pH-Sensitive doxorubicin delivery using zinc oxide nanoparticles as a rectified theranostic platform: in vitro anti-proliferative, apoptotic, cell cycle arrest and in vivo radio-distribution studies.

Despite enormous advancements in its management, cancer is the world's primary cause of mortality. Therefore, tremendous strides were made to produce intelligent theranostics with mitigated side effects and improved specificity and efficiency. Thus, we developed a pH-sensitive theranostic platform composed of dextran immobilized zinc oxide nanoparticles, loaded with doxorubicin and radiolabeled with the technetium-99m radionuclide (99mTc-labelled DOX-loaded ZnO@dextran). The platform measured 11.5 nm in diameter with -12 mV zeta potential, 88% DOX loading efficiency and 98.5% radiolabeling efficiency. It showed DOX release in a pH-responsive manner, releasing 93.1% cumulatively at pH 5 but just 7% at pH 7.4. It showed improved intracellular uptake, which resulted in a high growth suppressive effect against MCF-7 cancer cells as compared to the free DOX. It boasted a 4 times lower IC50 than DOX, indicating its significant anti-proliferative potential (0.14 and 0.55 µg ml-1, respectively). The in vitro biological evaluation revealed that its molecular mode of anti-proliferative action included downregulating Cdk-2, which provoked G1/S cell cycle arrest, and upregulating both the intracellular ROS level and caspase-3, which induced apoptosis and necrosis. The in vivo experiments in Ehrlich-ascites carcinoma bearing mice demonstrated that DOX-loaded ZnO@dextran showed a considerable 4-fold increase in anti-tumor efficacy compared to DOX. Moreover, by utilizing the diagnostic radionuclide (99mTc), the radiolabeled platform (99mTc-labelled DOX-loaded ZnO@dextran) was in vivo monitored in tumor-bearing mice, revealing high tumor accumulation (14% ID g-1 at 1 h p.i.) and reduced uptake in non-target organs with a 17.5 T/NT ratio at 1 h p.i. Hence, 99mTc-labelled DOX-loaded ZnO@dextran could be recommended as a rectified tumor-targeted theranostic platform.

Multi-functionalization of reduced graphene oxide nanosheets for tumor theragnosis: Synthesis, characterization, enzyme assay, in-silico study, radiolabeling and in vivo targeting evaluation.

BACKGROUND: In this study, a combination of nanotechnology, organic synthesis and radiochemistry were utilized in order to design an efficient nano-system conjugated with a suitable radionuclide and an antitumor agent for possible application as tumor theragnostic agent. METHOD: Four novel compounds (3 and 4a-c) bearing tetrahydroquinazoline-7-sulfonohydrazide or 1,2,3,4-tetrahydroquinazoline-7-sulfonamide scaffold were designed. Then, docking study predicted that the compounds can be considered as potential inhibitors for PARP-1. Following that; the four compounds were synthesized and properly characterized using 1HNMR, 13CNMR, IR and Mass spectroscopy. The cytotoxic effect of the four compounds was evaluated against breast cancer cell line (MDA-MB-436), where compound 3 showed the most promising cytotoxic effect. The inhibitory effect of the four compounds was evaluated in vitro against PARP-1. RESULT: Carboxylated graphene oxide nanosheets (NGO-COOH) were synthesized by a modified Hummer's method and has size of range 40 nm. The NGO-COOH nanosheets were proven to be safe and biocompatible when tested in vitro against normal human lung fibroblast cells (MRC-5). The prepared NGO-COOH nanosheets were conjugated with compound 3 then radiolabeled with 99mTc to yield 99mTc-NGO-COOH-3 with a radiochemical yield of 98.5.0 ± 0.5%. 99mTc-NGO-COOH-3 was injected intravenously in solid tumor bearing mice to study the degree of localization of the nano-system at tumor tissue. The results of the study revealed, excellent localization and retention of the designed nano-system at tumor tissues with targeting ratio of 9.0. CONCLUSION: Stirred a new candidate tumor theragnostic agent that is safe, selective and stable.

Computational, in vitro and radiation-based in vivo studies on acetamide quinazolinone derivatives as new proposed purine nucleoside phosphorylase inhibitors for breast cancer.

The present work describes a quinazolinone-based lead optimization for the development of novel purine nucleoside phosphorylase (PNP) inhibitors with quinazolinone scaffold. Nineteen compounds were proposed and docked against PNP, the best 14 compounds with highest docking and affinity scores and low RMSD values were synthesized. Synthesis of new quinazolinone derivatives with variable acetamide substituents on two positions on quinazoline ring was performed. The structures assigned to the products were concordant with the microanalytical and spectral data. In vitro cytotoxicity on human breast cancer cell line (MCF7) was performed and identified compound 6g as the most potent with IC50 (0.99 ± 0.11 µM) which was further tested against five different breast cancer cell lines in addition to normal breast cell to determine the selectivity. Compound 6g was subjected to molecular dynamic simulation study, radiolabelling and biodistribution study to investigate its stability and selectivity toward breast cancers. The in vitro PNP inhibition results were aligned with the in silico, cytotoxicity, and biodistribution results where 6g showed the most potent PNP inhibitory activity with IC50 (0.159 ± 0.007 µM) when compared to Peldesine (BCX-34) IC50 (0.041 ± 0.002 µM).

New frontier radioiodinated probe based on in silico resveratrol repositioning for microtubules dynamic targeting.

PURPOSE: As the 'de novo' drug discovery faces a highly attrition rates, drug repositioning procures a heighten concern in identifying novel uses for existing medications. This study aimed to fabricate radioiodinated resveratrol as a potent microtubules interfering agent for cancer theragnosis. METHODS: Resveratrol was radiolabeled with radioactive iodine where the radioiodination efficiency was enlightened and the computational approaches were employed to investigate the affinity and specificity with tubulins. Furthermore, the in-vivo distribution and pharmacokinetic studies in normal and tumor induced mice were investigated. RESULTS: The maximum radioiodination yield (94.6 ± 1.66) was achieved at optimum preparation parameters stated as 100 µg/mL of oxidizing agent, 100 µg/ml of resveratrol, reaction time of 30 min and reaction pH 5. The in silico studies showed that di-iodinated resveratrol (compound 6) exhibited the best binding score (-34.46) and interaction with the ß-tubulin binding site. The in vivo distribution in tumor models revealed a significant accumulation (4.02% ID/g) in tumor lesion at 60 min p.i. The rate of drug elimination demonstrated a mono-exponential decline of radioactivity versus time in the blood. CONCLUSION: Radioiodinated resveratrol revealed good microtubules targeting which render it as a novel theranostic probe for cancer management.

Multifunctional 99mTc-5-azacitidine Gold Nanoparticles: Formulation, In Vitro Cytotoxicity, Radiosynthesis, and In Vivo Pharmacokinetic Study.

BACKGROUND: 5-azacitidine is a very potent chemotherapeutic agent that suffers from certain disadvantages. OBJECTIVE: This study aims to prepare gold nanoparticles as a new nano-formula of 5-azacitidine that can improve its bioavailability and decrease its side effects. METHODS: 5-azacytidine-loaded GA-AuNPs were prepared and characterized by UV-Vis spectroscopy, infrared (IR), and electronic transmission microscope (TEM). This new platform was characterized in vitro by measuring its zeta potential, particle size, and drug loading efficacy, and the anti-proliferative effect on the MCF-7 cell line was evaluated. In vivo biodistribution studies of 99mTc-5-aza solution and 99mTc-5-aza-gold nano formula were conducted in tumor-bearing mice by different routes of administration (intravenous and intra-tumor). RESULTS: 5-Aza-GA-AuNPs formula was successfully prepared with an optimum particle size of ≈34.66 nm, the zeta potential of -14.4 mV, and high entrapment efficiency. 99mTc-5-Aza-GA-AuNPs were successfully radiosynthesized with a labeling yield of 95.4%. Biodistribution studies showed high selective accumulation in tumor and low uptake in non-target organs in the case of the 5-Aza-GA-AuNPs formula than the 99mTc-5-azacitidine solution. CONCLUSION: 99mTc-5-Aza-GA-AuNPs improved the selectivity and uptake of 5-azacitidine in cancer. Moreover, 99mTc-5-Aza-GA-AuNPs could be used as hopeful theranostic radiopharmaceutical preparation for cancer.

New 5-Aryl-1,3,4-Thiadiazole-Based Anticancer Agents: Design, Synthesis, In Vitro Biological Evaluation and In Vivo Radioactive Tracing Studies.

A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (3), substituted piperazines (4a-g), benzyl piperidine (4i), and aryl aminothiazoles (5a-e) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds 4e and 4i displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of 4e and 4i towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound 4e or 4i induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either 4e or 4i indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound 4i proved its targeting ability to sarcoma cells in a tumor-bearing mice model.

IAEA Contribution to Nanosized Targeted Radiopharmaceuticals for Drug Delivery.

The rapidly growing interest in the application of nanoscience in the future design of radiopharmaceuticals and the development of nanosized radiopharmaceuticals in the late 2000's, resulted in the creation of a Coordinated Research Project (CRP) by the International Atomic Energy Agency (IAEA) in 2014. This CRP entitled 'Nanosized delivery systems for radiopharmaceuticals' involved a team of expert scientist from various member states. This team of scientists worked on a number of cutting-edge areas of nanoscience with a focus on developing well-defined, highly effective and site-specific delivery systems of radiopharmaceuticals. Specifically, focus areas of various teams of scientists comprised of the development of nanoparticles (NPs) based on metals, polymers, and gels, and their conjugation/encapsulation or decoration with various tumor avid ligands such as peptides, folates, and small molecule phytochemicals. The research and development efforts also comprised of developing optimum radiolabeling methods of various nano vectors using diagnostic and therapeutic radionuclides including Tc-99m, Ga-68, Lu-177 and Au-198. Concerted efforts of teams of scientists within this CRP has resulted in the development of various protocols and guidelines on delivery systems of nanoradiopharmaceuticals, training of numerous graduate students/post-doctoral fellows and publications in peer reviewed journals while establishing numerous productive scientific networks in various participating member states. Some of the innovative nanoconstructs were chosen for further preclinical applications-all aimed at ultimate clinical translation for treating human cancer patients. This review article summarizes outcomes of this major international scientific endeavor.

Hepatoprotective, antioxidant and anti-inflammatory potentials of Vit-E/C@SeNPs in rats: Synthesis, characterization, biochemical, radio-biodistribution, molecular and histopathological studies.

This study aimed to synthesize a nano-structure between selenium, Vit. C, and Vit. E (Vit-E/C@SeNPs) as a promising protective and therapeutic agent for hepatocellular carcinoma. Vit-E/C@SeNPs were characterized using TEM and DLS and its zetapotential was measured to evaluate its stability. DPPH assay and SRB test were performed to estimate its antioxidant capacity and cytotoxicity, respectively. A radiosynthesis of 99mTc-Vit-E/C@SeNPs was done for further in-vivo pharmacokinetic studies on normal and solid tumor induced mice. Further, in-vivo studies were conducted to investigate Vit-E/C@SeNPs efficacy against hepatocellular damage in Wistar albino rats induced by diethylnitrosamine (DEN) / Carbon Tetra chloride (CCl4). The synthesis results showed spherical Vit-E/C@SeNPs with core size of 50 nm, radical scavenging activity (%RSC) of 75.9%, and IC50 of 27.9 µg/ml. The biochemical analysis results showed that the lower liver function biomarker values (ALT, AST, ALP, total bilirubin and GGT) has gone for the Vit-E/C@SeNPs prevention and treated group, which also showed significant depletion of liver tissue l-MDA, and obvious increase in GSH concentration and CAT activity and marked improvement in the histological feature of liver tissue. Additionally, a significant up-regulation of mRNA gene expression levels of inflammatory gene (TGFß1, NFκB, iNOS, PPAR-γ and TNFα) and Apoptotic gene (P53) were determined by using Quantitative real-time PCR (qPCR). The values down regulate and tend to normal in prevention and control group. All of these introduce Vit-E/C@SeNPs as a promising agent as protective and therapeutic agent against DEN/ CCl4-induced hepatocellular damage (Hepatocellular carcinoma).

Polyethylene oxide-polyacrylic acid-folic acid (PEO-PAAc) nanogel as a 99m Tc targeting receptor for cancer diagnostic imaging.

Nanoparticles are frequently used as targeting delivery systems for therapeutic and diagnostic radiopharmaceuticals. Polyethylene oxide-polyacrylic acid (PEO-PAAc) nanogel was prepared via γ-radiation-induced polymerization. Variable factors affecting nanoparticles size were investigated. The nanogel was radiolabeled with the imaging radioisotope 99m Tc and finally conjugated with folic acid to target folate receptor actively. PEO-PAAc-folic acid gel was characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). Biodistribution was studied in normal mice and solid tumor-bearing mice via intravenous and intratumor injections of the radiolabeled PEO-PAAc-folic acid nanogel. Results of biodistribution showed high selective uptake of the prepared complex in tumor muscle compared with normal muscle for both intravenous and intratumor injections. The T/NT ratio was found to be 6.186 and 294.5 for intravenous and intratumor injections, respectively. Consequently, 99m Tc-PEO-PAAc-folic acid complex could be a promising agent for cancer diagnostic imaging.

Amelioration of Tumor Targeting and In Vivo Biodistribution of 99mTc-Methotrexate-Gold Nanoparticles (99mTc-Mex-AuNPs).

Gold nanoparticles (AuNPs) represent very attractive and promising drug delivery carriers due to their unique dimensions, adjustable surface functions, and controllable drug release. Therefore, AuNPs are used to overcome the limitations of conventional chemotherapy, for example methotrexate (Mex), one of the first-generation chemotherapy drugs for cancer treatment, whose usefulness has been restricted due to drug resistance and dose-dependent side effects. In the present study, the AuNPs drug delivery system was synthesized and loaded with technetium-99 m radiolabeled Methotrexate (99mTc-Mex) to produce new potential nanoradiopharmaceutical for tumor targeting and further imaging. The Methotrexate loaded gold nanoparticles (Mex-AuNPs) successfully prepared in small spherical particle size (20.3 nm), polydispersity index PDI (< 0.5) and a zeta potential (-17.6 mV) with loading efficiency% (93 ± 1.2%) of methotrexate at 30 min as an optimum stirring time and showed strong absorption peak for Mex-AuNPs at λmax, 525 nm. The in vitro release profile of Mex-AuNPs showed high release percent of methotrexate at pH 5; the Q0.5 h and Q8h were 21.2 ± 1.5% and 92.9 ± 3.4%, respectively. The in vitro cytotoxicity was investigated at different concentrations (0.024-50 µl/100 µl) of Mex-AuNPs (1 mg/ml) against MCF-7 (Michigan Cancer Foundation-7) breast cancer cells by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay technique. Mex-AuNPs showed higher anticancer activity with low inhibitory concentration (IC50 = 0.098 µl/100 µl) that was three times lower than the inhibitory concentration (IC50) of methotrexate (IC50 = 0.3 µl/100 µl). 99mTc-Mex complex prepared by direct reduction method at maximum radiochemical yield (RCY)% Ì´ 98.3 ± 1.09 % was loaded in AuNPs to form 99mTc-Mex-AuNPs with loading efficiency% (93 ± 1.2 %) at 30 min of stirring time. 99mTc-Mex-AuNPs showed convenient in vitro stability in mice serum up to 24 h with RCY% > 90 %. The preclinical biodistribution studies of 99mTc-Mex-AuNPs were performed in 3 experimental groups A (intravenous (I.V.) injected normal mice), B and C (I.V. and intratumor (I.T.) injected tumor bearing mice, respectively). The 99mTc-Mex-AuNPs achieved highest tumor uptake (93 ± 0.39 %ID/g) and highest Target/NonTarget (T/NT) ratio (58.1 ± 0.91) with high Tumor/Blood (T/B) ratio (25.8 ± 0.11) at 10 min post I.T. injection and retained high tumor uptake (79 ± 0.65 %ID/g) up to 60 min post I.T. injection before escaping into blood stream. Consequently, 99mTc-Mex-AuNPs can be considered as new potential nanoradiopharmaceutical in tumor diagnosis.

New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: design, synthesis, computational and bio-distribution studies.

The current work represents the design and synthetic approaches of a new set of compounds 6-10 bearing the 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide scaffold. The biological evaluation revealed that most of the new compounds were promising selective dipeptidyl peptidase-IV (DPP-4) inhibitors and in vivo hypoglycemic agents utilizing linagliptin as a standard drug. The acute toxicity examination confirmed the safety profile of all compounds. Molecular docking studies related the significant DPP-4 suppression activity of compounds 9a, 10a, 10f, 10g to their nice fitting in the active pocket of DPP-4. In addition, the molecular dynamic study exhibited the stability of both 10a and 10g within the active site of DPP-4. The QSAR study showed that the difference between the predicted activities is very close to the experimental suppression effect. Moreover, both compounds 10a and 10g obeyed Lipinski's rule, indicating their efficient oral bioavailability. Compound 10a was radiolabeled, forming the 131I-SQ compound 10a to study the pharmacokinetic profile of this set of compounds. The biodistribution pattern hit the target protein since the tracer accumulated mainly in the visceral organs where DPP-4 is secreted in a high-level, thus with consequent stimulation of insulin secretion, leading to the target hypoglycemic effect.

Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design, synthesis, radiolabeling and biodistribution study.

Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC50 = 8.21-16.95 µM) superior to that of thiourea reference standard (IC50 = 20.04 µM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC50 = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of 99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.

99mTc-gallic-gold nanoparticles as a new imaging platform for tumor targeting.

Early and accurate detection of tumor assists in identifying more effective therapies. Gold nanoparticles (GNPs) were synthesized by green synthesis method using gallic acid (GA) then characterized and labeled with technetium-99m. This new platform was biologically evaluated in both normal and solid tumor bearing mice. The in-vivo study of [99mTc]Tc-gallic-GNPs via both I.V. and I.T injecton showed a high accumulation in tumor site. As a result, [99mTc]Tc-gallic-GNPs can be afforded as a potential nano-platform for tumor imaging.

99mTc-doxorubicin-loaded gallic acid-gold nanoparticles (99mTc-DOX-loaded GA-Au NPs) as a multifunctional theranostic agent.

The development of cancer theranostic nanomedicines is recommended to concurrently achieve and evaluate the therapeutic benefit and progress. The current work aims to develop gallic acid-gold nanoparticles (GA-Au NPs) as a theranostic probe for 99mTc-Doxorubicin (99mTc-DOX) based on the spatiotemporal release pattern induced intra-tumoral (IT) delivery. DOX-loaded GA-Au NPs were developed and identified via UV-Vis spectroscopy. The system was characterized for drug loading efficiency%, particle size, zeta potential, topography, in vitro DOX release and anti-proliferative activity against the MCF-7 cell-line. The factors influencing radiolabeling efficiency of DOX with 99mTc (DOX concentration, stannous chloride concentration, reaction time and pH) were optimized. The in vitro stability in mice serum and in vivo distribution studies in mice of 99mTc-DOX-loaded GA-Au NPs were investigated following IV and IT administration. Dox-loaded GA-Au NPs had a loading efficiency of 91%, a small particle size (≈50 nm), a promising zeta potential (-20 mV) and a sustained drug release profile at pH 5.3. GA-Au NPs exhibited increased anti-proliferative activity, with approximately a four-fold lower IC50 value (0.15 µg/ml) than free DOX. The optimized radiolabeling efficiency of 99mTc-DOX was ≈93%. It showed good physiological stability in mice serum for at least 8 h. The IT delivery of 99mTc-DOX-loaded GA-Au NPs in tumor-induced mice showed dramatic tumor accumulation. A maximum magnitude of 86.73%ID/g was achieved, at 15 min post-injection, with a target/non-target ratio of ≈56. 99mTc-DOX-loaded GA-Au NPs could be used for the selective IT delivery of a chemotherapeutic agent and an imaging agent to a target organ.

Exhibiting the diagnostic face of selenium nanoparticles as a radio-platform for tumor imaging.

Selenium nanoparticles (SeNPs) have become one of the most prospective and promising tools in the course of cancer diagnosis and therapy. Here we describe the synthesis of a novel radioactive platform for tumor imaging using selenium nanoparticles. SeNPs were synthetized using dithionite and glutathione as reducing and capping agent respectively with 5 mmol/L sodium selenite as a precursor and then SeNPs radiolabeled with technetium-99 m, the most common and famous radioactive isotope used for imaging purposes. A characteristic profile for the synthesized SeNPs was performed including size analysis, zeta potential, antioxidant activity, radiochemical yield and in-vivo biodistribution in normal and solid tumor bearing mice. Size analysis showed amorphous SeNP cores of a mean diameter of 21 ± 5 nm with a hydrodynamic size of 43 ± 8 nm and -28 mV zeta potential. The particles also showed a superior antioxidant activity of radical scavenging activity 55.6% according to DPPH assay, in addition, satisfying radiochemical yield up to 97 ± 1.5 was achieved. In vivo studies were applied on male Swiss albino mice that demonstrated a good biodistribution pattern in normal mice with a moderate accumulation in liver at 30 min post injection. Excellent T/NT ratios were obtained in solid tumor bearing mice throughout the experimental time points. The as-synthetized selenium nanoparticles demonstrated surprising and satisfying features which make them promising enough for tumor theranosis.

New acrylamide-sulfisoxazole conjugates as dihydropteroate synthase inhibitors.

New functionalized acrylamide derivatives bearing sulfisoxazole moiety were designed to target bacterial dihydropteroate synthase (DHPS). The in vitro antimicrobial activities of these compounds were assessed. The E-configuration of compound 5b was proved by single crystal X-ray analysis. Compounds 5g and 5h displayed double the activity of ampicillin against B. subtilis. Also, 5h was two times more active than gentamycin against E. coli. Interestingly, compounds 5f-g, 7c, 8a, 8c exhibited two folds the potency of amphotericin B against S. racemosum while 5h displayed three folds the activity of amphotericin B against S. racemosum. Most of the synthesized compounds showed superior activities to the parent sulfisoxazole and were non-toxic to normal cells. DHPS is confirmed to be a putative target for our compounds via antagonizing their antibacterial activity by the folate precursor (p-aminobenzoic acid) and product (methionine) on E. coli ATCC 25922. Docking experiments against DHPS rationalized the observed antibacterial activity. Additionally, compound 5g was evaluated as a selective targeting vector for 99mTc that showed a remarkable uptake and targeting ability towards the infection site that was induced in mice.

New benzenesulfonamide scaffold-based cytotoxic agents: Design, synthesis, cell viability, apoptotic activity and radioactive tracing studies.

A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b, 5c and 5e, were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the <2n phase. To further confirm apoptosis induction, caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model.

Rational design of some substituted phenyl azanediyl (bis) methylene phosphonic acid derivatives as potential anticancer agents and imaging probes: Computational inputs, chemical synthesis, radiolabeling, biodistribution and gamma scintigraphy.

Bisphosphonates are widely used for treatment of osteoporosis. Recently, they have been reported to be effective anticancer agents. In this work, we designed some substituted phenyl (azanediyl) bis (methylene phosphonic acid) to be tested for their anticancer effect. Both molecular docking and dynamics studies were used to select the top ranked highly scored compounds. The selected hits showed potential in vitro anticancer effect against some cell lines. Biodistribution pattern and gamma scintigraphy were conducted to the most effective derivative (BMBP) after radiolabeling with 99mTc. Results of biodistribution and scintigraphic imaging of 99mTc-BMBP in tumor bearing mice showed a notable tumor affinity, and confirmed the targeting affinity of BMBP to the tumor tissues. As a conclusion, BMBP could act as potential anticancer agent and imaging probe.

Superiority of DEAE-Dx-Stabilized Cationic Bile-Based Vesicles over Conventional Vesicles for Enhanced Hepatic Delivery of Daclatasvir.

The purpose of our study was to improve the delivery of a direct-acting antiviral drug, daclatasvir, to the site of action, liver tissues, using physically and biologically stable cationic bile-based vesicles. Accordingly, cationic bile-based vesicles were prepared as pro-bile-based vesicles and diethylaminoethyl dextran (DEAE-Dx)-stabilized bile-based vesicles to increase their stability without negatively affecting their hepatic affinity. The prepared bile-based vesicles were characterized for particle size, polydispersity index, ζ-potential, in vitro daclatasvir release, and ex vivo permeation using non-everted gut sac intestine. The in vivo biodistribution was experimented after oral administration utilizing the radiolabeling assay, where the liver showed the highest accumulation of the DEAE-Dx-stabilized bile-based vesicles after 4 h, reaching a value of 4.6% ID/g of the total oral administered dose of the labeled drug compared to drug solution, pro-bile-based vesicles, and cationic bile-based vesicles where the accumulation was 0.19, 1.3, and 0.31% ID/g, respectively. DEAE-Dx-stabilized bile-based vesicles increased the drug deposition into the liver about 42-fold compared to oral solution. The high physical stability and the high resistance to opsonization and clearance show that DEAE-Dx-stabilized bile-based vesicles could be efficiently applied for enhancing daclatasvir delivery to the liver after oral administration.

Adaptation of hard gelatin capsules for oral delivery of aqueous radiopharmaceuticals.

PURPOSE: Oral administration of Iodine-131 (I-131) solutions causes high risk of contamination for patients and dispensers. The objective of the study was to adapt hard gelatin capsules (HGCs) for filling with radiopharmaceutical solutions without deformation. METHODS: Polystyrene (PS) internally lining films with different thicknesses were used to protect HGCs. The insulated HGCs were evaluated for their physicochemical characteristics and rupturing time in different dissolution media. HGCs internally lined with PS were examined for withstand loading with different volumes and radioactivities of I-131 solutions. Radioactivity release was studied in deionized water and acidic media. Quality control of released I-131 was inspected for radiochemical purities. RESULTS: There was a directly proportion between PS lining thickness and stability of HGCs after filling with 500 µl aqueous methylene blue solution. HGCs internally lined with PS 100 µm thickness withstand deformation for ˃ two months; however showed fast in-vitro rupturing time in different dissolution media. Internally lined HGCs loaded with different volumes and radioactivities of I-131 solutions resisted for one week without radioactive leakage. Yet, revealed complete release of I-131 after 20 min in dissolution media with great radiochemical purity. CONCLUSION: The study promises safely I-131 aqueous solution delivery via adapted HGCs. Graphical abstract Oral administration of radiopharmaceuticals.