Paradigm shift in theranostics of neuroendocrine tumors: conceptual horizons of nanotechnology in nuclear medicine.

We present a comprehensive review of Neuroendocrine Tumors (NET) and the current and developing imaging and therapeutic modalities for NET with emphasis on Nuclear Medicine modalities. Subsequently, nanotechnology and its emerging role in cancer management, especially NET, are discussed. The article is both educative and informative. The objective is to provide an insight into the developments made in nuclear medicine and nanotechnology towards management of NET, individually as well as combined together.

Evaluation of cytotoxic and tumor targeting capability of (177)Lu-DOTATATE-nanoparticles: a trailblazing strategy in peptide receptor radionuclide therapy.

OBJECTIVE: We propose an innovative strategy of nanoparticle-mediated-peptide receptor radionuclide therapy (PRRT) employing PLGA-nanoparticles together with anti-ß-hCG antibodies that can protect kidneys from radiation damage while simultaneously enhancing its tumor targeting and cytotoxic ability for somatostatin receptor (SSR) positive tumors. METHODS: PEG-coated-(177)Lu-DOTATATE-PLGA-nanoparticles (PEG-LuD-NP) were formulated and characterized. In vitro toxicity of these particles was tested on human glioblastoma cell line U87MG over a radiation dose range of 19-78 Gy, using MTT assay and flow cytometry. To further enhance cytotoxicity and test the feasibility of active tumor targeting, apoptosis-inducing anti-ß-hCG monoclonal antibodies were employed in vitro, after confirming expression of ß-hCG on U87MG. In vivo tumor targeting ability of these particles, in comparison to uncoated particles and un-encapsulated (177)Lu-DOTATATE, was assessed by intravenous administration in tumor-induced wistar rats. Rats were first imaged in a gamma camera followed by euthanasia for organ extraction and counting in gamma counter. RESULTS: The particles were spherical in shape with mean diameter of 300 nm. Highest cytotoxicity that could be achieved with PEG-LuD-NP, on radio-resistant U87MG cells, was 35.8 % due to complex cellular response triggered by ionizing radiation. Interestingly, synergistic action of antibodies and PEG-LuD-NP doubled the cytotoxicity (80 %). PEG-LuD-NP showed the highest tumor uptake (4.3 ± 0.46 % ID/g) as compared to (177)Lu-DOTATATE (3.5 ± 0.31 %) and uncoated-(177)Lu-DOTATATE-nanoparticles (3.4 ± 0.35 %) in tumor-inoculated wistar rats (p < 0.001). Renal uptake/retention was decreased 3-4 folds with these particles, resulting in the highest tumor-to-kidney ratio (8.58; p < 0.01) while tumor-to-liver and tumor-to-bone ratios were comparable to un-encapsulated-drug. CONCLUSION: Nanocarrier-mediated-PRRT is an effective way of targeting SSR positive tumors for enhanced cytoxicity and reduced renal radiation dose associated with conventional PRRT. To our knowledge of literature, this is the first study to establish in vitro and in vivo efficacy profile of nanoparticles in PRRT providing a stepping-stone for undergoing and future research endeavors in the direction of abating associated radiation concerns of radionuclide therapy and may offer a paradigm shift in PRRT strategy.

PLGA nanoparticles for peptide receptor radionuclide therapy of neuroendocrine tumors: a novel approach towards reduction of renal radiation dose.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT), employed for treatment of neuroendocrine tumors (NETs) is based on over-expression of Somatostatin Receptors (SSTRs) on NETs. It is, however, limited by high uptake and retention of radiolabeled peptide in kidneys resulting in unnecessary radiation exposure thus causing nephrotoxicity. Employing a nanocarrier to deliver PRRT drugs specifically to the tumor can reduce the associated nephrotoxicity. Based on this, (177)Lu-DOTATATE loaded PLGA nanoparticles (NPs) were formulated in the present study, as a potential therapeutic model for NETs. METHODOLOGY AND FINDINGS: DOTATATE was labeled with Lutetium-177 ((177)Lu) (labeling efficiency 98%; R(f)∼0.8). Polyethylene Glycol (PEG) coated (177)Lu-DOTATATE-PLGA NPs (50:50 and 75:25) formulated, were spherical with mean size of 304.5±80.8 and 733.4±101.3 nm (uncoated) and 303.8±67.2 and 494.3±71.8 nm (coated) for PLGA(50:50) and PLGA(75:25) respectively. Encapsulation efficiency (EE) and In-vitro release kinetics for uncoated and coated NPs of PLGA (50:50 & 75:25) were assessed and compared. Mean EE was 77.375±4.98% & 67.885±5.12% (uncoated) and 65.385±5.67% & 58.495±5.35% (coated). NPs showed initial burst release between 16.64-21.65% with total 42.83-44.79% over 21 days. The release increased with coating to 20.4-23.95% initially and 60.97-69.12% over 21 days. In-vivo studies were done in rats injected with (177)Lu-DOTATATE and (177)Lu-DOTATATE-NP (uncoated and PEG-coated) by imaging and organ counting after sacrificing rats at different time points over 24 hr post-injection. With (177)Lu-DOTATATE, renal uptake of 37.89±10.2%ID/g was observed, which reduced to 4.6±1.97% and 5.27±1.66%ID/g with uncoated and coated (177)Lu-DOTATATE-NP. The high liver uptake with uncoated (177)Lu-DOTATATE-NP (13.68±3.08% ID/g), reduced to 7.20±2.04%ID/g (p = 0.02) with PEG coating. CONCLUSION: PLGA NPs were easily formulated and modified for desired release properties. PLGA 50:50 NPs were a more suitable delivery vehicle for (177)Lu-DOTATATE than PLGA 75:25 because of higher EE and slower release rate. Reduced renal retention of (177)Lu-DOTATATE and reduced opsonisation strongly advocate the potential of (177)Lu-DOTATATE-PLGA-PEG NPs to reduce radiation dose in PRRT.

SPECT/CT in the Diagnosis of Skull Base Osteomyelitis.

Skull base osteomyelitis is a potentially fatal disease. We demonstrate here the utility of SPECT/CT in diagnosing this entity, which was not obvious on a planar bone scan. A (99m)Tc MDP bone scan with SPECT/CT was carried out on a patient with clinically suspected skull base osteomyelitis. Findings were correlated with contrast-enhanced CT (CECT) and MRI. Planar images were equivocal, but SPECT/CT showed intense uptake in the body of sphenoid and petrous temporal bone as well as the atlas corresponding to irregular bone destruction on CT and MRI. These findings indicate that SPECT/CT may have an additional role beyond planar imaging in the detection of skull base osteomyelitis.

Diuretic radionuclide renography in assessing Anderson-Hynes pyeloplasty in unilateral pelviureteric junction obstruction.

The topic of whether improvement can be expected after pyeloplasty in patients with pelvi-ureteric junction obstruction (PUJO) continues to generate debate. The aim of this study was to analyse the functional outcome of unilateral Anderson-Hynes (A-H) pyeloplasty using differential renal function (DRF) and drainage patterns determined by diuretic radionuclide renography (DRR). A retrospective study was carried out by evaluation of the records of patients who underwent A-H pyeloplasty for unilateral PUJO and reported for a follow up renal dynamic scan between the years 2000 and 2003. A total of 126 patients (93 males and 33 females) aged three months to 40 years had undergone pre-operative and post-operative DRR and were followed for at least six months after operation. For comparison, the renal function prior to and after pyeloplasty was classified into three Groups based on the DRF: Group A: > or = 40% DRF 52 patients, Group B: 20%-39% DRF 65 patients and Group C: < 20% DRF 9 patients. The difference between pre-operative and post-operative DRF in the last follow up study, which ranged from six months to 144 months after operation, was calculated for each patient. To account for an accepted error of measurement, an absolute difference in DRF of more than 5% was considered significant. Improvement in drainage was assessed by the time Tmax 1/2 of the renographic curve. Unpaired t test was applied between Group A and Group B patients. Chi square analysis was applied to estimate the proportion of improvement between Groups A and B. Post-pyeloplasty scans revealed stable renal function in 102 (81%) subjects, while improvement was noticed in 14 (11%) subjects. The remaining 10 (8%) subjects had deterioration in renal function. No improvement in renal function was seen in Group C patients. Our results have shown that in the majority of cases studied, after A-H pyeloplasty renal function remains stable. A-H pyeloplasty applied in patients with preserved DRF and obstruction will result in long term preservation of renal function.

Technetium-99m-L,L-ethylenedicysteine renal scan as a single-modality investigation for the evaluation of renal morphology and function: a comparative study with technetium-99m-dimercaptosuccinic acid.

AIM: To evaluate whether cortical scars can be detected using the summed images of technetium-99m-L,L-ethylenedicysteine (99mTc-L,L-EC) renal dynamic scan, and to compare the results with technetium-99m-dimercaptosuccinic acid (99mTc-DMSA) scan. To evaluate the inter-observer variability for 99mTc-L,L-EC and 99mTc-DMSA scan reporting. METHODS: One hundred and three patients were initially included in the study; 21 were excluded, five due to a single functioning kidney and 16 due to impaired renal function (serum creatinine>2.5 mg.dl(-1)). Eighty-two patients (39 females, 43 males), including 31 children, with a mean age of 33.4+/-11.3 years (range, 4 months to 74 years), underwent both 99mTc-DMSA and 99mTc-L,L-EC scintigraphy within a period of 14 days. 99mTc-L,L-EC images were regrouped into 2 min image sets, and the initial 2 min summed image (cortical phase) was used for the evaluation of scars. Three independent observers analysed both images separately on different days without being aware of the identity and clinical details of the patients. Their 99mTc-L,L-EC findings were compared with the consensus 99mTc-DMSA scan findings taken as reference. RESULTS: The overall sensitivity of 99mTc-L,L-EC scans was 93% and the specificity was 96%. The inter-observer variability was 0.91 for 99mTc-L,L-EC and 0.94 for 99mTc-DMSA scan reporting, using the weighted kappa analysis at P<0.05. CONCLUSIONS: 99mTc-L,L-EC is an excellent single-modality comprehensive investigational agent for renal morphology, function and outflow tract evaluation with the added advantages of lower cost, convenience and low radiation exposure to the patient.

Soft tissue uptake of Tc99m-MDP in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is associated rarely with hypercalcemia. This may be due to elevated levels of parathyroid hormone-related peptide (PTHrP). We report a case of an 18-year-old female patient who was presented with a pathological fracture of left intertrochanteric region. Bone scintigraphy was consistent with features of hypercalcemia associated with metastatic calcification. A bone marrow biopsy led to the diagnosis of ALL. The mechanism of hypercalcemia in ALL, metastatic calcification and soft tissue uptake of bone seeking agents in this case are discussed in detail.