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Abstract Background Noscapine, an alkaloid from Papaver somniferum, 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. Methods 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. Results 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. Conclusion 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.

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection action, but it suffers from high first pass metabolism and limited ability to cross blood brain barrier. Severe gastric toxicity following oral administration further limits its utility. Hence, the aim of this study was to investigate whether ibuprofen loaded mucoadhesive microemulsion (MMEI) could enhance the brain uptake and could also protect the dopaminergic neurons from MPTP-mediated neural inflammation. In this work, ibuprofen loaded polycarbophil based mucoadhesive microemulsion (MMEI) was developed by using response surface methodology (RSM). Male C57BL/6 mice were intranasally given 2.86 mg ibuprofen/kg/day for 2 consecutive weeks, which were pre-treated with four MPTP injections (20 mg/kg of body weight) at 2 h interval by intraperitoneal route and immunohistochemistry was performed. Globule size of optimal MMEI was 46.73 nm ± 3.11 with PdI value as 0.201 ± 0.19. Histological observation showed that optimal MMEI was biocompatible and suitable for nasal application. The result showed very significant effect (p < 0.05) of all three independent variables on the responses of the developed MMEI. Noticeable improvement in motor performance with spontaneous behavior was observed. TH neurons count in substantia nigra with the density of striatal dopaminergic nerve terminals after MMEI administration. Results of this study confirmed neuroprotection action of ibuprofen through intranasal MMEI against MPTP induced inflammation in dopaminergic nerves in animal model and hence, MMEI can be useful for prevention and management of Parkinson disease (PD). [ABSTRACT FROM AUTHOR]

In this work matrix based nanoparticulate polymer systems have been designed using the diacrylate derivative of the well-known biocompatible polymer, poly(ethylene glycol) (PEG). This has been crosslinked using bifunctional (ethyleneglycol dimethacrylate) and tetrafunctional (pentaerythritol tetraacrylate) crosslinkers in varied concentrations (10-90%) to result in a polymeric network. The crosslinked polymers thus obtained were characterized by spectroscopic techniques (NMR and FTIR) and then prepared nanoparticles by the nanoprecipitation technique. Particle size analysis showed sizes of ~150 nm (PDI < 1) (with tetrafunctional crosslinker) and ~300 nm (with bifunctional crosslinker). Both the systems however showed unimodal narrow particle size distributions with negative zeta potential values of -15.6 and -7.3 respectively. Cytotoxicity of these formulations was evaluated by MTT assay showing non-cytotoxic nature of these carrier systems. drug loading and release studies were carried out using a model chemotherapeutic drug, methotrexate(MTX). These MTX loaded nanoformulations have also been evaluated biologically with the help of studies using radiolabeling techniques (with 99mTc radionuclide). The blood kinetics profile of the formulations was studied on New Zealand Albino rabbits while the biodistribution studies were performed on balb/c mice (with EAT tumours), which revealed a hepatobiliary mode of elimination. These preliminary studies clearly demonstrated the ability of these multifunctional crosslinkers to result in tight nanosized networks with biocompatible polymers such as PEG and their potential to carry chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Background:The present study is to investigate the neuroprotective effect of ibuprofen by intranasal administration of mucoadhesive microemulsion (MMEI) against inflammation-mediated by dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease (PD). Methods:Ibuprofen-loaded polycarbophil-based MMEI was developed by using response surface methodology (RSM). Ibuprofen with dose of 2.86 mg/kg/day was administered intranasally to male C57BL/6 mice for two consecutive weeks which were pre-treated with four intraperitoneal injections of MPTP (20 mg/kg of body weight) at 2 h intervals. Immunohistochemistry was performed. Results:Optimal MMEI was stable and non-ciliotoxic with 66.29 ± 4.15 nm as average globule size and −20.9 ± 3.98 mV as zeta potential. PDI value and transmission electron microscopy result showed the narrow globule size distribution of MMEI. The result showed that all three independent variables had a significant effect (p < 0.05) on the responses. Rota-rod and open-field test findings revealed the significant improvement in motor performance and gross behavioral activity of the mice. The results from in vivo study and immunohistochemistry showed that nasal administration of Ibuprofen significantly reduced the MPTP-mediated dopamine depletion. Furthermore TH neurons count in the substantia nigra and the density of striatal dopaminergic nerve terminals were found to be significant higher for ibuprofen treated groups. Conclusion:Findings of the investigation revealed that Ibuprofen through developed MMEI was shown to protect neurons against MPTP-induced injury in the Substantia nigra pars compacta (SNpc) and striatum and hence, could be a promising approach for brain targeting of Ibuprofen through intranasal route to treat PD. [ABSTRACT FROM PUBLISHER]

The novel tetraaza macrobicyclic chelator 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-2,10-dione ( TBPD) and pentaaza macrotricyclic chelator 9-oxa-3,6,12,15,21-pentaazatricyclo[15,3,2,1]trieicos-1(21),17,19-triene-2,7,11,16-tetradione ( OPTT) were synthesized, characterized, and radiolabeled with 99mTc to produce 99mTc- TBPD and 99mTc- OPTT. These radiolabeled complexes were prepared with high radiolabeling yield, radiochemical purity, and good in vitro stability up to 24 h. The labeling efficiency of 99mTc- TBPD and 99mTc- OPTT was found 98% and 97%. In vitro serum stability of 99mTc- TBPD was found to be 95.2%, while that of 99mTc- OPTT 94.2% up to 24 h. Blood kinetics experiments of 99mTc-labeled complexes showed biphasic pattern of blood clearance. About 99.57 ± 0.89% activity of 99mTc- TBPD and 99.42 ± 0.88% activity of 9mTc- OPTT were cleared off blood stream at 24 h postadministration. The biological half-life of 99mTc- TBPD was observed: t1/2(F) 1 h 5 min and t1/2(S) 12 h and biological half-life of 99mTc- OPTT was observed: t1/2(F) 1 h 10 min and t1/2(S) 9 h 50 min, respectively. The biodistribution studies revealed that maximum uptake of 99mTc- TBPD was found in liver, concluded that excretory pathway is hepatobiliary, while that of 99mTc- OPTT was renal as well as hepatobiliary. The negligible activity observed in stomach confirming the stability of radiolabeled complex in biological milieu. In vitro cytotoxicity study of TBPD and OPTT did not show any considerable antiproliferative activity against cancer cells of human cervical SW756, HeLa, and glioblastoma U-87, U373 cell lines. [ABSTRACT FROM AUTHOR]

Macrocyclic chelating agents 1-oxa-4,7,10-triazacyclopentadecane-3,11-dione (OTDD) and 1-thia-4,7, 10-triazacyclododecane-3,11-dione (TTDD) have been synthesized and labeled with radionuclide (Tc), with radiolabeling efficiency 97.6 and 98.4 % respectively. The radiochemical purity of labeled complex (Tc-OTDD and Tc-TTDD) was determined 97.5 and 98.1 %, respectively. The in vitro stability of the labeled chelates in human serum exhibited only <8 % dissociation upto 24 h. The in vivo distribution pattern of the labeled chelators in BALB/c mice suggested that major route of excretion in Tc-TTDD is hepatobilliary and minor is renal, while in case of Tc-OTDD hepatobilliary as well as renal both comparable. The in vivo blood kinetic studies of radio-complexes of Tc-OTDD and Tc-TTDD showed 99.26 and 99.4 % blood clearance over 24 h post injection. The biological half-life of Tc-OTDD and Tc-TTDD with t(F) 1 h 10 min, t(S) 18 h 50 min and t(F) 1 h 42 min, t(S) 18 h 20 min respectively. In vitro cytotoxicity study of OTDD and TTDD did not exhibit any significant antiproliferative property against cancer cells of human glioblastoma U-87, U373 and cervical SW756, HeLa cell lines. [ABSTRACT FROM AUTHOR]

Gamma Glutamyl Transferase (GGT) is an important biomarker in malignant cancers. The redox processes ensuing from GGT-mediated metabolism of extracellular GSH are implicated in critical aspects of tumor cell biology. Reportedly, Glutathione monoethyl ester (GSHMe) is a substrate of GGT, which has been used for its rapid transport over glutathione. Exploring GGT to be an important target, a homobivalent peptide system, DT(GSHMe)2 was designed to target GGT-over expressing tumors for diagnostic purposes. DT(GSHMe)2 was synthesized, characterized and preclinically evaluated in vitro using toxicity, cell binding assays and time dependent experiments. Stable and defined radiochemistry with 99mTc and 68Ga was optimized for high radiochemical yield. In vivo biodistribution studies were conducted for different time points along with scintigraphic studies of radiolabeled DT(GSHMe)2 on xenografted tumor models. For further validation, in silico docking studies were performed on GGT (hGGT1, P19440). Preclinical in vitro evaluations on cell lines suggested minimal toxicity of DT(GSHMe)2 at 100 μM concentration. Kinetic analysis revealed transport of 99mTc-DT(GSHMe)2 occurs via a saturable high-affinity carrier with Michaelis constant (Km) of 2.25 μM and maximal transport rate velocity (Vmax) of 0.478 μM/min. Quantitative estimation of GGT expression from western blot experiments showed substantial expression with 41.6 ± 7.07 % IDV for tumor. Small animal micro PET (Positron Emission Tomography)/CT(Computed Tomography) coregistered images depicted significantly high uptake of DT(GSHMe)2 at the BMG-1 tumor site. ROI analysis showed high tumor to contra lateral muscle ratio of 9.33 in PET imaging studies. Avid accumulation of radiotracer was observed at tumor versus inflammation site at 2 h post i.v. injection in an Ehrlich Ascites tumor (EAT) mice model, showing evident specificity for tumor. We propose DT(GSHMe)2 to be an excellent candidate for prognostication and tumor imaging using PET/SPECT. [ABSTRACT FROM AUTHOR]

The development of drug delivery nanocarriers is emerging as a promising therapeutic tool to transport anti-cancer agents to tumors. In this contribution, preparation of nanoparticles (NPs) highly loaded with cisplatin using the bio-inspired hybrid nucleoside-lipids has been reported. The construction of these NPs using a “layer-by-layer’’ approach allows surface functionalization with polyethylene glycol and targeting moieties. Uridine moieties were pegylated for folic acid (FA) functionalisation to render specificity for active targeting. The uridine moieties at the surface of the nanoparticle act as ligands for 99mTc radiolabeling, whereas the lipid chains maintain the structure of the nanoparticle. In vitro, these hybrid NPs are stable and actively internalize in two different cell lines overexpressing the folic acid receptor. In vivo scintigraphy shows that nucleolipid functionalized NPs notably improved the pharmacokinetic profile of cisplatin (enhanced blood circulation time) and accumulated in the tumor xenografted mice model. [ABSTRACT FROM AUTHOR]

The present investigation deals with the development of topical (top.) formulation for co-delivery of cisplatin and imiquimod to enhance the antitumor efficacy of the drug for skin-cited malignancies even in immune compromised patient. Cisplatin (CDDP) and imiquimod-loaded protransfersome gel (CDDP-Imi-Pts gel) formulation was characterized for entrapment efficiency, pH, and viscosity. Further, fluorescence-labeled (6-carboxyfluorescin) and radiolabeled (99mtechnetium) drug-loaded formulations were compared with respect to biodistribution and pharmacokinetic studies. Gamma scintigraphy of mice following radiolabeled formulation administrations was performed to accomplish the localization of drugs in various organs. The percentage entrapment efficiency of cisplatin and imiquimod in the protransfersome gel formulations were found to be 36.22 ± 6.41 and 63.11 ± 3.73. The skin/blood localization ratio of 1.096, 120.13, 0.174, and 349.88 was found for intraperitoneal radiolabeled drug solution (99m-Tc-CDDP-Imi-Sol), top. radiolabeled drug-loaded protransfersome gel formulation (99m-Tc-CDDP-Imi-Pts gel), intraperitoneal 6-carboxyfluorescin labeled drug solution (6-Cf-CDDP-Imi-Sol), top. 6-carboxyfluorescin labeled drug-loaded protransfersome gel formulation (6-Cf-CDDP-Imi-Pts gel), respectively after 0.5h of administration. CDDP-Imi-Pts gel has a potential for site specific delivery and reduces the systemic toxicity of anti cancer drugs. These findings suggest that the cisplatin-imiquimod co-delivery offers an attractive, novel approach for treatment of skin-cited malignancies. [ABSTRACT FROM AUTHOR]

Aim of present study was to develop a solid nanoemulsion preconcentrate of paclitaxel (PAC) using oil [propylene glycol monocaprylate/ glycerol monooleate, 4 : 1w/w], surfactant [polyoxyethylene 20 sorbitan monooleate/polyoxyl 15 hydroxystearate, 1 : 1w/w], and cosurfactant [diethylene glycol monoethyl ether/polyethylene glycol 300, 1 : 1w/w] to form stable nanocarrier. The prepared formulation was characterized for droplet size, polydispersity index, and zeta potential. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to assess surface morphology and drug encapsulation and its integrity. Cumulative drug release of prepared formulation through dialysis bag and permeability coefficient through everted gut sac were found to be remarkably higher than the pure drug suspension and commercial intravenous product (Intaxel), respectively. Solid nanoemulsion preconcentrate of PAC exhibited strong inhibitory effect on proliferation of MCF-7 cells in MTT assay. In vivo systemic exposure of prepared formulation through oral administration was comparable to that of Intaxel in γ scintigraphy imaging. Our findings suggest that the prepared solid nanoemulsion preconcentrate can be used as an effective oral solid dosage form to improve dissolution and bioavailability of PAC. [ABSTRACT FROM AUTHOR]

A bisphosphonate derivative DTPA-bis(alendronate) conjugate has been synthesized and evaluated as potential radiopharmaceutical for bone imaging. The compound was synthesized by the covalent coupling of DTPA-bis(anhydride) with alendronate and was char-acterized on the basis of IR, NMR and mass spectroscopy. It was labelled with 99mTc with 96% efficacy and was found stable for about 24 h under physiological conditions. Blood kinetic studies of 99mTc DTPA-bis(alendronate) showed a biexponential pattern as well as quick washout from the blood circulation. The biological t1/2(F) and t1/2(S) were found to be 50 min ± 0.001 and 6 h 30 min ± 0.005, respectively. Imaging and biodistribution studies showed a significant accumulation of 99mTc DTPA-bis(alendronate) conjugate at bone site. Bone-to-muscles ratios were 12.08 ± 0.001 at 1 h, 45.33 ± 0.001 at 4 h and 35.83 ± 0.001 at 24 h after post-injection, respectively. The receptor binding of the 99mTc- DTPA-bis (alendronate) was established on human bone cell line (Soas-2) revealed KD = 0.86 n m. The preliminary result of the 99mTc- DTPA-bis(alendronate) is encouraging to carrying out further in vivo experiment for targeted bone imaging because of good-bone-to-normal-organ contrast. Further docking analysis with molecular targets, farnesyl diphosphate synthase, geranylgeranyl pyrophosphate and osteocalcin revealed the high affinity of −17.419 and thus represents strong potential of bone-imaging agent. [ABSTRACT FROM AUTHOR]

The purpose of present investigation was to formulate and characterize the cyclobenzaprine HCl (CBZ)-loaded thiolated chitosan nanoparticles and assessment of in-vitro cell viability, trans-mucosal permeability on RPMI2650 cell monolayer, in-vivo pharmacokinetic and pharmacodynamic study of thiolated chitosan nanoparticles on Swiss albino mice after intranasal administration. A significant high permeation of drug was observed from thiolated chitosan nanoparticles with less toxicity on nasal epithelial cells. Brain uptake of the drug after 99mTc labeling was significantly enhanced after thiolation of chitosan. CBZ-loaded thiolated chitosan NPs significantly reverse the N-Methyl-.-Aspartate (NMDA)-induced hyperalgesia by intranasal administration than the CBZ solution. The studies of present investigation revealed that thiolation of chitosan significantly reduce trans-mucosal toxicity with enhanced trans-mucosal permeability via paracellular pathway and brain uptake of a hydrophilic drug (normally impermeable across blood brain barrier) and pain alleviation activity via intranasal route. [ABSTRACT FROM AUTHOR]

This study describes corneal permeation of gatifloxacin from solid lipid nanoparticle (SLN) through the cornea and its effect on corneal hydration level. The aqueous humor levels of gatifloxacin after single topical instillation in Gate® Eyedrops and positively charged SLN-C were determined. A 3.37-fold increase in the relative bioavailability was observed with the SLN-C (AUC0→∞ 2.192 μg mL−1 h) (AUC, area under the curve) as compared to Gate® Eyedrops (AUC0→∞ 0.651 μg mL−1 h). The t1/2 of drug in SLN-C exhibited a 2.34-fold higher than Gate® Eyedrops seem to be significantly increased ( p > 0.05), Cmax of gatifloxacin from SLN-C showed 1.09-fold higher concentration as compared to Gate® Eyedrops. The results suggested that SLNs could enhance ocular bioavailability of gatifloxacin and prolong its residence time in the eyes. Moreover, no signs of ocular irritation were seen with the SLN formulations, indicating their relative safety compared to the marketed drops. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]