Radioimmunodetection of residual, recurrent or metastatic germ cell tumors using technetium-99 anti-(alpha-fetoprotein) Fab' fragment.

PURPOSE: The majority of patients with germ cell tumors are cured by multimodality therapy that consists of cisplatin-based chemotherapy and/or surgical resection. Serum tumor markers and conventional radiographs are utilized to stratify patients into treatment categories. Efforts to individualize chemotherapy or minimize surgical interventions without compromising outcome are important. Immunomedics (Morris Plains, New Jersey) developed an anti-(alpha-fetoprotein) (anti-AFP) monoclonal antibody IMMU-30 labeled with 15-20 mCi technetium-99, and the purpose of this study is to determine the sensitivity and specificity of radioimmunoscintigraphy using 99mTc anti-AFP antibody for the diagnosis of active germ cell tumors. METHODS: A group of patients with germ cell tumors were enrolled in a non-prospective fashion and 48 AFP scans using 99Tc anti-AFP Fab' fragment were obtained. At the time of the AFP scan, serum AFP was elevated in 40 measurements with a median level of 21 ng/ml (1.6-66, 210.0 ng/ml). AFP scans were obtained at the initial staging, during treatment, at relapse or at long-term follow-up and compared with conventional radiographs done within 4 weeks of the AFP scans. RESULTS: An overall diagnostic sensitivity of 89% and specificity of 58% were obtained. CONCLUSIONS: AFP scanning appears useful and to be sufficiently sensitive to justify prospective studies comparing the procedure with conventional imaging.

99mTc-labelled diphytanoylphosphatidylcholine liposomes: in vitro and in vivo studies.

The uniquely structured diphytanoylphosphatidylcholine (DphPC) forms liposomes more stable than conventional straight chain phospholipids. In this study DphPC and pegylated DphPC (DphPC-PEG) liposomes were radiolabelled and evaluated in vitro and in vivo. 99mTc-DphPC liposomes were found to be nontoxic to human white blood cells in vitro. In addition 99mTc labelled DphPC-PEG liposomes were evaluated as a nonspecific infection imaging agent in a mouse model. Infection sites were imaged within 30 min postinjection, and the radiopharmaceutical exhibited a remarkable in vivo stability. As their biodistribution and pharmacokinetic patterns can be size-modulated, DphPC-based lipsomes are excellent candidates for diagnostic and therapeutic applications.

99Tcm-IMMU4 imaging in recurrent colorectal cancer: efficacy and impact on surgical management.

The aims of this study were to evaluate the efficacy of scintigraphy with the 99Tcm-labelled anti-carcinoembryonic antigen (CEA) monoclonal antibody Fab' fragment (IMMU4) in the diagnosis of recurrent colorectal carcinoma and to investigate its usefulness in the intraoperative surgical management of patients undergoing re-operation because of a rising serum CEA. We evaluated 24 patients prospectively who had rising serum CEA 6-19 months after initial surgery for colorectal carcinoma. Ten patients had lesions confirmed by computed tomography, ultrasound, magnetic resonance imaging, endoscopic examination or barium enema. Fourteen patients had negative findings on one or more of the above studies, but were suspected of having occult disease from their rising serum CEA. All patients were scheduled for surgery for restaging during a "second look' procedure. Planar and single photon emission tomography (SPET) imaging was performed in all patients. All scintigraphic findings were correlated with surgical and histopathological results. The overall sensitivity, specificity and accuracy were 81, 90 and 86% respectively when analysed by lesion, and 95, 60 and 88% respectively when analysed by patient. Ten of 14 (71%) patients with occult disease were correctly diagnosed as having recurrent disease. The SPET images were shown to have superior detectability (80%) compared with the planar images (35%). The surgeon judged the study to have had a neutral impact in 75% of the patients, but to have been helpful in 25%. We conclude that this antibody is potentially useful in detecting recurrent colorectal carcinoma in patients with rising serum CEA, especially when conventional imaging is negative or equivocal. It can also be helpful in altering planned surgery.

Enhanced TAG-72 expression and tumor uptake of radiolabeled monoclonal antibody CC49 in metastatic breast cancer patients following alpha-interferon treatment.

The IFNs, alpha and gamma, have been shown to enhance the tumor-associated glycoprotein (TAG-72) on adenocarcinoma cells in vitro and in mice with human breast cancer xenografts, resulting in improved targeting of monoclonal antibody CC49. To determine the effect of IFN-alpha on biodistribution and tumor uptake of 131I-labeled CC49, patients with metastatic breast cancer were randomized to either receive or not receive IFN-alpha (3 million units daily for 14 days) by s.c. injection. Three days after beginning IFN-alpha, all patients received 10-20 mCi of 131I-CC49 (specific activity, 16.7 mCi/mg) i.v. Total-body Anger camera scans, along with total-body blood and plasma pharmacokinetics, were performed. Tumor biopsies were taken in all patients before and 48 h after IFN-alpha treatment. There were no significant differences in number of metastases imaged or whole-body, blood and plasma pharmacokinetics between IFN-alpha-treated and untreated patients. Quantitative immunohistochemistry on biopsy specimens from IFN-alpha-treated patients demonstrated a significant increase in mean +/- SEM TAG-72 expression (45.7 +/- 19.4%) compared to patients that were not given IFN-alpha (1.3 +/- 0.95%; P < 0.05). Although slight increases in the percent injected dose of 131I-CC49 in tumor occurred after IFN-alpha-treatment, the changes were not significant at the P < 0.05 level. These data suggest that IFN-alpha may be useful in enhancing TAG-72 antigen expression in vivo in humans, despite modest improvement in tumor uptake of CC49, possibly because of limited tumor access or other unknown factors.

Pharmacokinetics, dosimetry and toxicity of holmium-166-DOTMP for bone marrow ablation in multiple myeloma.

UNLABELLED: In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marrow transplantation received a bone-seeking radiopharmaceutical for bone marrow ablation. The pharmacokinetics, dosimetry, and toxicity of this radiopharmaceutical were studied. METHODS: Patients received from 519 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (166Ho) complexed with a bone-seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid). The reproducibility of pharmacokinetics from multiple injections of 166Ho-DOTMP administered to these myeloma patients was demonstrated from blood (r2 = 0.926) and whole-body retention (r2 = 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. RESULTS: Over 50% of the 166Ho-DOTMP injected dose was excreted within 2-3 hr postinjection, increasing to 75%-85% over a 24-hr period. Rapid blood clearance minimized radiation dose to nontarget tissue: less than 10% of the injected activity was retained in the blood pool at 1 hr postinjection, and less than 2% remained after 5 hr. The total radiation absorbed dose delivered to the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. CONCLUSION: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count < 1,000 cells/microliters, two patients exhibited marrow ablation (WBC count < 100 cells/microliters), and no other toxicity > or = grade 2 was observed in any of the patients.

Indium-111 labeled leukocytes in evaluation of active specific immunotherapy responses.

Active immunization of patients utilizing viral oncolysates (VO) has been studied in clinical trials. VO are extracts of cultured tumor cells that have been infected with certain types of viruses, particularly surface budding varieties. The objectives of the current studies were to examine the trafficking patterns of Indium (In)-111-labeled leukocytes or lymphocytes in two groups of patients with gynecologic malignancies to determine whether these cells migrate to sites of active immunization after VO. Eight patients with ovarian cancer received VO intraperitoneally followed by In-111-labeled leukocytes or lymphocytes (500 &mgr;Ci) intravenously. In a separate trial, three patients with cervical cancer received In-111-labeled lymphocytes after they had been treated with VO administered by the intralymphatic route. Gamma camera imaging was performed to evaluate the distribution patterns of the labeled cells at several time intervals after injection. Results indicate that metastatic tumor sites exposed to VO therapy show significant uptake of In-111 cells. These sites of malignancies were confirmed by computerized tomography and ultrasound scans. In patients with ovarian cancer no uptake of the radiolabeled cells was observed in metastatic tumors of the liver and lymph nodes. In patients with cervical cancer, lymph node metastases exposed to intralymphatic VO therapy were visualized very well. Other known tumor sites not exposed to VO therapy showed no uptake of radioactivity. These findings confirm that VO induces immune responses. This diagnostic nuclear medicine technique may prove to be a useful method for following-up responses to immunotherapy.

Active intralymphatic immunotherapy of uterine cervical carcinoma with viral oncolysate: a pilot study.

A pilot clinical trial was conducted in patients with squamous carcinoma of the uterine cervix to evaluate the clinical and biologic effects of active intralymphatic immunotherapy (AILI) with allogenic viral oncolysate (VO) prior to radiation therapy. Sixteen patients with advanced primary squamous carcinoma of the uterine cervix and lymph node metastases underwent bipedal intralymphatic injections of VO. VO was derived from lysates of cervical carcinoma cells that had been infected with influenza A virus. AILI was repeated after 2 weeks and followed one week later by standard or extended-field radiation therapy (RT). The first seven patients were treated at one of the three dose levels: 6 mg (three patients), 12 mg (three patients) and 18 mg (one patient). Remaining patients were treated at the 12 mg dose level. Sixteen patients received 63 injections (one patient received three of four doses) of AILI-VO without significant toxicity. Eleven patients have died of persistent or recurrent carcinoma with a total median survival of 19.4 months. Examination of humoral and cellular immunity during AILI-VO showed an increase in the serum liters of antibodies to a surface antigen on cervical carcinoma cells and to the influenza virus. Increased non-MHC restricted lymphocyte cytotoxicity was exhibited by three of four patients treated above the first dose level. Two of the three patients are survivors. By contrast, lymphocytes of patients treated with AILI-VO exhibited either an increase or a decrease in proliferation responses to cervical carcinoma cells. Similarly, post-treatment lymphocytes exhibited either helper or suppressor inducer effects on pre-treatment lymphocytes.

Phase II radioimmunotherapy trial with 131I-CC49 in colorectal cancer.

BACKGROUND: Radiolabeled CC49, a second generation high affinity monoclonal antibody (MoAb) reactive with tumor-associated glycoprotein 72 (TAG72) has undergone previous Phase I testing in patients with colon cancer. Based on this report, the authors treated 15 refractory metastatic colon cancer patients with 131I-CC49 to determine its overall toxicity and the response to therapy of patients treated with it. METHODS: Patients received 75 mCi/m2 131I-CC49 (20 mg MoAb) intravenously for a period of 30-60 minutes. Whole body retention was derived from the measured dose-rate of I-131 monitored daily at 1 m using an ion chamber. Two whole-body and static-gamma camera images were taken of patients on days 4 and 7 after the infusion. RESULTS: Nonhematologic toxicity (Grade 1-2) consisted of nausea (two patients), arthralgias (three patients), transient fever and chills (two patients), and transient blood pressure changes (two patients). At 4-5 weeks posttreatment, reversible Grade 3-4 thrombocytopenia was observed in 7 of 15 patients, and reversible Grade 3-4 granulocytopenia was observed in 6 of 15 patients. Twelve of 13 patients tested developed human anti-mouse antibody (range, 161 to > 20,000 ng/ml) at 6-8 weeks postinfusion. Mean +/- SD whole-body half-life (whole-body retention) of 131I-CC49 was 57.3 +/- 13.4 hours. Tumors were seen in all patients. In two of three patients treated a second time, an increased whole body clearance rate correlated with elevated human anti-mouse antibody, reduced uptake in tumor, and enhanced uptake in the thyroid. Estimated tumor doses ranged from 19-667 rads. Red marrow dose estimated from whole body retention ranged from 60 to 117 rads and correlated with decreases in platelet count. No objective tumor responses (i.e., partial or complete) were observed. CONCLUSIONS: Despite minimal toxicity and favorable tumor uptake, efficacy has been limited at this dose and schedule.

Comparative tumor localization of whole immunoglobulin G anticarcinoembryonic antigen monoclonal antibodies IMMU-4 and IMMU-4 F(ab')2 in colorectal cancer patients.

BACKGROUND: Previous studies in the literature have suggested that radiolabeled F(ab')2 fragments might be superior to whole immunoglobulin G (IgG) for imaging and therapy of cancer because of their greater penetration in tumors. To test this hypothesis, the authors compared tumor and normal tissue uptake along with plasma clearance of 125I-labeled monoclonal antibody (MoAb) IMMU-4 whole IgG with its 131I-labeled F(ab')2 fragment. METHODS: Five patients with either liver metastases from colorectal cancer (n = 4) or intact primary tumors (n = 1) received a combination of 125I-IMMU-4 IgG (2 mCi/1 mg) plus 131I-IMMU-4 F(ab')2 (10 mCi/1 mg) as a single 1-hour intravenous infusion on day 1. Serial blood samples were taken for up to 72 hours postinfusion to determine plasma clearance of each MoAb. On days 3-9, patients underwent exploratory laparotomy in which biopsies of tumor as well as normal tissues (liver, normal colon, lymph node, and blood) were obtained. Tissues were weighed and counted in a gamma counter, and the percent of injected dose per kilogram (%ID/kg) of each antibody, along with the radiolocalization index (RI), was computed (RI = %ID/kg tumor.%ID/kg normal tissue). RESULTS: Tumor uptake of both antibodies (2.3 +/- 0.53 %ID/kg) was significantly higher than that of normal tissues (0.56 +/- 0.12; P < 0.001), except for blood (2.8 +/- 0.83), resulting in an RI > or = 3. There were no significant differences in uptake (%ID/g) between F(ab')2 and IgG (F[ab']2 = 2.0 +/- 0.57; IgG = 2.6 +/- 0.94). The mean +/- SD of plasma T1/2 was slightly shorter for F(ab')2 (28.8 +/- 7.2 hours) than for IgG (45.9 +/- 16.7; P = 0.08). CONCLUSION: In short, the biodistribution and pharmacokinetics of IMMU-4 F(ab')2 were comparable to those of IMMU-4-IgG.

Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors.

PURPOSE: The purpose of this phase I trial was to determine the toxicity and maximum-tolerated dose (MTD) of murine monoclonal antibody (Mab) 14G2a (anti-GD2) in cancer patients. PATIENTS AND METHODS: Following tracer doses of iodine-131-labeled 14G2a to determine tumor uptake, 18 patients with refractory melanoma, neuroblastoma, or osteosarcoma received unlabeled 14G2a at total concentrations of 50, 100, and 200 mg/m2 administered as daily 24-hour infusions for 5 days. RESULTS: The overall sensitivity of external immunoscintigraphy was 64 of 74 known metastases (86%). Toxicity from prolonged infusion of 14G2a consisted of severe generalized pain, hyponatremia, fever, rash, paresthesias, weakness, and chronic refractory postural hypotension (two patients). Toxicity was less severe in pediatric patients. The MTD of Mab was 100 mg/m2. Sixteen of 18 patients developed human antimouse antibodies (HAMA) to 14G2a. Terminal-phase half-life (T1/2) of unlabeled Mab was 6.6 +/- 1.8 hours for patients receiving 50 mg/m2 and 39.5 +/- 13.3 hours at the 100-mg/m2 level. Tumor biopsies from six melanoma patients were positive for GD2 antigen, but only two of six had trace amounts of 14G2a present. Three mixed responses (two melanoma, one osteosarcoma) and two partial responses (PRs; neuroblastoma) were observed. CONCLUSION: Mab 14G2a has modest antitumor activity at the expense of significant toxicity. Dose-limiting neurologic sequelae may significantly limit phase II studies other than in pediatric patients with neuroblastoma.

Dosimetry and toxicity of samarium-153-EDTMP administered for bone pain due to skeletal metastases.

UNLABELLED: Palliation of bone pain in patients with cancer metastatic to bone is being evaluated in several cancer centers by the administration of the bone-seeking phosphonate ethylenediaminetetramethylenephosphonic acid (EDTMP) chelated with the beta particle-emitting radionuclide 153Sm. METHODS: In this study, 153Sm-EDTMP was intravenously injected into 19 patients over a 1-min period. Patients received up to four injections of 18.5 MBq (0.5 mCi) or 37 MBq (1.0 mCi) per kilogram of body weight. Skeletal retention was calculated from urinary excretion. RESULTS: No uptake of 153Sm-EDTMP in nonskeletal tissues was observed in whole-body gamma camera images. The mean skeletal uptake for all patients was 54% +/- 16% of the injected dose (%ID). This resulted in the bone marrow receiving 89 cGy/GBq +/- 27 cGy/GBq (3.28 cGy/mCi +/- 0.99 cGy/mCi), with calculated marrow doses ranging from 27 cGy to 338 cGy. For each patient, the estimated radiation absorbed dose to the marrow was correlated to the percent decrease in platelet number, ranging from 7.4% to 78.9%. CONCLUSION: Since the deviation of uptake between the four injections for a given patient (7.6% ID) was less than the deviation for all patients (16% ID), the initial dose may be used to estimate the skeletal uptake for the remaining doses. These radiation dose estimates permit patients at risk to be identified prior to reaching myelotoxicity and develop dose-response models. Thirteen patients (68%) reported significant pain relief from this radionuclide therapy. Bone pain appears to be alleviated by 153Sm-EDTMP with limited red marrow doses and no toxic effects in other organs.

Preliminary experimental evaluation of temporary segmental hepatic venous occlusion: angiographic, pathologic, and scintigraphic findings.

PURPOSE: Pigs were used to evaluate temporary segmental hepatic venous occlusion as a means of improving the selective delivery of therapeutic agents within the liver. MATERIALS AND METHODS: Hepatic angiography and scintigraphy were performed alone and in combination with hepatic venous occlusion. RESULTS: Arteriograms obtained during venous obstruction demonstrated a greater number of peripheral arterial branches in the occluded area compared with the nonoccluded areas. A prolonged hepatogram showing hepatofugal opacification of the portal branches was observed in the occluded area. Microscopically, mild congestion of the sinusoids and central veins was seen immediately after 60-minute occlusion, but these changes were not evident 2 hours after balloon deflation. Severe congestion and focal hemorrhage were found in the occluded segment of the liver 2 hours after 90-minute venous occlusion. When the right or left hepatic vein was occluded during hepatic arterial infusion of technetium-99m macroaggregated albumin, there was a significant (P < or = .05) increase in the amount of radioactivity measured in the obstructed segment and a significant (P < or = .05) decrease in that found in the nonoccluded regions. CONCLUSION: These results indicate that temporary segmental hepatic vein occlusion is safe for up to 60 minutes and may be clinically applicable as a means of improving the therapeutic index of agents within the liver when they are administered via concomitant hepatic arterial infusion.

Analysis of urine samples from metastatic bone cancer patients administered 153Sm-EDTMP.

153Sm-EDTMP is currently undergoing clinical evaluation as a radiotherapeutic agent for the relief of pain associated with cancer metastatic to bone. These clinical studies have demonstrated biodistributions similar to those seen earlier in animals, namely, rapid clearance from blood, selective uptake in bone and in particular metastatic bone lesions. The radioactivity not deposited in bone is cleared through the kidneys into the urine. In this study, urine samples collected from 9 patients injected with 153Sm-EDTMP underwent complexation analysis via Pharmacia SP-Sephadex C25 cation exchange chromatography. The results showed 96.9 +/- 1.7% of the radioactivity in the urine to be present as a complex of 153Sm. An HPLC method was developed and it was demonstrated that different complexes of 153Sm could be separated. A non-radioactive analytical standard of the Sm-EDTMP chelate was synthesized, characterized and shown to have the same HPLC retention profile as the 153Sm-EDTMP drug product. HPLC analysis was performed on six urine samples and in each case a single radioactivity peak with an elution profile the same as that of a 153Sm-EDTMP standard was observed. These results indicate that the 153Sm-EDTMP chelate is excreted intact in the urine of patients.

Use of 111In-labelling to follow tissue distribution of Candida albicans in mice.

Two strains of Candida albicans, a wild type and a derived mutant, were labelled with 111Inoxine. Labelled cells were injected into mice and tissue distribution patterns were determined from 0.5 to 48 h. During the first 4-h post-injection phase, remarkable differences in tissue distribution were observed between the two strains. Radiolabelling of C. albicans with 111Inoxine is shown to be a much more reliable method for determining early tissue distribution patterns in infected animal models than culturing the infected tissue.

Liposome distribution after intravenous and selective intraarterial infusion in dogs.

In an effort to improve hepatic uptake of liposomes for drug delivery, empty vesicles were administered by means of selective arterial infusion. Negatively charged, multilamellar liposomes were labeled with technetium-99m and infused into healthy adult dogs. Each dog received 100 mg/m2 of lipid over 10 minutes at 2 mL/min. Liposomes were administered via the common hepatic artery after proximal occlusion of the gastroduodenal artery, via the cranial mesenteric artery, and via the cephalic vein. Distribution (liver, spleen, and lungs) was determined by computer-assisted external imaging techniques. On the average, after arterial infusion, 69.2% of the total activity was located in the liver, 3.6% in the spleen, 3.2% in the lungs, and 3.5% in the general circulation. Following venous injection, 50.7% of the radioactivity was found in the liver, 9.1% in the spleen, 8.6% in the lungs, and 6.7% in the peripheral blood. Once the liposomes entered the systemic circulation, they were cleared at the same rate (half-life beta = 21.5 hours) independent of their route of administration. Increased hepatic liposome uptake should translate into higher local and lower systemic liposomal drug levels.

Localization of indium-111 leukocytes in noninfected neoplasms.

Indium-111-labeled autologous leukocyte studies in general carry a high sensitivity, specificity, and accuracy for the investigation of infections and abscesses. However, past studies have described sporadic cases in which 111In leukocytes localized in tumors. Our experience using 111In leukocytes for the investigation of fever of unknown origin in cancer patients, however, indicates a relatively high incidence of 111In leukocyte localization in noninfected neoplasms. Out of the 61 patients studied for fever of unknown origin, 21 patients (34%) manifested abnormal localization of 111In leukocytes in neoplasms without clinical evidence of infection. These included patients with abnormal localization in: (a) lymph nodes, (b) soft-tissue tumors, and (c) bone neoplasms. The tumors included both primary and secondary lesions, and hematologic as well as solid tumors. The mechanism of 111In leukocyte localization in tumors is still not completely explained. Interpretations of 111In leukocyte studies in cancer patients with fever should take into consideration the possibility that localization may occur in neoplastic tissue per se and does not always indicate the presence of infection.

Effects on the monocyte-macrophage system and antitumor activity against L1210 leukemia of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane -platinum (II) encapsulated in multilamellar vesicles.

Multilamellar vesicles (MLVs) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a molar ratio of 7:3 were used as carriers of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane-p latinum (II) (CPDP). The encapsulation efficiency of liposomal CPDP (L-CPDP) was 87.6%, and its stability in normal saline at 14 days was 94.4%. The in vitro and in vivo effects on the function of the monocyte-macrophage system and the antitumor activity against L1210 leukemia were investigated in CD-1 and (C57BL/6J X DBA/2J)F1 mice. L-CPDP and cisplatin (CDDP) caused a comparable inhibition of murine-resident peritoneal macrophage (PM) protein and RNA synthesis and superoxide anion release. PM-mediated tumor cell cytotoxicity was completely inhibited at a concentration of 10 micrograms CDDP and L-CPDP/ml but not at concentrations of 1 and 5 micrograms/ml. The differences in plasma clearance of 99mTc-labeled MLV and phagocytic capacity of the liver among animals pretreated with the maximum tolerated doses of L-CPDP (25 mg/kg), empty liposomes, or CDDP (10 mg/kg) were not statistically significant (plasma clearance % of control: 105, 110, and 100, respectively: P greater than .05; liver uptake % of control: 87, 96, and 104, respectively: P greater than .05). At the maximum tolerated doses, the antitumor activity of L-CPDP against L1210 leukemia was similar to that of CDDP when a single dose was administered [median survival of treated mice/median survival of control mice X 100 (%T/C): 181 vs. 175] and slightly higher with the use of a triple-dose schedule (%T/C: 275 vs. 225). L-CPDP is easy to prepare, has a high-encapsulation efficiency and stability, is not more toxic than CDDP to the monocyte-macrophage system, and is at least as effective as CDDP against L1210 leukemia.

Distribution of technetium-99m-labeled multilamellar liposomes in patients with Hodgkin's disease.

The distribution of 99mTc-labeled multilamellar liposomes composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a molar ratio of 7:3, administered intravenously, was studied in ten patients with Hodgkin's disease (HD). The dose of lipid was 150 mg/m2 and the mean dose of radioactivity injected per patient was 8.1 mCi (range 6.7-9.8). Whole-body imaging techniques were used, and for each organ an uptake index was calculated as the percent photographic density (PD) relative to the PD of the liver. Results were compared to those in a group of six patients with other malignancies. Increased liposome uptake in several skeletal areas was observed in one patient with HD with diffuse bone involvement and in the bone marrow of two patients with HD with bone marrow involvement. No definite liposome uptake was observed in lymph nodes involved by HD or in tumor areas of patients with other malignancies. Patients with HD had a significantly higher uptake by bone marrow (23.8% compared with 10.2% at 4 hr p = 0.02), and lungs (59.6% compared with 25.0% at 4 hr, p = 0.01) than patients with other malignancies. Among patients with HD, the uptake by bone marrow and lungs were higher in those with constitutional symptoms (bone marrow at 4 hr 31.4% compared with 16.2%, p = 0.02; lungs at 4 hr 68.8% compared with 50.4%, p = 0.19) and with liver involvement (bone marrow at 4 hr 30.8% compared with 16.8%, p = 0.03; lungs at 4 hr 73.6% compared with 45.6%, p = 0.03). These results suggest that patients with HD have a different pattern of distribution of multilamellar liposomes which may be related to a combination of nonspecific stimulation of the reticuloendothelial system and tumor uptake. It does not appear that liposomal 99mTc is capable of adequately imaging HD for clinical diagnosis.

Distribution of radiolabeled multilamellar liposomes injected intralymphatically and subcutaneously.

The distribution of negatively charged multilamellar vesicles (MLV) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol administered subcutaneously (s.c.) and intralymphatically (i.l.) was studied in rats and dogs. In rats, the drainage of 99mTc-MLV from the s.c. space was slow, with 35% of the activity still remaining at the site of injection after 48 h and minimal systemic distribution (less than 5% at any time point). In the dog, 99mTc-MLV and 111In-MLV injected s.c. on the dorsal surface of a hindpaw were drained both by the lymphatic system and the systemic circulation; at 24 and 72 h, significant activity still remained at the site of injection. Lymphatic uptake was almost limited to the popliteal nodes and was enhanced by dividing the dose in several s.c. injections. Liver and kidney uptake was also observed, most likely as a result of direct liposome absorption into the systemic circulation. The i.l. administration (via left hindpaw) of 99mTc-MLV to a dog resulted in an immediate uptake in the abdominal and mediastinal lymph nodes, and in the liver and spleen. Compared with small unilamellar vesicles, MLV injected s.c. can provide a slower and more prolonged delivery of drugs to the regional lymph nodes.