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99mTc-Diethylenetriaminepentaacetic acid-mannosyl-dextran

99mTc-DTPA-Mannosyl-dextran

, PhD, , PhD, , MD, FACS, , MD, , MD, and , PhD.

Author Information
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
, PhD
Department of Radiology, School of Medicine, University of California, San Diego, CA, Corresponding Author
, MD, FACS
Department of Surgery, School of Medicine, University of California, San Diego, CA
, MD
Department of Radiology, School of Medicine, University of California, San Diego, CA
, MD
Department of Medicine, School of Medicine, University of California, San Diego, CA
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: March 2, 2011.

Chemical name:99mTc-Diethylenetriaminepentaacetic acid-mannosyl-dextranImage Lymphoseek.jpg
Abbreviated name:99mTc-DTPA-mannosyl-dextran
Synonym:Lymphoseek™, 99mTc-mannosyl-dextran, 99mTc-tilmanocept
Agent category:Compound: dextran polysaccharide
Target:Macrophage mannose receptors (MRCs) or mannose binding protein (MBP), or CD206
Target category:Receptor
Method of detection:Gamma planar imaging, single-photon emission computed tomography, SPECT, intra-operative gamma detection
Source of signal/contrast:99mTc
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
  • Checkbox Humans
99mTc-DTPA-mannosyl-dextran structure.
.

Background

[PubMed]

99mTc-Diethylenetriaminepentaacetic-mannosyl-dextran (99mTc-DTPA-mannosyl-dextran) is a 99mTc-labeled molecular imaging agent designed for sentinel lymph node (SLN) detection and mapping with a gamma-detecting probe or gamma imaging (1-6). 99mTc-DTPA-Mannosyl-dextran binds specifically to the macrophage mannose (mannose-fucose) receptors (MRCs) or mannose binding protein (MBP). It is currently an investigational agent developed for intraoperative lymphatic mapping. 99mTc is a gamma radionuclide with a physical half-life (t½) of 6.01 h.

The primary function of the lymphatic system is to drain ~10% of the interstitial fluid from small capillaries to lymphatic vessels through lymph nodes and finally to the venous system (2, 7-10). Lymph nodes form a natural filter for the lymphatic drainage and prevent the possible migration of cancer cells from the lymphatic system into the body. As the first lymph node that receives lymph drainage from a tumor bed, the SLN is very likely to contain cancer cells if the primary tumor has spread via the lymphatics (1, 2). Because lymphatic drainage may be directed to more than one lymph node, accurate identification and mapping of SLN is critically important. This observation has formed the basis of the sentinel node concept and the clinical applications of SLN mapping that have been applied to staging, management, and treatment of cancer (3, 5). Successful applications of SLN mapping have been reported in patients with melanomas, breast cancers, and some other cancers (1-3). Injection of isosulfan blue dye and 99mTc-sulfur colloid (99mTc-SC) near the tumor have been the two primary methods of SLN mapping (8).

The lymphatic system is complex, and its detection and mapping remain challenging (7, 8, 11, 12). However, with advances of new imaging agents and techniques, imaging and mapping of both the lymphatic vessels and the lymph nodes are now possible with x-ray–computed tomography, ultrasound, nuclear medicine, and magnetic resonance imaging (12-14). Most conventional SLN imaging agents, such as filtered 99mTc-SC or 99mTc-albumin nanocolloids, are nonspecific particles or macromolecules, and they work by passive diffusion to follow the lymphatic drainage after injection around the tumor and accumulate within the lymph node by phagocytes (2, 15, 16). They generally lack the ideal imaging properties of rapid injection-site clearance and high SLN extraction (2, 16). Molecular imaging of the lymphovascular system is possible with the development of agents designed for specific molecular targets (1, 12). Vera et al. (2) first reported the synthesis of 99mTc-DTPA-mannosyl-dextran, which is designed to bind to MRCs within the lymphoid tissues for SN imaging. The MRC is a165-kD membrane glycoprotein, and MRC belongs to the C-type lectin superfamily (1, 6). They are involved in mediating phagocytosis of microbes and intracellular killing mechanisms (17). Lymphoid tissues contain macrophages, and lymph nodes become enlarged from the accumulation of macrophages. 99mTc-DTPA-Mannosyl-dextran consists of a clinical grade dextran, a polysaccharide backbone with an average molecular weight of 9,500 (2, 9, 18). The molecule contains 55 mannose glycosides for ultrahigh-affinity binding to MRCs, and 8 DTPA for 99mTc chelation. Vera et al. (2) suggested that the resulting linear molecule with a diameter of 7.1 nm would be an ideal size to promote injection site clearance.

Synthesis

[PubMed]

Vera et al. (2) reported the synthesis of 99mTc-DTPA-mannosyl-dextran using the commercially available dextran C10, a clinical grade dextran with a mean molecular weight of 9,500 g/mol. Amino-terminated leashes were first covalently attached to the hydroxyl units of dextran by a two-step process to prevent cross-linking. In the first step, the dextran hydroxyl units were activated with allyl bromine in the presence of sodium hydroxide and sodium borohydride at 50ºC (pH 11). In the second step, the resulting allyl-dextran was reacted with aminoethanethiol in dimethylsulfoxide in the presence of ammonium persulfate at 50ºC to produce an amino-terminated dextran. The mixed anhydride method (19) was used to conjugate DTPA to dextran by activating DTPA first with isobutylchloroformate in acetonitrile at –30ºC. The activated DTPA was then added to the amino-terminated dextran in bicarbonate buffer (pH 9). The mixture was stirred overnight at room temperature, and DTPA-dextran was obtained after diafiltration. DTPA-Dextran was conjugated with mannose by imidate coupling (20). In this procedure, cyanomethyl-2,3,4,6-tetra-O-acetyl-1-thio-β-d-mannoside was first deacetylated with sodium methoxide in methanol. After removal of methanol, DTPA-dextran in Clark’s borate buffer (pH 9.0) was added and reacted at room temperature for 2 h. DTPA-Mannosyl-dextran was purified by ultrafiltration and dialysis. The molecular mass was determined to be 35,800 g/mol, and the molecular diameter determined by dynamic light scattering was 7.1 ± 0.9 nm. The amino, mannose, and DTPA densities were determined to be 23, 55, and 8 mol/dextran, respectively. 99mTc-Labeling of DTPA-mannosyl-dextran was performed by the tin reduction method. 99mTc-Pertechnetate was added to DTPA-mannosyl-dextran, and the reaction vial was purged with nitrogen for 10 min. Ascorbic acid (0.5 μmol/ml) and acidified tin chloride solution were added, and the reaction mixture was incubated at room temperature for 1 h. 99mTc-DTPA-Mannosyl-dextran was purified by size-exclusion chromatography for in vitro binding studies and biodistribution studies. Radiochemical yield was >98%, and the specific activity was 74 × 106 GBq/mol (2 × 106 Ci/mol).

Hoh et al. (9) described a two-component kit for preparing 99mTc-DTPA-mannosyl-dextran in phase I clinical trial studies. The labeling component consisted of 50 nmol DTPA-mannosyl-dextran, 55 nmol tin chloride, and 250 nmol ascorbic acid. The diluent component was sodium phosphate–buffered saline solution. These components could be stored at 5ºC for >6 months. For radiolabeling, 93–930 MBq (2.5–25 mCi) sodium pertechnetate 99mTc was added to the labeling vial and incubated at room temperature for 30 min. After filtration and proper dilution with phosphate-buffered saline from the diluent component, 2.5 nmol/ml 99mTc-DTPA-mannosyl-dextran was ready for use. The radiochemical yields were >98%. Wallace et al. (6) reported their preparations of 99mTc-DTPA-mannosyl-dextran to have an average molecular mass of 28,200 g/mol, and the average DTPA and mannose densities were 2.1 and 42 mol/dextran, respectively. The mean molecular diameter was 7.1 nm. The radiochemical purity was 97.7–99.2% (n = 12).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In an in vitro micronucleus study with bacteria, 99mTc-DTPA-mannosyl-dextran demonstrated to have no mutagenic potential (21). This was confirmed by a negative bacterial reverse mutation assay. The in vitro stability of 99mTc-DTPA-mannosyl-dextran was measured by gel chromatography and instant thin-layer chromatography (2). 99mTc-DTPA-Mannosyl-dextran was stable for at least 6 h in phosphate-buffered saline (pH 7.2). An in vitro binding assay of 99mTc-DTPA-mannosyl-dextran was conducted in homogenized rabbit liver tissue on the basis of evidence that MRCs had equivalent affinities for liver and lymph node binding (14, 15). The equilibrium dissociation constant (Kd) was determined to be 0.12 ± 0.07 nM. Hoh et al. (9) reported that the unlabeled DTPA-mannosyl-dextran in saline (0.88 nM) was stable at room temperature for at least 8 days.

Animal Studies

Rodents

[PubMed]

Phase I preclinical acute toxicity studies were performed in rats (n = 5) of both sexes (9). Each rat received a single dose into the right hind footpad and was observed for 14 d. The low-dose group received 0.7 nmol/kg and the high-dose group received 7.0 nmol/kg. No evidence of significant physical, hematological, or histopathological toxicity was found with either group. In a repeat-dose study in rats, subcutaneous injection revealed no clinical abnormalities and no changes in body weight, food intake, physical and ophthalmic examination, urinalysis, or gross and histopathology with a 99mTc-DTPA-mannosyl-dextran dose up to 2.5 nmol/kg per day when consecutively administered for 14 days (21). In a lymphoma mutagenesis assay in mice with or without Aroclor-induced rat liver S9 activation, no mutagenic potential could be shown for 99mTc-DTPA-mannosyl-dextran (21). A mouse micronucleus study was concluded to be negative based on the results that there was no significant increase in incidence of micronucleated polychromatic erythrocytes in mice that received 99mTc-DTPA-mannosyl-dextran doses up to 0.12 mmol/kg (21).

Other Non-Primate Mammals

[PubMed]

In an acute toxicity study conducted in rabbits, subcutaneous injection of 99mTc-DTPA-mannosyl-dextran at doses up to 7.0 nmol/kg had no effect on survival, clinical observations, body weight, or gross and histopathology (21). In all treated rabbits, eight out of ten male rabbits, and one control male rabbit, mild centrolobular hepatocytic hypertrophy was noted microscopically. In the study of perivascular irritation in rabbits, intramuscular injection of 99mTc-DTPA-mannosyl-dextran at doses up to 14.3 nmol/kg had no significant clinical effects on survival, clinical observations including the injection site, or histopathology of the injection site (21). In another sensitization study in guinea pigs, an intravenous injection of 99mTc-DTPA-mannosyl-dextran at doses up to 17 nmol/kg did not induce any anaphylactic reactions in the guinea pigs (21). No effects were observed on mortality, clinical and cage side observations, and body weight.

In an acute toxicity study in dogs, subcutaneous injection of 99mTc-DTPA-mannosyl-dextran at doses up to 25 nmol/kg had no effect on mortality, clinical observations, body weight, food intake, or gross and histopathology (21). Mild inflammatory reaction was observed, consistent with a foreign material response by the host, rather than a direct toxic effect of 99mTc-DTPA-mannosyl-dextran. When 99mTc-DTPA-mannosyl-dextran was administered subcutaneously at doses up to 2.5 nmol/kg per day consecutively for 14 days, no clinical abnormalities and no changes in body weight, food intake, physical and ophthalmic examination, urinalysis, or gross and histopathology. There were no effects no hematologic and cardiovascular parameters. In a cardiac safety pharmacology study, i.v. injection of 99mTc-DTPA-mannosyl-dextran up to 50 nmol/kg had no effect on blood pressure, heart rate, EKG, body temperature, or plasma histamine and thromboxane B2 levels (21). There were also no effects noted on mortality, clinical observations, or body weight.

Vera et al. (2) conducted lymph node uptake studies of 99mTc-DTPA-mannosyl-dextran in rabbits. Each rabbit received ~3.7 MBq (0.1 mCi) or 0.22 nmol of 99mTc-DTPA-mannosyl-dextran on their four footpads. 99mTc-DTPA-Mannosyl-dextran appeared to have significantly faster injection-site clearance than filtered 99mTc-SC.The radioactivity levels expressed in percentage injected dose for the popliteal lymph nodes (%IDpopliteal) were 6.1 ± 4.5 and 6.1 ± 5.5 at 1 h and 3 h, respectively. The popliteal extraction (%IDpopliteal – %IDiliac) × 100/%IDpopliteal) values were 90.1 ± 10.7% and 97.7 ± 2.0% at 1 h and 3 h, respectively. In comparison, the filtered 99mTc-SC had %IDpopliteal values of 4.8 ± 1.5 and 6.0 ± 3.3 at 1 h and 3 h, respectively. The popliteal extractions of filtered 99mTc-SC were 78.8 ± 6.5% and 67.4 ± 26.8%, respectively.

In a preclinical study of 99mTc-DTPA-mannosyl-dextran in normal rabbits, the biodistribution pattern of 99mTc-DTPA-mannosyl-dextran was studied with a dose of 0.1 nmol/0.05 ml in rear right footpad injection (9). The radioactivity levels (% ID) in the right rear paw (n = 3–4) were 82.7 ± 0.06 (0.25 h), 60.1 ± 0.09 (1 h), and 38.4 ± 0.31 (3 h). The injection site exhibited a biological t½ of 2.21 ± 0.27 h. The radioactivity levels (% ID) in the right popliteal lymph nodes were 1.67 ± 0.72 (0.25 h), 1.77 ± 0.54 (1 h), and 1.04 ± 0.47 (3 h). The radioactivity levels (% ID/g) in the blood were 0.015 ± 0.53 (0.25 h), 20.3 ± 0.12 (1 h), and 7.87 ± 0.17 (3 h). The radioactivity levels (% ID/g) in the liver were 0.004 ± 0.22 (0.25 h), 0.012 ± 0.16 (1 h), and 0.013 ± 0.32 (3 h). The radioactivity levels (% ID/g) in the kidneys were 0.032 ± 0.15 (0.25 h), 0.40 ± 0.34 (1 h), and 0.51 ± 0.15 (3 h). Most other organs exhibited <1% ID at all time points. Phase I preclinical toxicity studies were performed in rabbits (n = 5) of both sexes (9). Each rabbit received a single dose in the right hind footpad and was observed for 14 d. The low-dose group received 0.7 nmol/kg and the high-dose group received 7.0 nmol/kg. Although no evidence of significant physical, hematological, or histopathological toxicity was found in either group, a minimal to mild hepatocytic hypertrophy was microscopically observed. The irritant potential of a single intramuscular dose of 99mTc-DTPA-mannosyl-dextran was also tested in rabbits with doses of 7.15 or 14.3 nmol/kg (100 and 1,000 times the scaled human dose) (9). No effect was observed on survival or injection-site histopathology. Acute cardiovascular pharmacological effects in four dogs with a single i.v. dose of 28 nmol/kg showed no significant effect on survival, electrocardiogram, or blood pressure (9). Both thromboxane B2 and histamine levels did temporarily increase.

Mendez et al. (22) studied detection of gastric and colonic SLN by endoscopic administration of 99mTc-DTPA-mannosyl-dextran in four pigs. 99mTc-DTPA-Mannosyl-dextran demonstrated high radioactivity levels in SLNs and their uptake was in concordance with SLN staining with the isosulfan blue dye. Similarly, Ellner et al. (23) studied SLN mapping of the colon and stomach in eight pigs. The mean clearance of 99mTc-DTPA-mannosyl-dextran was faster, but the mean SLN radioactivity level was similar to that of filtered 99mTc-SC. Wallace et al. (5) studied colon SLN mapping with 99mTc-DTPA-mannosyl-dextran and a gamma-detecting probe in eight pigs. They reported a signal/background (S/B) ratio that ranged from 38 to 315, and all identified SNs were confirmed by blue dye. In a similar study, Salem et al. (10) studied prostate SLN mapping with a gamma probe in 12 pigs; the mean S/B was 449 ± 531, and the radioactivity level was 1.74 ± 1.92% ID/g after 5–19 min.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

In a dose-dependent study, groups of six breast cancer patients received 0.2, 1.0, or 5.0 nmol of 99mTc-DTPA-mannosyl-dextran (24). There appeared to be a dose-dependent radioactivity uptake, and the 5-nmol dose was the saturation dose. No clinically significant alterations in serum chemistry, hematology, or urinalysis parameters were observed for all three doses. The absorbed radiation doses to the injected breast (critical organ) were calculated to be 8.0 × 10–2 mGy/MBq (2.96 × 102 mrad/mCi), 8.0 × 10–2 mGy/MBq (2.96 × 102 mrad/mCi), and 1.0 × 10–1 mGy/MBq (3.70 × 102 mrad/mCi) for the doses of 0.2 nmol, 1.0 nmol, and 5.0 nmol, respectively. The effective doses were 1.3 × 10–2 mSv/MBq (48.1 mrem/mCi), 1.0 × 10–2 mSv/MBq (37.0 mrem/mCi), and 1.7 × 10–2 mSv/MBq (62.9 mrem/mCi) for the doses of 0.2 nmol, 1.0 nmol, and 5.0 nmol, respectively.

In a phase I clinical trial, 20 women with breast cancer received peritumoral/subdermal injections of 18.5 MBq (0.5 mCi) or 0.25 nmol 99mTc-DTPA-mannosyl-dextran or filtered 99mTc-SC (6). The injections were made in four doses of 4.6 MBq (0.125 mCi) at the 3-, 6-, 9-, and 12-o’clock positions surrounding the breast lesion. Gamma imaging was performed at 15-min intervals for 1 h, and then at 2 and 3 h after injection. SLN biopsy using a gamma probe was performed with the standard technique. The mean injection-site clearance rate constant (kc) and clearance t½ (t½c) were 0.255 ± 0.147 h–1 (n = 6) and 2.72 ± 1.57 h, respectively. In comparison, filtered 99mTc-SC had a mean kc of 0.014 ± 0.018 h–1 and t½c of 49.5 ± 38.5 h. The radioactivity levels (% ID) of 99mTc-DTPA-mannosyl-dextran at the site of injection and at SLN were 26.6 ± 16.8 and 0.55 ± 0.43, respectively. For filtered 99mTc-SC, these values were 94.9 ± 15.7% ID and 0.65 ± 0.63% ID, respectively. 99mTc-DTPA-Mannosyl-dextran had detected a mean of 1.3 SLNs/study, whereas filtered 99mTc-SC detected a mean of 1.7 SLNs/study. However, 99mTc-DTPA-mannosyl-dextran had an 86% concordance with the blue dye in detecting primary SLN, whereas 99mTc-SC had a 64% concordance. In another phase I trial with 10 breast cancer patients, 5 patients received a single intradermal administration of 1.0 nmol (0.1 ml) 99mTc-DTPA-mannosyl-dextran above the tumor, and 5 patients received filtered 99mTc-SC (3). Similar site clearance and SLN uptake of both radiotracers were found as reported previously by Wallace et al. (6). However, 99mTc-DTPA-mannosyl-dextran detected an average of 2.2 SLN/study, which was comparable to the average of 2.3 SLN/study for the filtered 99mTc-SC. In a later study with 11 breast cancer patients with a single intradermal injection of ~37 MBq (1 mCi) 99mTc-DTPA-mannosyl-dextran or unfiltered 99mTc-SC using a “2-day” protocol for SLN mapping, Wallace et al. (25) found t½c values of 2.18 ± 1.09 h (n = 5) and 57.4 ± 92.8 h (n = 6) (P < 0.001), respectively. The mean sentinel lymph node uptake for 99mTc-DTPA-mannosyl-dextran (1.5±1.7%) and unfiltered 99mTc-SC (3.5±3.1%) was not significantly different (P =. 277).

Wallace et al. (4) reported a phase I clinical trial with 99mTc-DTPA-mannosyl-dextran in 24 patients with melanoma. Groups of 6 patients received an intradermal administration of 18.5 MBq (0.5 mCi) radioactivity in 1.0, 5.0, or 10.0 nmol of 99mTc-DTPA-mannosyl-dextran. The radioactivity was divided into four doses of 4.6 MBq (0.125 mCi) in 0.1 ml and injected at the 3-, 6, 9-, and 12-o’clock positions surrounding the tumor. Filtered 99mTc-SC was similarly administered to groups of 6 patients for comparison. The injection-site clearance was monitored by gamma imaging for 3 h, and SLNs were obtained for assay by gamma probe–guided biopsy 4–8.7 h after injection. The mean injection-site kc and t½c of all three 99mTc-DTPA-mannosyl-dextran dose levels were 0.319 ± 0.141 h–1 (n = 18) and 2.17 ± 0.96 h, respectively. In comparison, filtered 99mTc had a kc of 0.047 ± 0.020 h–1 (n = 6) and a t½c 14.7 ± 6.3 h, respectively. The radioactivity levels (% ID) of 99mTc-DTPA-mannosyl-dextran at the site of injection and SLNs were 26.7 ± 17.4 (n = 18) and 0.73 ± 0.94, respectively. The radioactivity levels of filtered 99mTc-SC were 73.1 ± 12.8% ID (n = 6) at the site of injection and 0.85 ± 1.19% ID in the SLN. For 99mTc-DTPA-mannosyl-dextran, the mean number of detected SLN/basin was 1.6, whereas filtered 99mTc-SC detected 1.9 SLN/basin. No clinically meaningful adverse effects were observed. At all three dose levels, the absorbed doses to the testes, ovaries, red marrow, and total body were all <1.89 × 10–2 mGy/MBq (<7.0 × 10–2 rad/mCi).

Leong et al. (26) reported a phase II clinical trial with 99mTc-DTPA-mannosyl-dextran in 78 patients (47 melanoma, 31breast cancer). A 99mTc-DTPA-mannosyl-dextran hot spot was identified in 94.5% of 55 patients with lymphoscintigraphy before surgery. Intraoperatively, 99mTc-DTPA-mannosyl-dextran identified at least one regional SLN in 75 (96.2%) of 78 patients: 46 (97.9%) of 47 in melanoma and 29 (93.5%) of 31 in breast cancer patients. Tissue specificity of 99mTc-DTPA-mannosyl-dextran for lymph nodes was 100%, displaying 95.1% mapping sensitivity by localizing in 173 of 182 lymph nodes removed during surgery. The overall proportion of 99mTc-DTPA-mannosyl-dextran-identified lymph nodes that contained metastases was 13.7%.

NIH Support

R01 CA72751, R21 CA09764, R21 CA112940, K23 CA109115-01A3

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This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.

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