The potential medical applications of nanomaterials are shaping the landscape of the nanobiotechnology field and driving it forward. A key factor in determining the suitability of these nanomaterials ...must be how they interface with biological systems. Single walled carbon nanotubes (CNT) are being investigated as platforms for the delivery of biological, radiological, and chemical payloads to target tissues. CNT are mechanically robust graphene cylinders comprised of sp(2)-bonded carbon atoms and possessing highly regular structures with defined periodicity. CNT exhibit unique mechanochemical properties that can be exploited for the development of novel drug delivery platforms. In order to evaluate the potential usefulness of this CNT scaffold, we undertook an imaging study to determine the tissue biodistribution and pharmacokinetics of prototypical DOTA-functionalized CNT labeled with yttrium-86 and indium-111 ((86)Y-CNT and (111)In-CNT, respectively) in a mouse model.
The (86)Y-CNT construct was synthesized from amine-functionalized, water-soluble CNT by covalently attaching multiple copies of DOTA chelates and then radiolabeling with the positron-emitting metal-ion, yttrium-86. A gamma-emitting (111)In-CNT construct was similarly prepared and purified. The constructs were characterized spectroscopically, microscopically, and chromatographically. The whole-body distribution and clearance of yttrium-86 was characterized at 3 and 24 hours post-injection using positron emission tomography (PET). The yttrium-86 cleared the blood within 3 hours and distributed predominantly to the kidneys, liver, spleen and bone. Although the activity that accumulated in the kidney cleared with time, the whole-body clearance was slow. Differential uptake in these target tissues was observed following intravenous or intraperitoneal injection.
The whole-body PET images indicated that the major sites of accumulation of activity resulting from the administration of (86)Y-CNT were the kidney, liver, spleen, and to a much less extent the bone. Blood clearance was rapid and could be beneficial in the use of short-lived radionuclides in diagnostic applications.
Following disastrous earthquakes in Alaska and in Niigata, Japan in 1964, Professors H. B. Seed and I. M. Idriss developed and published a methodology termed the "simplified procedure" for evaluating ...liquefaction resistance of soils. This procedure has become a standard of practice throughout North America and much of the world. The methodology which is largely empirical, has evolved over years, primarily through summary papers by H. B. Seed and his colleagues. No general review or update of the procedure has occurred, however, since 1985, the time of the last major paper by Professor Seed and a report from a National Research Council workshop on liquefaction of soils. In 1996 a workshop sponsored by the National Center for Earthquake Engineering Research (NCEER) was convened by Professors T. L. Youd and I. M. Idriss with 20 experts to review developments over the previous 10 years. The purpose was to gain consensus on updates and augmentations to the simplified procedure. The following topics were reviewed and recommendations developed: (1) criteria based on standard penetration tests; (2) criteria based on cone penetration tests; (3) criteria based on shear-wave velocity measurements; (4) use of the Becker penetration test for gravelly soil; (4) magnitude scaling factors; (5) correction factors for overburden pressures and sloping ground; and (6) input values for earthquake magnitude and peak acceleration. Probabilistic and seismic energy analyses were reviewed but no recommendations were formulated.
Tumors metastasizing to the CNS and leptomeninges (LM) are associated with significant mortality. We tested the toxicity, pharmacokinetics, and dosimetry of intraventricular iodine-131-labeled ...monoclonal antibody 3F8 (131I-3F8) targeting GD2-positive CNS/LM disease in a phase I clinical trial.
Adequate CSF flow was determined by pretreatment indium-111-DTPA studies. Fifteen patients received a tracer (1 to 2 mCi) and therapeutic injection (10 to 20 mCi) of intra-Ommaya 131I-3F8. 131I-3F8 pharmacokinetics were studied by serial CSF and blood samplings. Dosimetry was based on pharmacokinetics and region of interest (ROI) analyses on whole-body gamma camera scans. Tumor response was determined by clinical, radiographic, and cytologic criteria.
Total absorbed CSF dose was 1.12 to 13.00 Gy by sampling and 1.00 to 13.70 Gy by ROI data. Average dosimetry ratio (Gy/mCi) of the therapy/tracer administration was 0.88 (+/- 0.58) and 1.08 (+/- 0.66) based on CSF pharmacokinetics and ROI analysis, respectively. CSF half-life by sampling was 3 to 12.9 hours. Toxicities included self-limited headache, fever, and vomiting. Dose-limiting toxicity was reached at the 20-mCi dose, when transient elevations in intracranial pressure and chemical meningitis were seen. Three of 13 assessable patients achieved objective radiographic and/or cytologic responses. No late toxicities have been seen in two patients who remain in remission off therapy for more than 3.5 years.
Intra-Ommaya 131I-3F8 was generally well tolerated; the maximum-tolerated dose was 10 mCi. A high CSF-to-blood ratio was achieved. Tracer studies reliably predicted the therapeutic dose to the CSF. Radioimmunoconjugates targeting GD2 may have clinical utility in the treatment of CNS/LM malignancies.
Herpes virus type 1 thymidine kinase (HSV1-tk) and the mutant HSV1-sr39tk are the 2 most widely used "reporter genes" for radiotracer-based imaging. Two pyrimidine nucleoside analogs, 18FFEAU ...(1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-ethyluridine) and 18FFFEAU (1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-(2-fluoroethyl)uridine), have generated recent interest as potential new probes for imaging HSV1-tk and HSV1-sr39tk gene expression.
We compared 18FFEAU and 18FFFEAU with a series of other pyrimidine nucleoside derivatives (including 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-iodouridine FIAU) and with acycloguanosine analogs using a stable HSV1-tk transduced cell line (RG2TK+) and wild-type RG2 cells.
The in vitro accumulation data and the calculated and normalized clearance constant, nKi, as well as sensitivity and selectivity indices indicated that 2 pyrimidine nucleoside probes, 18FFEAU and 18FFFEAU, had the best uptake characteristics. These probes were selected for further dynamic PET studies in nude rats bearing subcutaneous RG2TK+ and RG2 tumors. The 2-h postinjection 18FFEAU uptake levels were 3.3% +/- 1.0% and 0.28% +/- 0.07% dose/cm3 in subcutaneous RG2TK+ and RG2 tumors, respectively, and 2.3% +/- 0.2% and 0.19% +/- 0.01% dose/cm3, respectively, for 18FFFEAU. The corresponding RG2TK+/RG2 uptake ratios were 11.5 +/- 1.5 and 12.2 +/- 1.4, respectively. The inherent problem of comparing different radiolabeled pyrimidine nucleoside and guanosine-based probes for imaging HSV1-tk expression using different transduced cell lines and assay systems in the absence of an independent thymidine kinase-enzyme assay is discussed.
For HSV1-tk reporter systems that require a 1- to 4-h PET paradigm, HSV1-tk-18FFEAU is the current top contender.
Unlike β particle–emitting isotopes, α emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets ...myeloid leukemia cells and has activity against minimal disease. When labeled with the β-emitters 131I and 90Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of β-emitting constructs, the α-emitting isotope 213Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg 213Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the 213Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with β-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of 213Bi-HuM195, and it is the first proof-of-concept for systemic targeted α particle immunotherapy in humans.
A novel alpha-particle emitting monoclonal antibody construct targeting the external domain of prostate-specific membrane antigen (PSMA) was prepared and evaluated in vitro and in vivo. The chelating ...agent, N-2-amino-3-(p-isothiocyanatophen-yl)propyl-trans-cyclohexane-1, 2-diamine-N,N',N',N'',N''-pentaacetic acid, was appended to J591 monoclonal antibody to stably bind the 213Bi radiometal ion. Bismuth-213 is a short-lived (t 1/2 = 46 min) radionuclide that emits high energy alpha-particles with an effective range of 0.07-0.10 mm that are ideally suited to treating single-celled neoplasms and micrometastatic carcinomas. The LNCaP prostate cancer cell line had an estimated 180,000 molecules of PSMA per cell; J591 bound to PSMA with a 3-nM affinity. After binding, the radiolabeled construct-antigen complex was rapidly internalized into the cell, carrying the radiometal inside. 213BiJ591 was specifically cytotoxic to LNCaP. The LD50 value of 213BiJ591 was 220 nCi/ml at a specific activity of 6.4 Ci/g. The potency and specificity of 213BiJ591 directed against LNCaP spheroids, an in vitro model for micrometastatic cancer, also was investigated. 213BiJ591 effectively stopped growth of LNCaP spheroids relative to an equivalent dose of the irrelevant control 213BiHuM195 or unlabeled J591. Cytotoxicity experiments in vivo were carried out in an athymic nude mouse model with an i.m. xenograft of LNCaP cells. 213BiJ591 was able to significantly improve (P < 0.0031) median tumor-free survival (54 days) in these experiments relative to treatment with irrelevant control 213BiHuM195 (33 days), or no treatment (31 days). Prostate-specific antigen (PSA) was also specifically reduced in treated animals. At day 51, mean PSA values were 104 ng/ml +/- 54 ng/ml (n = 4, untreated animals), 66 ng/ml +/- 16 ng/ml (n = 6, animals treated with 213BiHuM195), and 28 ng/ml +/- 22 ng/ml (n = 6, animals treated with 213BiJ591). The reduction of PSA levels in mice treated with 213BiJ591 relative to mice treated with 213BiHuM195 and untreated control animals was significant with P < 0.007 and P < 0.0136, respectively. In conclusion, a novel 213Bi-radiolabeled J591 has been constructed that selectively delivers alpha-particles to prostate cancer cells for potent and specific killing in vitro and in vivo.
This review discusses the application of alpha particle-emitting radionuclides in targeted radioimmunotherapy. It will outline the production and chemistry of astatine-211, bismuth-212, lead-212, ...actinium-225, bismuth-213, fermium-255, radium-223 and terbium-149, which at present are the most promising alpha-emitting isotopes available for human clinical use. The selective cytotoxicity offered by alpha particle-emitting radioimmunoconstructs is due to the high linear energy transfer and short particle path length of these radionuclides. Based upon the pharmacokinetics of alpha particle-emitting radioimmunoconstructs, both stochastic and conventional dosimetric methodology is discussed, as is the preclinical and initial clinical use of these radionuclides conjugated to monoclonal antibodies for the treatment of human neoplasia.
The purpose of this prospective study was to determine the ability of fluorine-18 fluorodeoxyglucose positron emission tomography to assess extent of pathologically confirmed rectal cancer response ...to preoperative radiation and 5-fluorouracil-based chemotherapy.
Patients with primary rectal cancer deemed eligible for preoperative radiation and 5-fluorouracil-based chemotherapy because of a clinically bulky or tethered tumor or endorectal ultrasound evidence of T3 and/or N1 were prospectively enrolled. Positron emission tomography and CT scans were obtained before preoperative radiation and 5-fluorouracil-based chemotherapy (5,040 cGy to the pelvis and 2 cycles of bolus 5-fluorouracil with leucovorin) and repeated four to five weeks after completion of radiation and 5-fluorouracil-based chemotherapy. In addition to routine pathologic staging, detailed assessment of rectal cancer response to preoperative radiation and 5-fluorouracil-based chemotherapy was performed independently by two pathologists. Positron emission tomography parameters studied included conventional measures such as standardized uptake value (average and maximum), positron emission tomography-derived tumor volume (size), and two novel parameters: visual response score and change in total lesion glycolysis.
Of 21 patients enrolled, prospective data (pretreatment and posttreatment positron emission tomography, and complete pathologic assessment) were available on 15 patients. All 15 demonstrated pathologic response to preoperative radiation and 5-fluorouracil-based chemotherapy. This was confirmed in 100 percent of the cases by positron emission tomography compared with 78 percent (7/9) by CT. In addition, one positron emission tomography parameter (visual response score) accurately estimated the extent of pathologic response in 60 percent (9/15) of cases compared with 22 percent (2/9) of cases with CT.
This pilot study demonstrates that fluorine-18 fluorodeoxyglucose positron emission tomography imaging adds incremental information to the preoperative assessment of patients with rectal cancer. However, further studies in a larger series of patients are needed to verify these findings and to determine the value of fluorine-18 fluorodeoxyglucose positron emission tomography in a preoperative strategy aimed at identifying patients suitable for sphincter-preserving rectal cancer surgery.
Synthesis of three novel 2‘-deoxy-2‘-18Ffluoro-1-β-d-arabinofuranosyluracil derivatives 18FFPAU, 18FFBrVAU, and 18FFTMAU is reported. The compounds were synthesized by coupling of ...1-bromo-2-deoxy-2-fluoro sugars with corresponding silylated uracil derivatives. In vitro cell uptake indicated that all three compounds are taken up selectively in RG2TK+ cells with negligible uptake in RG2 cells. The results indicate that 18FFBrVAU and 18FFTMAU have better uptake profiles in comparison to 18FFPAU and have potential as PET probes for imaging HSV1-tk gene expression.
A comprehensive, SPECT-based, patient-specific 3-dimensional (3D) dosimetry analysis has been performed using 3D-ID, a previously developed software package. The role of the total-body tumor burden, ...individual lesion size, tumor absorbed dose, and the spatial distribution of the absorbed dose on response and on the time course of tumor shrinkage has been examined in patients with lymphoma treated by radioimmunotherapy.
Data from 15 patients participating in a phase II study of (131)I-labeled anti-B1 antibody (tositumomab) were used. Patients were administered a tracer dose of (131)I for imaging and pharmacokinetics. Dose estimates from the tracer studies were used to prescribe the therapeutic administration such that the whole-body absorbed dose did not exceed 75 cGy. All patients received a fixed mass amount of antibody for both the tracer and the therapeutic administrations. SPECT and planar imaging were performed 3-4 d after the therapeutic administration. CT or MRI scans were available on all patients. Total tumor burden was assessed by drawing contours around all lymphoma lesions identified on whole-body CT or MRI. Mean absorbed doses were estimated for selected, index lesions by conventional dosimetry and also by 3D SPECT-based dosimetry. Using a patient-specific dosimetry package, 3D-ID, dose-volume histograms were also generated to assess the spatial distribution of absorbed dose. This approach made it possible to obtain estimates of the minimum and maximum absorbed doses for individual tumors in addition to the mean.
Mean absorbed dose estimates obtained by patient-specific SPECT-based dosimetry using 3D-ID were within 2%-5% of estimates obtained by conventional dosimetry. None of the absorbed dose parameters (mean, minimum, maximum, uniformity) were found to have a significant correlation with tumor response. The total-body tumor burden did not impact on overall response or toxicity.
This analysis represents the first full reported implementation of a patient-specific 3D dosimetry package. The absence of a dose-response relationship for tumors is surprising and suggests that absorbed dose is not the sole determinant of tumor response in these patients. The absence of a correlation between the total-body tumor burden and overall response or toxicity suggests that tailoring the milligram amount of administered antibody to patient tumor burden is not likely to improve response or reduce toxicity.
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