Photodynamic therapy for intracranial neoplasms: investigations of photosensitizer uptake and distribution using indium-111 Photofrin-II single photon emission computed tomography scans in humans with intracranial neoplasms.

Photodynamic therapy is being investigated as an adjuvant treatment for intracranial neoplasms. The efficacy of this therapy is based on the uptake of photosensitizer by neoplastic tissue, its clearance from surrounding brain tissue, and the timing and placement of photoactivating sources. Photofrin-II is the photosensitizer most actively being investigated. We labeled Photofrin-II with Indium-111 and studied the uptake and distribution of this agent in 20 patients with intracranial neoplasms, using single photon emission computed tomography (SPECT) with volume rendering in three dimensions. Of these patients, 16 had malignant glial tumors, 2 had metastatic deposits, 1 had a chordoma, and 1 had a meningioma. Anatomical-spatial data correlated well between the SPECT images and contrast-enhanced computed tomography or magnetic resonance images. Regions of focal uptake on SPECT images correlated with the surgical histopathological findings of the neoplasm. The kinetics of photosensitizer uptake varied according to the tumor's histological findings, the patient's use of steroids, and among patients with similar types of tumor histology. Peak ratios of target-to-nontarget tissue varied from 24 to 72 hours after injection. The study data show that, to be most effective, photodynamic therapy may need to be tailored for each patient by correlating SPECT images with anatomical data produced by computed tomography or magnetic resonance images. Photoactivating sources then can be placed, using computer-assisted stereotactics, to activate a prescribed volume of photosensitized tumor at the optimal time for treatment.

Comparison of myocardial imaging with iodine-123-iodophenyl-9-methyl pentadecanoic acid and thallium-201-chloride for assessment of patients with exercise-induced myocardial ischemia.

Iodine-123-iodophenyl-9-methyl-pentadecanoic acid [( 123I]MPDA) and thallium-201 (201Tl) were sequentially injected in 11 patients during exercise-induced myocardial ischemia. Simultaneous dual-energy planar images were obtained at 5 min, 3 and 5 hr. All studies were concordantly either positive (8/11) or negative (3/11) by both radionuclides. Exact agreement for segmental uptake was 93%, 94% and 94% for 5-min, 3- and 5-hr images, respectively. Exact agreement for defect reversibility by 3 and 5 hr were 95% and 92%. The initial defect contrasts and myocardial-to-lung ratios were similar by both agents but myocardial-to-liver ratio was lower by [123I]MPDA at 5 min, which became similar to 201Tl at 5 hr. Normal percent myocardial clearances of both agents were comparable and significantly higher than those in defect zones. Thus [123I]MPDA is suitable for myocardial imaging and correlates closely with 201Tl for initial postexercise myocardial uptake and defect reversibility. Defect reversibility appears to result from differential myocardial clearance from normal and ischemic regions.

Indium-111-Photofrin-II scintillation scan.

Photodynamic therapy is under intense investigation as an adjuvant treatment for malignant glial tumors of the central nervous system. Photofrin-II (HpD-II) is currently the most actively investigated photosensitizing agent. A crucial issue regarding the safe and efficacious usage of HpD-II-based photodynamic therapy is the individual in vivo kinetics of tumor uptake and retention, compared with normal brain clearance. The optimal time for photoactivation of sensitized tumor must be known to ensure a high target-to-nontarget ratio, resulting in the maximal tumor destruction while preserving normal brain. Our laboratory developed a radionuclide scan based on 111indium (111In)-labeled HpD-II to evaluate HpD-II localization and clearance noninvasively within a canine model of intracerebral gliosarcoma. Synthesis of the 111In-HpD-II complex in greater than 90% yield is achieved by a simple, rapid labeling method. Radiochemical purity and stability were verified by high-performance liquid chromatography. Using the canine model of intracerebral gliosarcoma, we followed the uptake of 111In-HpD-II in tumors with serial scintillation scanning. Localization of the tumor by 111In-HpD-II has been verified by contrast-enhanced computed tomographic scan followed by gross and histological examination of the enhancing brain region. Total body biodistribution of 111In-HpD-II at various times after injection has been evaluated. The ratio of uptake in tumor compared with surrounding brain peaked at 72 hours after injection. The knowledge of regional distribution and concentration of a photosensitizing agent within a tumor mass and surrounding brain allows for the most efficacious timing and localization of a photoactivating source.

Biomaterial pretreatment with ECGF to augment endothelial cell proliferation.

ECGF, a polypeptide of bovine hypothalamic derivation, is the most potent endothelial cell mitogen known, with mitogenic and chemotactic effects well demonstrated in vitro on human endothelial cells. These effects are synergized by heparin. In vivo re-endothelialization of blood-contacting biomaterials may be enhanced by bonding ECGF and heparin to prosthetic surfaces. Long woven Dacron (24 mm) and woven PDS vascular prostheses were treated first with human plasma fibronectin (10 micrograms/cm2). Porcine sodium heparin (20 micrograms/cm2) was added by means of fibronectin's heparin affinity. Pure 125I-ECGF (95% alpha, 5% beta; 1 ng/cm2) was next fixed by the heparin affinity of ECGF and followed by a second heparin layer (20 micrograms/cm2) to synergize with and stabilize ECGF. 125I-ECGF adherences were determined by scintillation counts. Attachment efficiency averaged 25%. Prostheses were interposed into rabbit aortas and harvested in triplicate from 0 to 30 days to establish in vivo washout curves. After explantation, residual 125I-ECGF was eluted from prostheses, and intact ECGF was identified by SDS gel electrophoresis. Similarly prepared but nonradioiodinated Dacron and PDS prostheses were explanted after 7 days and their ECGF eluted off for in vitro activity documentation. This ECGF retained its mitogenic properties, causing a 1000% to 1200% increase in 3H-thymidine incorporation into newly synthesized DNA in test murine LE-II cells. Fibronectin-heparin-ECGF fixation to blood-contacting biomaterials may enhance spontaneous re-endothelialization and/or hasten the confluence of transplanted endothelial cells.

Preparation of 111In leukocytes after hemolytic removal of erythrocytes.

An optimized procedure is described for isolation and high-efficiency radiolabeling of leukocytes using 111In-oxine. The chief advantages over conventional methods include virtually no loss of leukocytes during washing and separation steps; a significant reduction in the time required to prepare leukocytes for radiolabeling compared to non-hemolytic preparations; a 28% increase in the average labeling efficiency obtained using 111In-oxine; greater than 95% cell viability as measured by the trypan blue exclusion test; elimination of contaminating red blood cells from the leukocyte pellet prior to labeling; and 80% survivability at 15 min post injection (measured as per cent of blood activity on leukocyte fraction).

Intracranial tumors: unexpected uptake of I-123 HIPDM.

I-123 HIPDM is a brain imaging agent thought to reflect cerebral cortical perfusion. Increased uptake of I-123 HIPDM occurred unexpectedly in two cases of intracranial tumors.

Work in progress: intra-arterial P-32 chromic phosphate for prevention of postoperative liver metastases in high-risk colorectal cancer patients.

Eight patients with locally extensive colorectal cancer were treated with colloidal P-32 chromic phosphate via the superior mesenteric artery following resection to prevent development of liver metastases. Less than 2% of the injected dose was found in the right atrial blood following the first pass through the liver and less than 1% in the urine. Therapy was tolerated well by all patients, with no acute complications. Long-term follow-up is needed to determine the effect of P-32 on the liver and the frequency of hepatic metastases.

A new method for radiolabeling of Gelfoam particles with 99mTc.

Embolization of the spleen and other organs using Gelfoam has recently gained acceptance as a therapeutic procedure. A simple non-invasive determination of the placement of Gelfoam particles is needed and this requires labeling Gelfoam with radionuclides. We have developed a simple, reliable reproducible, and inexpensive method of labeling Gelfoam with 99mTc using commercial sulfur colloid kits. Optimal reaction conditions include room temperature incubation for 60 min at 12 rpm rotation. In vitro stability indicated no loss of 99mTc activity up to 3 h post labeling. Imaging of intra-arterially placed 99mTc Gelfoam at 1 h and 24 h in animals and humans has consistently produced well-defined images of the radioemboli.

Technical parameters of in vivo red blood cell labeling with Technetium-99m.

The in vivo labeling of red blood cells (RBC) using sequential injections of stannous pyrophosphate and 99mTc-pertechnetate has resulted in excellent blood pool images since it was initiated in our laboratory in 1975. Recently certain technical parameters of the procedure have been further researched and clarified. The optimum RBC labeling has been obtained by using 1.43 mg "cold" Sn-PYP/1000 ml blood and a 30-minute lag time prior to pertechnetate injection (15-20 mCi). The binding of 99mTc to RBCs is not instantaneous, but requires several minutes for completion. The "secondary" RBC labeling effect of additional pertechnetate, added after the initial in vivo labeling, demonstrates an initial rapid fall in the labeling efficiency as a function of time followed by a more gradual decrease; the level of baseline (spontaneous) RBC labeling is achieved approximately 8 days after an initial in vivo labeling. Monitoring in vivo RBC labeling over several hours indicates that more than 90% of the initial activity was still in the vascular blood pool at 4 hours, bound to RBCs.

Biological distribution of chemical analogs of fatty acids and long chain hydrocarbons containing a strong chelating agent.

The pharmaceutical preparation, chromatography, and biological distribution of a series of new chemical analogs of palmitic acid and diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, or diethylenetriamine are described. The biological distribution in rabbits 30 min after intravenous administration of these 99mTc-labeled and 57Co-labeled derivatives was compared to the biological distribution of the parent compound, 3H-palmitic acid. The average myocardial uptake for these compounds was 0.04%/g, compared to 0.15%/g for palmitic acid. The heart to blood ratio at 30 min reached a maximum of 3:1 for the best physiological analog of palmitic acid, compared to an average of 30:1 for palmitic acid. Although none of these analogs appears to be clinically useful, their production methods might be applicable to the synthesis of new compounds that might increase the specificity of radiopharmaceuticals.

New compounds: fatty acid and long chain hydrocarbon derivatives containing a strong chelating agent.

Fatty acid and long chain hydrocarbon analogs that contain a strong chelating group were synthesized as part of an effort to determine if the biological function of the fatty acid can be used to transport metallic isotopes to the myocardium.