Targeted delivery of antineoplastic agent to bone: biodistribution studies of technetium-99m-labeled gem-bisphosphonate conjugate of methotrexate.

UNLABELLED: A methotrexate-bisphosphonate conjugate containing a peptide bond has been found to possess over five times greater antineoplastic activity against osteosarcoma in experimental animal models compared with methotrexate alone. METHODS: The conjugate was labeled with 99mTc in the presence of stannous ions to determine biologic distribution, with special reference to osseous tissue. Biodistribution studies were carried out in mice after intravenous administration of the labeled conjugate. Radionuclide imaging of rabbits was also performed. RESULTS: The labeled conjugate behaved like a bone-seeking agent. CONCLUSION: The present study indicates that the concept of treating osteosarcoma or metastatic tumors of bone with this class of agents has a firm basis.

Bone density variation within lumbar vertebrae in apparently normal women.

Using dual energy x-ray absorptiometry, lumbar bone mineral density was measured in 236 consecutive nonathletic white women of ages 36-85 years, who had been referred for evaluation of possible osteoporosis. Of these, 141 women had an average lumbar density of 100 +/- 15% of age, race, sex and weight matched normal adults. These apparently normal women were analyzed for the distribution of bone density values between lumbar vertebrae L2, L3 and L4. The difference between the highest and lowest lumbar vertebral density was determined, and expressed as a percent. Distribution of the density differences in this population was log-normal. A density difference of over 25% was found in 11% of the population, and its occurrence was age dependent. In the age group below 46 years, none exceeded the 25% difference value; in those over 75 years, 40% exceeded the 25% difference. For age groups between 46 and 75, the fraction of the population exceeding a 25% density difference increased linearly. A description of lumbar vertebral density values should include a statement of variation between the vertebrae.

Radiopharmaceuticals for palliation of metastatic osseous lesions: biologic and physical background.

The intimate admixing of bone matrix and bone marrow is a central point in devising therapy of metastatic lesions. Since specific modalities are not yet available for destroying the malignant cells, treatment is usually palliative. The use of stable gallium (Ga-nitrate) and of a diphosphonate (aminohydroxypropylidine diphosphonate disodium) as osteoclast inhibitors is discussed. The marrow, as well as the matrix, can be affected by external radiation. This is also true with bone-seeking radiopharmaceuticals. There is no ideal radiopharmaceutical available for treating metastases in bone, but the characteristics of several presently available (or proposed) are discussed, and possible use of tumor radiation sensitizers or bone marrow protectors is mentioned. Difficulties are also encountered in calculating accurate dosimetry. Clinical experience is needed to determine a reasonable optimal dose with any particular radiopharmaceutical for relief of pain with low bone marrow toxicity.

Assessment of bone remodeling in the temporomandibular joint by serial uptake measurement of technetium 99m-labeled methylene diphosphonate with a cadmium telluride probe.

Regional uptake of technetium 99m-labeled methylene diphosphonate was measured serially over time to follow the healing course of surgically generated lesions, induced unilaterally in the condyles of beagles. A small portable cadmium telluride probe was used for radiation detection, with and without a gold collimator attached. Radioactivity was measured at six periarticular sites on both the operated and the contralateral control sides and expressed as a ratio with respect to a reference site over the sagittal suture. The use of a collimator was crucial to separate the activity associated with bone mineralization in the condylar head from that arising in the adjoining bones. The uptake in the condylar region increased 2 weeks after surgery and remained at a constant level above the presurgery baseline (p less than 0.05) until termination of the study (10 weeks). Postmortem histologic examinations confirmed the high bone turnover level by revealing newly formed bone as well as the presence of osteoclasts. The time course of nuclide uptake in the temporomandibular joint is different from the general pattern of rise and fall of activity displayed in other bones and indicates the persistence of bone remodeling processes during a prolonged period of at least 10 weeks.

Studies on focal alveolar bone healing with technetium (Tc)-99m labeled methylene diphosphonate and gold-collimated cadmium telluride probe.

The benefit of using a collimator for a miniaturized cadmium telluride probe was evaluated by monitoring the bone-healing processes for 13 weeks after the induction of small iatrogenic alveolar bone lesions in one side of the mandible in beagles. Technetium (Tc)-99m labeled methylene diphosphonate (200 to 300 MBq, 5.1 to 8.1 mCi, in a solution of 0.5 to 1 ml, intravenously) was used as a bone-seeking radiopharmaceutical. The radioactivity over the bone lesion (L) and the contralateral normal site (C) in the mandible were measured between 1.5 and 2 hours after injection of the tracer, and the activity ratio L/C served as an index of relative bone uptake. A study of six dogs revealed that the healing response to a hemispheric bone defect of 2 mm diameter in the cortical bone could not be detected by an uncollimated probe, and in a repeated study in two dogs the use of a gold collimator (5 mm in diameter, 5 mm in length) did not increase the L/C ratio significantly. A second study in six dogs with 5 mm lesions showed that although systematic trends in the time courses of the L/C ratio obtained both with and without the collimator could be demonstrated, the L/C ratio of collimated versus uncollimated measurements was significantly (p less than 0.005) increased. In three of the latter six dogs, abscesses developed after 9 weeks, leading to a second increase (p less than 0.05) of the L/C ratio with collimation compared with the noninflammation group; without collimation no significant (p greater than 0.15) difference between the two groups could be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Radioiodination and biodistribution of analogs of a calichemicin constituent.

Analogs of the aromatic constituent of calichemicins were labeled with 131I by exchange reactions. Radiochemical yield for methyl-4-hydroxy-5-iodo-2,3-dimethoxy-6-methylbenzoate was approx. 90%. For methyl-4-benzyloxy-2-hydroxy-3-iodo-6-methylbenzoate the yield was about 30%. Biodistribution studies were carried out in mice following intravenous administration of tracer doses. Average brain uptake of the first compound at 3 min was 0.28%, and that of the second 1.96%. Tissue distribution of the two compounds elsewhere was similar in nature. High uptake was observed initially in the liver; this reduced with time, while radioactivity in the GI-tract increased. The benzylated compound appeared potentially useful for designing a brain imaging radiopharmaceutical.

Nuclear medicine studies of aging--VIII. Bone to soft-tissue ratio of 99mTc labeled MDP and HMDP vs age.

An objective approach to determine whether there was an advantage of using 99mTc-MDP or 99mTc-HMDP for bone imaging, particularly in elderly subjects, was evaluated by measuring the bone to soft-tissue ratio in relation to age. This was done by quantifying analog images of the femoral region by using an optical densitometer. A ratio (mean for right and left thighs) was determined for mid-femur to adjacent soft-tissue. These values were analyzed in relation to the age of patients studied with either MDP or HMDP. Little correlation with age was observed. An analysis at 10-year intervals of age indicated a decline in the ratio after 70 years, without any significant difference between MDP and HMDP.

Nuclear medicine studies of aging--IV. Femoral proximal to distal radionuclide uptake gradient.

Analyses of radionuclide bone scans were carried out to determine if, with the aging process, there were measurable changes in the femoral gradient of activity from proximal to distal portions of bone. Images of the femoral region were obtained using a gamma camera 2-3 h after i.v. administration of 99mTc labeled MDP. Sixty patients (1-85 years old) were selected based on the criteria that their femoral images appeared normal and there was no history of limb disease. Radionuclide concentrations at the upper, middle, and lower regions of the femur were determined from the femoral scans by using an optical densitometer, and background corrected. Results were expressed as ratios of upper to middle, lower to middle, and upper to lower regions of the femur. The analysis showed that the lower to middle ratio declined with age.

Nuclear medicine studies of aging--III. Radial bone mineral content by single and dual photon absorptiometry.

Measurement of bone mineral content of the radius has been possible by single photon absorptiometry. Recently, dual photon devices have become widely used for measuring the quantity of lumbar vertebral bone mineral. Therefore, we studied the utility of a dual beam machine for quantifying the bone mineral content of the radius, and compared results with those obtained by single photon absorptiometry in the same patient on the same day. There was an excellent correlation between single and dual beam measurements of the radius. The present study indicates that a dual photon machine can be used for assessing not only vertebral, but radial bone mineral content as well. This may facilitate studies of the two sites by use of one machine.

Technetium-99m-labeled phosphonic acid analog of serine: bone uptake.

A phosphonic acid analog of serine (PAAS), its P-methyl derivative, and an allied compound were labeled with 99mTc, and evaluated in experimental animals. These molecules were able to bind 99mTc in the presence of stannous ions, but the biologic behavior of the later two labeled compounds was quite different from that of the first one. Technetium-99m-labeled PAAS behaved like 99mTc-labeled methylene diphosphonate, but its P-methyl derivative and the third agent showed little bone accumulation. It appears that both hydroxyl groups attached to the phosphorus atom are essential for uptake in bone, but that only one is required for binding 99mTc.

Breast milk content of 131I in a hypothyroid patient.

An oral dose of 185 MBq of 131I (sodium iodide) was administered to a lactating mother for whole body scanning. Breast milk was collected at several points in time, and assayed for radioactivity. The radioiodine concentration in the milk was found to be 4 MBq/dL at 6 h (about 2% of the dose). The radioactivity in breast milk decreased with a biological half-life of about 15 h in this hypothyroid patient. Following ingestion of radioiodide (such as [131I]sodium iodide), the appearance of radiolabel in breast secretion has been well documented. However, data do not appear in the literature on this process in the grossly hypothyroid state. We, therefore, are reporting our experience with such a situation.

Comparison of biodistribution of 3H, 32P and 99mTc labeled Gpp(NH)p in tumor bearing hamsters.

Biodistribution and tumor uptake studies were carried out with intravenously injected tracer doses of Gpp(NH)p labeled with 3H, 32P or 99mTc . Syrian golden hamsters with cheek pouch carcinomas, induced by repeated topical applications of DMBA, were used as a tumor model. The biodistributions of these three radionuclides were different, indicating significant molecular cleavage of this nucleotide analog. It was also apparent that this compound labeled with 99mTc may not be useful for tumor imaging due to low tumor-to-blood specific activity ratio. The cheek pouch carcinoma tumor model may be valuable for the evaluation of tumor localizing radiopharmaceuticals.

Synthesis and biodistribution of radioarsenic labeled dimethylarsinothiols: derivatives of penicillamine and mercaptoethanol.

Arsenic analogs of sulfhydryl containing biomolecules can be derived from dimethylchloroarsine as a precursor. Arsenic-76 labeled dimethylarsinothiols (dimethylarsinopenicillamine and dimethylarsinomercaptoethanol) were synthesized, purified by chromatography, and their biodistributions obtained in mice. The present study demonstrates the possibility of developing a group of radioarsenicals from SH-containing biomolecules.