Scintigraphic Imaging Studies Research Articles

Lipid-Based Nanocarrier by Targeting with LHRH Peptide: A Promising Approach for Prostate Cancer Radio-Imaging and Therapy.

Prostate cancer is a prevalently detected malignancy with a dismal prognosis. Luteinizing-hormone-releasing-hormone (LHRH) receptors are overexpressed in such cancer cells, to which the LHRH-decapeptide can specifically bind. A lipid-polyethylene glycol-conjugated new LHRH-decapeptide analogue (D-P-HLH) was synthesized and characterized. D-P-HLH-coated and anticancer drug doxorubicin (DX)-loaded solid lipid nanoparticles (F-DX-SLN) were formulated by the cold homogenization technique and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, differential scanning calorimetry, dynamic light scattering, electron microscopy, entrapment efficiency, and drug-release profile studies. F-DX-SLN allows site-specific DX delivery by reducing the side effects of chemotherapy. Cancer cells could precisely take up F-DX-SLN by targeting specific receptors, boosting the cytotoxicity at the tumor site. The efficacy of F-DX-SLN on PC3/SKBR3 cells by the MTT assay revealed that F-DX-SLN was more cytotoxic than DX and/or DX-SLN. Flow cytometry and confocal microscopic studies further support F-DX-SLNs' increased intracellular absorption capability in targeting LHRH overexpressed cancer cells. F-DX-SLN ensured high apoptotic potential, noticeably larger mitochondrial transmembrane depolarization action, as well as the activation of caspases, a longer half-life, and greater plasma concentration. F-DX-SLN/DX-SLN was radiolabeled with technetium-99m; scintigraphic imaging studies established its tumor selectivity in PC3 tumor-bearing nude mice. The efficacy of the formulations in cancer treatment, in vivo therapeutic efficacy tests, and histopathological studies were also conducted. Results clearly indicate that F-DX-SLN exhibits sustained and superior targeted administration of anticancer drugs, thus opening up the possibility of a drug delivery system with precise control and targeting effects. F-DX-SLN could also provide a nanotheranostic approach with improved efficacy for prostate cancer therapy.

Multi-input deep learning approach for Cardiovascular Disease diagnosis using Myocardial Perfusion Imaging and clinical data.

Accurate detection and treatment of Coronary Artery Disease is mainly based on invasive Coronary Angiography, which could be avoided provided that a robust, non-invasive detection methodology emerged. Despite the progress of computational systems, this remains a challenging issue. The present research investigates Machine Learning and Deep Learning methods in competing with the medical experts' diagnostic yield. Although the highly accurate detection of Coronary Artery Disease, even from the experts, is presently implausible, developing Artificial Intelligence models to compete with the human eye and expertise is the first step towards a state-of-the-art Computer-Aided Diagnostic system. A set of 566 patient samples is analysed. The dataset contains Polar Maps derived from scintigraphic Myocardial Perfusion Imaging studies, clinical data, and Coronary Angiography results. The latter is considered as reference standard. For the classification of the medical images, the InceptionV3 Convolutional Neural Network is employed, while, for the categorical and continuous features, Neural Networks and Random Forest classifier are proposed. The research suggests that an optimal strategy competing with the medical expert's accuracy involves a hybrid multi-input network composed of InceptionV3 and a Random Forest. This method matches the expert's accuracy, which is 79.15% in the particular dataset. Image classification using deep learning methods can cooperate with clinical data classification methods to enhance the robustness of the predicting model, aiming to compete with the medical expert's ability to identify Coronary Artery Disease subjects, from a large scale patient dataset.

Apigenin-Loaded PLGA-DMSA Nanoparticles: A Novel Strategy to Treat Melanoma Lung Metastasis.

The flavone apigenin (APG), alone as well as in combination with other chemotherapeutic agents, is known to exhibit potential anticancer effects in various tumors and inhibit growth and metastasis of melanoma. However, the potential of apigenin nanoparticles (APG-NPs) to prevent lung colonization of malignant melanoma has not been well investigated. APG-loaded PLGA-NPs were surface-functionalized with meso-2,3-dimercaptosuccinic acid (DMSA) for the treatment of melanoma lung metastasis. DMSA-conjugated APG-loaded NPs (DMSA-APG-NPs) administered by an oral route exhibited sustained APG release and showed considerable enhancement of plasma half-life, Cmax value, and bioavailability compared to APG-NPs both in plasma and the lungs. DMSA-conjugated APG-NPs showed comparably higher cellular internalization in B16F10 and A549 cell lines compared to that of plain NPs. Increased cytotoxicity was observed for DMSA-APG-NPs compared to APG-NPs in A549 cells. This difference between the two formulations was lower in B16F10 cells. Significant depolarization of mitochondrial transmembrane potential and an enhanced level of caspase activity were observed in B16F10 cells treated with DMSA-APG-NPs compared to APG-NPs as well. Western blot analysis of various proteins was performed to understand the mechanism of apoptosis as well as prevention of melanoma cell migration and invasion. DMSA conjugation substantially increased accumulation of DMSA-APG-NPs given by an intravenous route in the lungs compared to APG-NPs at 6 and 8 h. This was also corroborated by scintigraphic imaging studies with radiolabeled formulations administered by an intravenous route. Conjugation also allowed comparatively higher penetration as evident from an in vitro three-dimensional tumor spheroid model study. Finally, the potential therapeutic efficacy of the formulation was established in experimental B16F10 lung metastases, which suggested an improved bioavailability with enhanced antitumor and antimetastasis efficacy of DMSA-conjugated APG-NPs following oral administration.

Synthesis of 99mTc-labeled 2-Mercaptobenzimidazole as a novel radiotracer to diagnose tumor hypoxia.

Discovery of 99mTc-labeled imidazole derivatives as a potential radiotracer for hypoxic tumor imaging is considered to be of great interest because of non-invasive detection capabilities. 2-Mercaptobenzimidazole (2-MBI) was successfully synthesized, characterized and radiolabeled with [99mTc (CO)3(H2O)3]+ intermediate to form 99mTc-2-MBI complex with radiochemical purity of ≥95% yield as observed by instant-thin layer chromatography (ITLC) and radio-high performance liquid chromatography (radio-HPLC). The 99mTc-2-MBI complex was observed to be stable in saline and serum with no noticeable decomposition at room temperature and 37 °C, respectively, over a time period of 24 h. Biodistribution results in Balb/c mice bearing S180 tumor show that 99mTc-2-MBI highly internalized in tumor tissue, also possess preferably high tumor/muscle and tumor/blood ratios 4.14 ± 0.77 and 3.91 ± 0.63, respectively at 24 h incubation. Scintigraphic imaging study shows 99mTc-2-MBI is visibly accumulated in hypoxic tumor tissue, suggesting it would be a promising radiotracer for early stage diagnosis of tumor hypoxia.

Folate decorated epigallocatechin-3-gallate (EGCG) loaded PLGA nanoparticles; in-vitro and in-vivo targeting efficacy against MDA-MB-231 tumor xenograft.

Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea exhibits significant anti-cancer potential over a wide range of cancer cells. We have developed folate peptide decorated PLGA-NPs loaded with EGCG (FP-EGCG-NPs) to bind folate receptor (FR) specific breast cancer cell lines and evaluated their efficacy in pre-clinical studies. EGCG loaded PLGA nanoparticles (EGCG-NPs) were characterised for size, surface morphology, surface charge, encapsulation efficacy and in-vitro drug release kinetics. Cellular uptake and in-vitro cytotoxicities of free drug, folate peptide conjugated and unconjugated EGCG-NPs were investigated against FR positive MDA-MB-231 and MCF-7 cells. The conjugated nanoparticles exhibited promising cytotoxic potentials as well as significantly high cellular internalisation in MDA-MB-231 cells as compared to unconjugated one. It also ensured longer half life, higher plasma concentration, favourably high apoptotic potential and significantly high mitochondrial depolarization effect as compared to free EGCG. The loaded nanoparticles were radiolabeled with technetium-99m and their tumor selectivity in MDA-MB-231 tumor bearing nude mice was investigated by scintigraphic imaging study. Finally in-vivo therapeutic efficacy studies in tumor bearing nude mice were also done to evaluate the efficacy of the formulation for cancer treatment.

Gemcitabine Co-Encapsulated with Curcumin in Folate Decorated PLGA Nanoparticles; a Novel Approach to Treat Breast Adenocarcinoma.

Curcumin (CUR), an antioxidant with p-glycoprotein inhibiting activity may be encapsulated with gemcitabine (GEM) as nanosuspension to enhance its anticancer potentiality synergistically. Folate conjugated single (CUR/GEM) and dual (CUR + GEM) drug-loaded nanoformulations were prepared and evaluated for P-glycoprotein-1 (pgy-1) gene resistance, followed by in vitro cellular uptake and cytotoxicity assay in cells. The in vivo biodistribution and scintigraphic imaging was done after radiolabeling the nanoparticles with 99mTechnetium (99mTc). The tumor inhibition study was conducted in nude mice bearing MDA-MB-231 xenografts. The folate conjugated dual drug formulations (FCGNPs) gave better results in suppressing the pgy-1 gene and also showed higher cellular uptake, cytotoxicity, apoptosis, and cell cycle arrest. The radiolabeled nanoformulations were highly stable and FCGNPs showed higher accumulation in the MDA-MB-231 tumor region than folate unconjugated dual drug NPs (CGNPs) as evidenced by scintigraphic imaging and biodistribution studies. The in vivo therapeutic efficacy of FCGNPs was higher compared to unconjugated and respective single-drug formulations. Two drugs in one platform lower breast adenocarcinoma by lowering drug resistance and improving cytotoxic effects.

Ce-141-labeled DOTMP: A theranostic option in management of pain due to skeletal metastases.

Owing to its favorable radioactive decay characteristics (T1/2 =32.51 d, Eβ [max]=434.6keV [70.5%] and 580.0keV [29.5%], Eγ =145.4keV [48.5%]), 141 Ce could be envisaged as a theranostic radionuclide for use in nuclear medicine. The present article reports synthesis and evaluation of 141 Ce complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (DOTMP) as a potent theranostic agent targeting metastatic skeletal lesions. Ce-141 was produced with 314±29MBq/mg (n=6) specific activity and >99.9% radionuclidic purity (n=6). Around 185MBq dose of [141 Ce]Ce-DOTMP was synthesized with 98.6±0.5% (n=4) radiochemical yield under optimized conditions of reaction, and the preparation showed adequately high in vitro stability. Biodistribution studies in normal Wistar rats demonstrated significant skeletal localization and retention of injected activity (2.73±0.28% and 2.63±0.22% of injected activity per gram in femur at 3hours and 14 days post-injection, respectively) with rapid clearance from non-target organs. The results of biodistribution studies were corroborated by serial scintigraphic imaging studies. These results demonstrate the potential utility of 141 Ce-DOTMP as a theranostic molecule for personalized patient care of cancer patients suffering from painful metastatic skeletal lesions.

99mTc radiolabeled archaeosomes as a potential melanoma imaging agent

Background: Melanoma incidence is growing worldwide. Although recent advances in imaging, there isn`t still available a specific melanoma agent that can be used for melanoma staging. Archaeosomes may be defined as liposomes composed of one or more polar lipids extracted from the Archaea domain (Archaebacterium). Objective:  As liposomes have been used as vehicles for drugs and isotopes, the aim of this work was to 99mTc radiolabel archaeosomes and evaluates its potential role as a melanoma imaging agent.Methods: Archaeosomes were prepared by hand shaken method and were radiolabeled with 99mTc; Radiolabelling efficiency and purity was evaluated through different chromatographic systems. In vitro stability of 99mTc-DTPA-archaeosomes was performed through L-cysteine challenge.Results: Archaeosomes size distribution was determined by laser light scattering, having nanometer size between 90 and 120 nm. Radiolabelling efficiency was greater than 90%; 99mTc-DTPA-Archaeosomes presented a radiochemical purity superior to 80% evaluated 24 hours post radiolabelling. For the highest concentration of L-cysteine (30mM) and 1h incubation, radiochemical purity was 92.90 %, 6.41 % was bound to cysteine and 0.69 % remained as 99mTcO4- . Biodistribution and scintigraphic imaging studies in healthy C57 black mice showed high liver, spleen uptake and renal elimination. Melanoma bearing mice, had similar biodistribution as healthy mice but increased melanoma uptake, with T/M ratio of 46 ±3.7.Conclusions:  Our results show the feasibility of 99mTc radiolabelling archaeosomes and their potential role as a melanoma imaging agent.

99mTc-hexoprenaline and 131I-dapoxetine: preparation, in silico modeling and biological evaluation as promising lung scintigraphy radiopharmaceuticals

Hexoprenaline and dapoxetine (two lung selective pharmaceutical compounds) were radiolabeled to produce lung imaging radiopharmaceuticals using 99mTc and 131I, respectively. Different factors affecting labeling process were examined and optimum radiochemical purities of 91.3 ± 0.294 and 96.5 ± 0.342% were obtained, respectively. In silico molecular modeling studies for 99mTc-hexoprenaline and 131I-dapoxetine were done. Molecular modeling studies of the radiolabeled compounds examined the effect of radiolabeling on structure activity relationship for hexoprenaline and dapoxetine. Biodistribution studies in Swiss albino mice showed poor lung uptake of 99mTc-hexoprenaline and high uptake for 131I-dapoxetine (15.26 ± 0.11 and 55.82 ± 0.201%ID/g, respectively) matching the molecular modeling expectations. Consequently, 131I-dapoxetine could be a hopeful radiopharmaceutical for lung scintigraphic imaging and further studies to radiolabel hexoprenaline with 131I are recommended.

Detection of bacterial infection by a technetium-99m-labeled peptidoglycan aptamer

Nuclear medicine clinicians are still waiting for the optimal scintigraphic imaging agents capable of distinguishing between infection and inflammation, and between fungal and bacterial infections. Aptamers have several properties that make them suitable for molecular imaging. In the present study, a peptidoglycan aptamer (Antibac1) was labeled with 99mTc and evaluated by biodistribution studies and scintigraphic imaging in infection‐bearing mice. Labeling with 99mTc was performed by the direct method and the complex stability was evaluated in saline, plasma and in the molar excess of cysteine. The biodistribution and scintigraphic imaging studies with the 99mTc-Antibac1 were carried out in two different experimental infection models: Bacterial-infected mice (S. aureus) and fungal-infected mice (C. albicans). A 99mTc radiolabeled library, consisting of oligonucleotides with random sequences, was used as a control for both models. Radiolabeling yields were superior to 90% and 99mTc‐Antibac1 was highly stable in presence of saline, plasma, and cysteine up to 6h. Scintigraphic images of S. aureus infected mice at 1.5 and 3.0h after 99mTc‐Antibac1 injection showed target to non-target ratios of 4.7±0.9 and 4.6±0.1, respectively. These values were statistically higher than those achieved for the 99mTc‐library at the same time frames (1.6±0.4 and 1.7±0.4, respectively). Noteworthy, 99mTc‐Antibac1 and 99mTc‐library showed similar low target to non-target ratios in the fungal-infected model: 2.0±0.3 and 2.0±0.6for 99mTc‐Antibac1 and 2.1±0.3 and 1.9 ± 0.6 for 99mTc‐library, at the same times. These findings suggest that the 99mTc‐Antibac1 is a feasible imaging probe to identify a bacterial infection focus. In addition, this radiolabeled aptamer seems to be suitable in distinguishing between bacterial and fungal infection.

Garcinol loaded vitamin E TPGS emulsified PLGA nanoparticles: preparation, physicochemical characterization, in vitro and in vivo studies

Garcinol (GAR) is a naturally occurring polyisoprenylated phenolic compound. It has been recently investigated for its biological activities such as antioxidant, anti-inflammatory, anti ulcer, and antiproliferative effect on a wide range of human cancer cell lines. Though the outcomes are very promising, its extreme insolubility in water remains the main obstacle for its clinical application. Herein we report the formulation of GAR entrapped PLGA nanoparticles by nanoprecipitation method using vitamin E TPGS as an emulsifier. The nanoparticles were characterized for size, surface morphology, surface charge, encapsulation efficiency and in vitro drug release kinetics. The MTT assay depicted a high amount of cytotoxicity of GAR-NPs in B16F10, HepG2 and KB cells. A considerable amount of cell apoptosis was observed in B16f10 and KB cell lines. In vivo cellular uptake of fluorescent NPs on B16F10 cells was also investigated. Finally the GAR loaded NPs were radiolabeled with technetium-99m with >95% labeling efficiency and administered to B16F10 melanoma tumor bearing mice to investigate the in vivo deposition at the tumor site by biodistribution and scintigraphic imaging study. In vitro cellular uptake studies and biological evaluation confirm the efficacy of the formulation for cancer treatment.

Ursolic Acid Loaded PLGA Nanoparticles: in vitro and in vivo Evaluation to Explore Tumor Targeting Ability on B16F10 Melanoma Cell Lines

Ursolic acid (UA), a pentacyclic triterpenoid extracted from plants, shows promising inhibitory effect in different tumor bearing cell lines. In the present study we fabricated UA loaded PLGA nanoparticles (UA-NPs) as the drug carrier and thoroughly evaluated in vitro and in vivo the differential tumor targeting effects of UA and UA-NPs in B16F10 melanoma cells. Ursolic acid loaded PLGA nanoparticles were prepared by emulsion solvent evaporation technique and evaluated for particle size, polydispersity, zeta potential and drug release potency. MTT assay as well as flow cytometric and confocal microscopic analyses were done in B16F10 mouse melanoma cell lines. Formulations were labeled with technetium-99m to evaluate the biodistribution and perform scintigraphic imaging studies following intravenous administration in tumor bearing mice model. Single emulsification technique produced smooth spherical nanoparticles of small size with relatively narrow size distribution (154 ± 4.56nm). On B16F10 cell line, the formulation showed higher cytotoxicity compared to the free drug due to increased in vitro cellular uptake. The formulation was successfully radiolabeled and remained substantially (>90%) stable when incubated (37°C, 6h) separately in normal saline or freshly collected rat serum or histidine solution. The radiolabeled UA-NPs exhibited slower blood clearance and comparatively high uptake in tumor region as evidenced by biodistribution and scintigraphic studies. The in vitro and in vivo studies have proved the tumor targeting potential of UA-NPs in B16F10 melanoma cell lines.

99mTc-phytate as a diagnostic probe for assessing inflammatory reaction in malignant tumors.

Once administered intravenously, technetium-99m (99mTc)-labeled phytate binds to calcium in the serum and behaves as a nanoparticle. On the basis of the high permeability of the tumor vasculature, 99mTc-phytate is expected to leak and accumulate specifically in inflammatory cells. The aim of this study was to evaluate the potential of 99mTc-phytate in assessing the degree of inflammation in Ehrlich solid tumors in mice. 99mTc-phytate was prepared by adding pertechnetate to a solution containing phytic acid and stannous chloride. The blood half-life of this particle following intravenous injection was determined using blood samples from healthy animals, whereas its size was measured by photon correlation spectroscopy. Scintigraphic imaging and biodistribution studies were carried out in tumor-bearing mice at 30 min and 2 h after injection. The average size of the particles was in the range of 200 nm, suggesting that they are capable of passively passing through fenestrations in tumor vessels, which are 200-2000 nm in size. The blood half-life for 99mTc-phytate was found to be 2.1 min, a result that is in agreement with previous studies. Data from tumor-bearing mice showed high tumor uptake at 2 h after 99mTc-phytate administration. As a result, a high tumor-to-muscle ratio was achieved (T/M = 25.9 ± 7.54). These findings indicate that 99mTc-sodium phytate has promising properties for identifying the type of tumor. This approach will have significant implications for characterizing tumor biology and treatment of malignant lesions.

Synthesis and biological evaluation of novel 99mTc labeled ornidazole xanthate complexes as potential hypoxia imaging agents

In this study, ornidazole xanthate (ONXT) ligand was successfully synthesized and its 99mTc-nitrido core, 99mTc-oxo core and [99mTc(CO)3]+ core complexes were prepared with high yields. The tumor cell experiments and the biodistribution in mice bearing S180 tumor showed that all of the complexes had a certain hypoxic selectivity and tumor uptake. Among them, 99mTcO-ONXT exhibited the highest tumor uptake and tumor/muscle ratio. Planar scintigraphic imaging studies showed the tumor detection was observable, suggesting it would be a potential radiotracer to target tumor hypoxia.

Formulation, preclinical evaluation, and preliminary clinical investigation of an in-house freeze-dried EDTMP kit suitable for the preparation of 177Lu-EDTMP.

The objective of the present work was to develop a freeze-dried ethylenediaminetetramethylene phosphonic acid (EDTMP) kit, suitable for the convenient and single-step preparation of (177)Lu-EDTMP, which is currently being evaluated as a promising radiopharmaceutical for providing palliative care to patients suffering from skeletal metastases and to assess the potential of the agent in human patients. Lyophilized EDTMP kits having identical composition with Quadramet(®) were prepared using EDTMP, NaOH, and anhydrous CaCO3. The (177)Lu-EDTMP patient dose was prepared by incubating the kit materials dissolved in 1 mL of water for injection and (177)LuCl3, produced in-house, at room temperature for 15 minutes. Pharmacokinetic behavior of the agent was studied by carrying out biodistribution and scintigraphic imaging studies in normal Wistar rats. Clinical studies were performed by administering the preparation in patients suffering from disseminated skeletal metastases. Five batches of freeze-dried EDTMP kits with 50 kit vials in each batch were prepared. Each kit vial comprised a lyophilized mixture of 35 mg EDTMP, 14.1 mg NaOH, and 5.8 mg of CaCO3. The (177)Lu-EDTMP complex was prepared with excellent radiochemical purity (>99%) and high stability (>98% until 9 days postpreparation) using these kits. Radiochemical studies showed that this kit could be used within a pH range of 6-9 and with (177)Lu having specific activity as low as 925 GBq · g(-1) (25 Ci · g(-1)) for the preparation of up to 3.7 GBq (100 mCi) of (177)Lu-EDTMP. Biodistribution studies in animals revealed selective accumulation of the agent in skeleton (∼ 60% of the injected activity) with major renal clearance. Preliminary clinical studies in 10 patients exhibited selective accumulation of the radiotracer in skeletal lesions and provided significant pain relief thereby improving the quality of life of the patients. Freeze-dried EDTMP kits, suitable for the preparation of patient doses of (177)Lu-EDTMP, have been developed and used in preliminary studies for treating the cancer patients with disseminated skeletal metastases. The kit may also find use for the preparation of other potential bone pain palliation agents, such as (153)Sm-EDTMP.

Hollow microspheres based on – Folic acid modified – Hydroxypropyl Cellulose and synthetic multi-responsive bio-copolymer for targeted cancer therapy: Controlled release of daunorubicin, in vitro and in vivo studies

HypothesisConventional chemotherapy drugs such as anthracyclines show no specific activity. They destroy cancer cells but also and the healthy ones, and for that reason exhibit high toxicity. In order to alleviate the toxic effects of chemotherapeutic drugs, the administration dose is being minimized, while their reactivity against tumor cells is lessened. This problem can be overcome or at least reduced by using nanoscale drug delivery systems to target the pathogenic area. The present work deals with the synthesis, characterization and biological evaluation of multi-responsive hollow microspheres coated with Hydroxypropyl Cellulose (HPC)-a biocompatible and thermosensitive polysaccharide-conjugated with folic acid as well promising drug vehicles for targeted cancer therapy. ExperimentsThe synthetic route consists of two steps. In the first step, a single layer of sensitive copolymers is ((Methacrylic acid (MAA), N-(2-Hydroxypropyl) methacrylamide (HPMA) and N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(2-methylacrylamide) (DSBMA)) fabricated on a sacrificial template of SiO2 and in the second step, an additional layer of the folic acid modified HPC coat the microspheres’ surface. The layers fabrication is performed through a combination of distillation precipitation co-polymerization and chemical deposition method. The loading capacity (% LC) and encapsulation efficiency (% EE) percentages of the chemotherapeutic agent daunorubicin (DNR) in the fabricated microspheres were calculated through the standard curve methodology. In addition, the releasing properties of the resulting spheres are investigated, using the above mentioned methodology. It is worth mentioning that, spheres release the entrapped drug under combined conditions such acidic and reductive environment along with conventional hyperthermia. Cytotoxic activity of the synthesized spheres was investigated by using the well-established method of MTT assay in MCF-7 (breast cancer), HeLa (cervical cancer) and HEK 293 (Human Embryonic Kidney healthy cells) cell lines. Confocal and fluorescence microscopy were used to confirm the in vitro targeted ability of folic acid modified drug loaded microspheres in HeLa, to that overexpress folate receptors, MCF-7 and 3T3 cells, as negative folate cell substrate. Finally, radiolabelling of the spheres is performed, with a gamma emitting radionuclide (99mTc), to assess their in vivo profile by means of scintigraphic imaging and biodistribution studies. FindingsHollow spheres release the encapsulated drug under acidic environment, conventional hyperthermia or in the presence of glutathione (reductive environment). The ability of modified drug carriers to target the HeLa cells, was confirmed by confocal and fluorescence microscopy. The resulting spheres are observed to be promising drug-carriers for cancer treatment due to their releasing properties under tumor’s environment and high concentration in HeLa cells via endocytosis. In addition, the empty vehicles have no toxicity in healthy cells and present antimicrobial activity.

A novel concept of radiosynthesis of a 99mTc-labeled dimeric RGD peptide as a potential radiotracer for tumor imaging

Radiolabeled Arg-Gly-Asp (RGD) peptides are promising agents for non invasive imaging of αvβ3 expression in malignant tumors. The integrin αvβ3 binding affinity and consequent tumor uptake could be improved when a dimeric RGD peptide is used as the targeting moiety instead of a monomer. Towards this, a novel approach was envisaged to synthesize a 99mTc labeled dimeric RGD derivative using a RGD monomer and [99mTcN]+2 intermediate. The dithiocarbamate derivative of cyclic RGD peptide G3-c(RGDfK) (G3=Gly-Gly-Gly, f=Phe, K=Lys) was synthesized and radiolabeled with [99mTcN]+2 intermediate to form the 99mTcN-[G3-c(RGDfK)]2 complex in high yield (∼98%). Biodistribution studies carried out in C57/BL6 mice bearing melanoma tumors showed good tumor uptake [4.61±0.04% IA/g at 30min post-injection] with fast clearance of the activity from non-target organs/tissue. Scintigraphic imaging studies showed visible accumulation of activity in the tumor with appreciable target to background ratio.

99mTc-N4amG: Synthesis biodistribution and imaging in breast tumor-bearing rodents

99mTc-N4-guanine (99mTc-N4amG) was synthesized and evaluated in this study. Cellular uptake and cellular fraction studies were performed to evaluate the cell penetrating ability. Biodistribution and planar imaging were conducted in breast tumor-bearing rats. Up to 17%ID uptake was observed in cellular uptake study with 40% of 99mTc-N4amG was accumulated in the nucleus. Biodistribution and scintigraphic imaging studies showed increased tumor/muscle count density ratios as a function of time. Our results demonstrate the feasibility of using 99mTc-N4amG in tumor specific imaging.

Design and Docking Studies of [Diethylenetriaminepentaacetic Acid–(Amino Acid)2] with Acetylcholine Receptor as a Molecular Imaging Agent for Single-Photon Emission Computed Tomographic Application

The acetylcholine receptor is an essential link between the brain and the muscles, so it is a sensitive location for attack. In this study, some reversible [diethylenetriaminepentaacetic acid-(amino acid)2] have been docked computationally to the active site of the acetylcholine receptor. The induced fit method was employed to perform the automolecular docking for these systems. The result of docking studies generated thermodynamic properties, such as free energy of bindings (Glide score) and their weak electrostatic interactions. On the basis of these results, scintigraphic imaging studies were performed in mice. Among the radiotracers evaluated in this study, compound derived from 5-hydroxytryptophan/tryptophan exhibited remarkable localization in the brain, whereas radiotracer derived from l-histidine shows moderate accumulation in the brain. Preliminary studies with these amino acid-based ligands are encouraging to carrying out further in vivo experiments for targeted imaging.

Radioiodinated dechloro-4-iodofenofibrate: A hydrophobic model drug for molecular imaging studies

Radiolabeling is a valuable option for tracking drug molecules in biodistribution experiments. In the development of innovative drug delivery systems the influence of the pharmaceutical formulation on the drugs’ pharmacokinetics has to be investigated. The hypolipidemic agent fenofibrate is an ideal model drug for testing the performance of drug delivery systems designed for poorly soluble compounds. Herein, we report a de novo synthesis of a fenofibrate derivative, dechloro-4-iodofenofibrate, as well as its conversion into its radioiodinated derivatives containing 125I or 131I. The enzymatic stability of the radiolabeled compounds synthesized was determined in vitro. A scintigraphic imaging study supplemented by biodistribution experiments and analysis of excreted metabolites revealed the stability required for in vivo applications and its similarity to fenofibrate. Therefore a convenient method is presented to synthesize radioiodinated derivatives of fenofibrate. These tracers show excellent in vitro and in vivo properties to study the behavior of lipophilic drugs.