Radiolabeling, biodistribution and gamma scintigraphy of noscapine hydrochloride in normal and polycystic ovary induced rats

<p>Abstract</p> <p>Background</p> <p>Noscapine, an alkaloid from <it>Papaver somniferum</it>, widely used as an antitussive, is being clinically studied in the treatment of polycystic ovary syndrome (PCOS) and a few other cancers primarily because of its anti-angiogenesis properties. With the advent of diverse application of noscapine, we sought to determine whether the radiolabeling method can be useful in studying uptake and kinetics of the molecule in-vivo. Specific objectives of this study were to radiolabel noscapine with Technetium-99m (Tc-99m), to determine its organ biodistribution in rat model and study its uptake kinetics in PCOS model.</p> <p>Methods</p> <p>A method for radiolabeling noscapine with Tc-99m was standardized using stannous reduction method and its in vitro and in vivo stability parameters were studied. The radiopharmaceutical was also evaluated for blood kinetics and biodistribution profile. An animal model of PCOS was created by using antiprogesterone RU486 and uptake of ^99mTc-noscapine in normal and PCOS ovaries was compared using gamma scintigraphy.</p> <p>Results</p> <p>Noscapine hydrochloride was successfully radiolabeled with Tc-99m with high labeling efficiency and in vitro stability. Most of the blood clearance of the drug (80%) took place in first hour after intravascular injection with maximum accumulation being observed in liver, spleen, kidney followed by the ovary. At 4 hours post injection, radiolabeled complex accumulation doubled in PCOS ovaries in rats (0.9 ± 0.03% ID/whole organ) compared to normal cyclic rats (0.53 ± 0.01% ID/whole organ). This observation was further strengthened by scintigraphic images of rats taken at different time intervals (1 h, 2 h, 4 h, and 24 h) where SPECT images suggested discrete accumulation in the PCOS ovaries.</p> <p>Conclusion</p> <p>Through our study we report direct radiolabeling of noscapine and its biodistribution in various organs and specific uptake in PCOS that may show its utility for imaging ovarian pathology. The increased ovarian uptake in PCOS may be related to its receptor binding suggesting possible role of ^99mTc-noscapine in PCOS diagnostics and therapeutics.</p

Mucoadhesive microemulsion of ibuprofen: design and evaluation for brain targeting efficiency through intranasal route

This study aimed at designing mucoadhesive microemulsion gel to enhance the brain uptake of Ibuprofen through intranasal route. Ibuprofen loaded mucoadhesive microemulsion (MMEI) was developed by incorporating polycarbophil as mucoadhesive polymer into Capmul MCM based optimal microemulsion (MEI) and was subjected to characterization, stability, mucoadhesion and naso-ciliotoxicity study. Brain uptake of ibuprofen via nasal route was studied by performing biodistribution study in Swiss albino rats. MEI was found to be transparent, stable and non ciliotoxic with 66.29 ± 4.15 nm, -20.9 ± 3.98 mV and 98.66 ± 1.01% as average globule size, zeta potential and drug content respectively. Transmission Electron Microscopy (TEM) study revealed the narrow globule size distribution of MEI. Following single intranasal administration of MMEI and MEI at a dose of 2.86 mg/kg, uptake of ibuprofen in the olfactory bulb was around 3.0 and 1.7 folds compared with intravenous injection of ibuprofen solution (IDS). The ratios of AUC in brain tissues to that in plasma obtained after nasal administration of MMEI were significantly higher than those after intravenous administration of IDS. Findings of the present investigation revealed that the developed mucoadhesive microemulsion gel could be a promising approach for brain targeting of ibuprofen through intranasal route.O objetivo deste trabalho foi planejar microemulsão/mucoaesiva em gel a fim de melhorar a captação cerebral de ibuprofeno por via intranasal. A microemulsão para mucoadesão com ibuprofeno (MMEI) foi desenvolvida pela incorporação de policarbofil como polímero mucoadesivo em microemulsão otimizada (MEI) com base em Capmul (MCM) e foi submetida à caracterização, estabilidade, mucoadesão e naso-ciliotoxicidade. A captação cerebral de ibuprofeno pela via nasal foi estudada por meio de estudo de biodistribuição em ratos albinos suíços. MEI se mostrou transparente, estável e não ciliotóxica, com 66,29 ± 4,15 nm, -20,9 ± 3,98 mV e 98,66 ± 1,01%, respectivamente, de tamanho médio dos glóbulos, potencial zeta e conteúdo do fármaco. O estudo revelou o estreita distribuição do tamanho dos glóbulos de MEI. Após administração intranasal única de MMEI e MEI, em dose de 2,86 mg/kg, a captação de ibuprofeno no bulbo olfativo foi em torno de 3,0 e 1,7 vezes maior, comparativamente, à injeção endovenosa de ibuprofeno (IDS). As taxas de ASC em tecido cerebral em relação ao plasma, obtidas após administração da MMEI nasal, foram, significativamente, mais elevadas do que aquelas observadas após a administração intravenosa de IDS. Os resultados do presente estudo mostraram que a microemulsão/mucoadesiva em gel poderia ser uma abordagem promissora para o direcionamento cerebral de ibuprofeno por via intranasal

PRELIMINARY EVALUATION OF AN ANTHRAQUINONE CONJUGATED DOTA DERIVATIVE AS SPECT AGENT

Objective: An anthraquinone derivative, DO3A-Act-AQ having DO3A (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-trisacetic acid) scaffold is radio labeled with 99mTc radioisotope and evaluated as a SPECT imaging agent for tumor.Methods: Preliminary in-vivo evaluation of 99mTc-DO3A-Act-AQ radioconjugate including blood kinetics, biodistribution and gamma scintigraphic imaging is performed on BMG-1 tumor xenografted mice after successful optimization of the radiolabeling condition.Results: The radiotracer, 99mTc-DO3A-Act-AQ was produced in high radiochemical yield of&gt;96% and specific activity of 3.62 MBq/nmol at pH 7.5 and 150 µg stannous chloride. Radioconjugate displayed excellent in-vitro and in-vivo stability with only ~2% transchelation of radiometal at 24 h p. i and rapid blood clearance from the system with t1/2(F) = 38.04±0.35 min and t1/2(S) = 5 h 30 min±0.67. Significant tumor-to-muscle ratio of&gt;7 at 2 h p. i. in biodistribution and SPECT imaging studies in BMG-1 tumor xenografted mice suggested the tumor specificity of the radioconjugate.Conclusion: Stable radiocomplex formation of 99mTc-DO3A-Act-AQ and its significant tumor specificity demonstrated its future application as a promising SPECT radioligand for tumor 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

The in vivo behavior and antitumor activity of doxorubicin-loaded poly(gamma-benzyl L-glutamate)-block-hyaluronan polymersomes in Ehrlich ascites tumor-bearing BalB/c mice

The in vivo efficacy of doxorubicin (DOX)-loaded poly(gamma-benzyl L-glutamate)-block-hyaluronan (PBLG(23)-b-HYA(10))-based polymersomes (PolyDOX) was evaluated. Samples were efficiently labeled with technetium-99m radionuclide with good stability for in vivo studies. PolyDOX enhanced circulation time compared to free DOX. Biodistribution studies revealed selective accumulation of PolyDOX in the Ehrlich ascites tumor (EAT) as a result of passive accumulation and active targeting (CD44-mediated endocytosis) in EAT-bearing mice. Toxicity studies demonstrated PolyDOX is a safe drug carrier, and no hemolysis was observed with PolyDOX equivalent to 200 mu g/mL of free DOX. PolyDOX dominantly controlled tumor growth by delaying doubling time of EATs compared to free DOX over 30 days after treatment. PolyDOX also increased life span six times more than free DOX. Hence, it is reasonable to expect that higher DOX levels attributable to PolyDOX improve the therapeutic index and reduce side effects due to site-specific drug accumulation

Design and Docking Studies of [Diethylenetriaminepentaacetic Acid–(Amino Acid) 2

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