980, 134, 237-239. RECEIVED

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Encapsulated Radiopaque Microcapsules - American Chemical Society

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