Role of Lipid-Soluble Complexes in Targeted Tumor Therapy

Role of Lipid-Soluble Complexes in Targeted Tumor Therapy

Mathew L. Thakur, PhD¹^,2, Ron Coss, PhD², Roger Howell, PhD³, Donka Vassileva-Belnikolovska, MD⁴, Jeff Liu, BS¹, Sampath P. Rao, PhD¹, Greg Spana, BS¹, Phyllis Wachsberger, PhD² and Dennis L. Leeper, PhD²

¹ Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
² Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
³ University of Medicine and Dentistry of New Jersey, Newark, New Jersey
⁴ National Center of Clinical and Transfusional Haematology, Sofia, Bulgaria

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FIGURE 1. Autoradiographic presentation of DU145 tumor cells labeled with ¹¹¹In-oxine. Cells were labeled in HEPES buffer, washed, spread on collagen-plated glass slides, autoradiographed using Kodak emulsion, and photographed. Intensely labeled cells are seen.

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FIGURE 2. Composite of stained gel (left) and gel that was autoradiographed (right). Major portion of radioactivity (right) was associated with 3 protein bands of apparent molecular weights >250, 22, and 6 kDa. Irrespective of different time periods for which ¹¹¹In remained in cells (2, 24, or 48 h), neither distribution nor portion of ¹¹¹In bound to proteins was changed.

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FIGURE 3. (A) Schematic diagram of tumor, needle, and sections of tumors cut in perpendicular to path of needle. Two autoradiographs show 2 separate 20-µm-thick sections of tumor into which ¹¹¹In was injected through sprinkler needle (D) and that of tumor that was injected with regular needle (C). Tumor injected with sprinkler needle has spread over larger portion of tumor than that injected with regular needle. Because of tumor necrosis (B), even with sprinkler needle, ¹¹¹In uptake in tumor is patchy and there is no ¹¹¹In in center. Necrotic tissue can be seen (lightly stained part) in histologic section of tumor (B).

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FIGURE 4. Tumor growth (diameter) as function of time in days after 2 groups of mice bearing experimental human prostate cancer DU145 each received $~$ 16.7 MBq ( $~$ 450 µCi) ¹¹¹In-oxine and other group, also bearing tumor, received only 10% EtOH solution in 0.9% NaCl. Dose received by tumors was $~$ 42 Gy ( $~$ 4,200 rad).

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FIGURE 5. Composite of posterior images of 2 nude mice bearing human prostate tumor DU145. Twenty days earlier, mouse at left was given 12.6 MBq (340 µCi) ¹¹¹In-oxine and mouse on right was given 16.7 MBq (450 µCi) ¹¹¹In-Merc. Images show that >90% of ¹¹¹In is still in tumor (intense white spot). In either case, tumor size had not increased. At sacrifice, 93% of ¹¹¹In was still associated with tumor, $~$ 2% was in kidneys, and 2% in liver. Remaining 2% was in carcass. Total amount of ¹¹¹In (corrected to decay) remaining in mice was 85% ± 3% of activity injected. Dose received by these tumors was estimated to be $~$ 32 Gy ( $~$ 3,200 rad) and $~$ 42 Gy (4,200 rad), respectively. (Note that because of low resolution of gamma camera, it appears in these images that ¹¹¹In is homogeneously spread in tumor, including that in necrotic portion of tumor. In autoradiographs, Fig. 3, better resolution is achieved and absence of ¹¹¹In in necrotic area is visible.).

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FIGURE 6. Absorbed dose as function of radial position r in 1-g tumor (diameter, 1.24 cm) containing 37 MBq (1 mCi) of uniformly distributed ¹¹¹In (thin solid line). Bold vertical lines denote boundaries between tumor (-0.62 < r < 62 cm) and normal tissue (-1.5 < r < -0.62 and 0.62 < r < 1.5 cm). Note precipitous drop in absorbed dose as one moves from tumor to normal tissue. Calculations were performed using methods described by Howell et al. (34). Also shown are dose profiles for ¹⁷⁷Lu (bold solid line) and ⁹⁰Y (dashed line). Profiles for these radionuclides correspond to injected activities (4.67 MBq [0.126 mCi] and 2.22 MBq [0.060 mCi], respectively) that deliver, on complete decay, same dose to center of tumor as 37 MBq (1 mCi) ¹¹¹In (96.2 Gy [9,620 rad]).