Atorvastatin-loaded cubosome: a repurposed targeted delivery systems for enhanced targeting against breast cancer.

Cancer ranks as one of the most challenging illnesses to deal with because progressive phenotypic and genotypic alterations in cancer cells result in resistance and recurrence. Thus, the creation of novel medications or alternative therapy approaches is mandatory. Repurposing of old drugs is an attractive approach over the traditional drug discovery process in terms of shorter drug development duration, low-cost, highly efficient and minimum risk of failure. In this study Atorvastatin, a statin drug used to treat abnormal cholesterol levels and prevent cardiovascular disease in people at high risk, was introduced and encapsulated in cubic liquid crystals as anticancer candidate aiming at sustaining its release and achieving better cellular uptake in cancer cells. The cubic liquid crystals were successfully prepared and optimized with an entrapment effieciency of 73.57% ±1.35 and particle size around 200 nm. The selected formulae were effectively doped with radioactive iodine 131I to enable the noninvasive visualization and trafficking of the new formulae. The in vivo evaluation in solid tumor bearing mice was conducted for comparing131I-Atorvastatin solution,131I-Atorvastatin loaded cubosome and 131I-Atorvastatin chitosan coated cubosome. The in vivo biodistribution study revealed that tumor radioactivity uptake of 131I-Atorvastatin cubosome and chitosan coated cubosome exhibited high accumulation in tumor tissues (target organ) scoring ID%/g of 5.67 ± 0.2 and 5.03 ± 0.1, respectively 1h post injection compared to drug solution which recorded 3.09 ± 0.05% 1h post injection. Concerning the targeting efficiency, the target/non target ratio for 131I-Atorvastatin chitosan coated cubosome was higher than that of 131I-Atorvastatin solution and 131I ATV-loaded cubosome at all time intervals and recorded T/NT ratio of 2.908 2h post injection.

Intranasal Radioiodinated Ferulic Acid Polymeric Micelles as the First Nuclear Medicine Imaging Probe for ETRA Brain Receptor.

INTRODUCTION: The aim of this work was to prepare a selective nuclear medicine imaging probe for the Endothelin 1 receptor A in the brain. MATERIAL AND METHODS: Ferulic acid (an ETRA antagonist) was radiolabeled using 131I by direct electrophilic substitution method. The radiolabeled ferulic acid was formulated as polymeric micelles to allow intranasal brain delivery. Biodistribution was studied in Swiss albino mice by comparing brain uptake of 131I-ferulic acid after IN administration of 131I-ferulic acid polymeric micelles, IN administration of 131I-ferulic acid solution and IV administration of 131I-ferulic acid solution. RESULTS: Successful radiolabeling was achieved with an RCY of 98 % using 200 µg of ferulic acid and 60 µg of CAT as oxidizing agents at pH 6, room temperature and 30 min reaction time. 131I-ferulic acid polymeric micelles were successfully formulated with the particle size of 21.63 nm and polydispersity index of 0.168. Radioactivity uptake in the brain and brain/blood uptake ratio for I.N 131I-ferulic acid polymeric micelles were greater than the two other routes at all periods. CONCLUSION: Our results provide 131I-ferulic acid polymeric micelles as a hopeful nuclear medicine tracer for ETRA brain receptor.

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.

Bone targeted new zoledronate derivative: design, synthesis, 99mTc-coupling, in-silico study and preclinical evaluation for promising osteosarcoma therapy.

Background: Zoledronate suppresses human sarcomas by blocking the formation of geranylgeranyl diphosphate (GGPP) via inhibiting GGPP synthase.Objectives: Designing of new derivative of dronic acid (1-hydroxy-2-(4-nitro-1H-imidazol-1-yl)ethan-1,1-diyl)bis phosphonic acid), structurally related to zoledronate to be used for osteosarcoma therapy.Methods: 1-hydroxy-2-(4-nitro-1H-imidazol-1-yl)ethan-1,1-diyl)bis(phosphonic acid) was synthesized in one pot reaction with a yield of 65 ± 4%. The synthesized nitro-zoledronate compound was successfully radiolabeled with 99mTc with a radiochemical purity of 92.05%. Docking accuracy and scoring reliability for the new nitro-zoledronate with human GGPPS using MOE software has been presented.Results and Conclusion: The nitro-zoledronate successfully coupled with technetium-99m at high yield to investigate its in-vivo biodistribution which indicated highly selective uptake in the skeletal system and rapid clearance from soft tissues. The in-vitro cytotoxicity of the nitro-zoledronate was evaluated and potently inhibited the osteosarcoma cell line (MG-63) after 72 hours with an IC50 value of 10 µM. To summarize, our data point to a promising candidate to improve osteosarcoma therapy.

Intra-articular formulation of colchicine loaded nanoemulsion systems for enhanced locoregional drug delivery: in vitro characterization, 99mTc coupling and in vivo biodistribution studies.

Colchicine (Col) is a drug used mainly for prevention and treatment of acute gouty arthritis. Unfortunately, colchicine has a narrow therapeutic index, with no obvious differentiation between toxic and nontoxic doses, resulting in a great deal of doubt and a disappointing outcome. To surmount such limitation, colchicine nanoemulsion systems (ColNE) were developed using water titration technique. The pseudoternary phase diagrams of surfactant (Span 20 or Span 60 or Tween 80), cosurfactant (ethanol) and oil (IPM) were constructed. The developed ColNE systems were characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP) and entrapment efficiency (EE %). ColNE-5 was selected as optimized system with PS = 103.34 ± 5.44 nm, ZP = 34.23 ± 0.94 mV, PDI = 0.26 ± 0.01% and EE % = 75.65 ± 0.34%. To track ColNE-5 in vivo, technetium 99 m (99mTc) was incorporated into this system via coupling with colchicine. 99mTc-ColNE-5 and 99mTc-Col solution (99mTc-ColS) were injected intra-articularly (IA) into the inflamed knee joint of Swiss albino mice joints stimulated by MSU crystals then the biodistribution pattern was studied. The findings revealed that IA injection of 99mTc-ColNE-5 significantly enhanced retention and the pharmacodynamic effects of Col compared to 99mTc-ColS. Herein, we concluded that nanoemulsion (NE) could be used as an IA injectable delivery vehicle to improve retention and localization of Col inside the inflamed joint.

Nanoparticle-Mediated Dual Targeting: An Approach for Enhanced Baicalin Delivery to the Liver.

In this study, water-soluble chitosan lactate (CL) was reacted with lactobionic acid (LA), a disaccharide with remarkable affinity to hepatic asialoglycoprotein (ASGP) receptors, to form dual liver-targeting LA-modified-CL polymer for site-specific drug delivery to the liver. The synthesized polymer was used to encapsulate baicalin (BA), a promising bioactive flavonoid with pH-dependent solubility, into ultrahigh drug-loaded nanoparticles (NPs) via the ionic gelation method. The successful chemical conjugation of LA with CL was tested and the formulated drug-loaded LA-modified-CL-NPs were assessed in terms of particle size (PS), encapsulation efficiency (EE) and zeta potential (ZP) using full factorial design. The in vivo biodistribution and pharmacokinetics of the designed NPs were assessed using 99mTc-radiolabeled BA following oral administration to mice and results were compared to 99mTc-BA-loaded-LA-free-NPs and 99mTc-BA solution as controls. Results showed that the chemical modification of CL with LA was successfully achieved and the method of preparation of the optimized NPs was very efficient in encapsulating BA into nearly spherical particles with an extremely high EE exceeding 90%. The optimized BA-loaded-LA-modified-CL-NPs showed an average PS of 490 nm, EE of 93.7% and ZP of 48.1 mV. Oral administration of 99mTc-BA-loaded-LA-modified-CL-NPs showed a remarkable increase in BA delivery to the liver over 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA oral solution. The mean area under the curve (AUC0-24) estimates from liver data were determined to be 11-fold and 26-fold higher from 99mTc-BA-loaded-LA-modified-CL-NPs relative to 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA solution respectively. In conclusion, the outcome of this study highlights the great potential of using LA-modified-CL-NPs for the ultrahigh encapsulation of therapeutic molecules with pH-dependent/poor water-solubility and for targeting the liver.

Synergistic Cytotoxicity Of Shikonin-Silver Nanoparticles As An Opportunity For Lung Cancer.

The combined action of shikonin and silver nanoparticles (AgNPs) for apoptosis in human cancer cells has not been elucidated. Hence, we investigated the synergistic combinatorial effect of shikonin and AgNPs in human lung cancer cells. Shikonin was used as a reducing and capping agent for AgNPs synthesis as a green method avoiding the hazards of chemical methods. Radiolabeling of shikonin-AgNPs with radioactive iodine forming [131 I]I-Shikonin-AgNPs was carried out to enable the intracellular tracking of NPs. The antitumor effect of a combined treatment (shikonin-AgNPs) was evaluated using tissue culture assay. The 50% inhibitory concentration (IC50 ) of SHK-AgNPs on A549 cells after 24 hours determined by an MTT assay is 2.4 ± 0.11 µg/mL. As a deduction, this study revealed that the combination of shikonin and AgNPs treatment significantly inhibited cell viability and proliferation of A549 cells (human lung carcinoma cell line) with a great potential than the monotherapy.

Post Discharge Formula Fortification of Maternal Human Milk of Very Low Birth Weight Preterm Infants: An Introduction of a Feeding Protocol in a University Hospital.

The objective of this study is to determine the growth parameters and nutritional biochemical markers and complications of fortification of human milk by post discharge formula of preterm very low birth weight newborns (VLBW). Fifty preterm infants less than 37 weeks with weight less than 1500 g were enrolled in the study. They received parental nutrition and feeding according to our protocol. When enteral feeding reached 100 cc/kg/day, infants were randomized into two groups: group I, Cases, n=25, where post discharge formula (PDF) was used for fortification, group II, Controls, n=25 with no fortification. Infants of both groups were given 50% of required enteral feeding as premature formula. This protocol was used until infants' weight reached 1800 g. Daily weight, weekly length and head circumference were recorded. Hemoglobin, albumin (Alb), electrolytes, blood urea nitrogen (BUN) and clinical complications were documented. Human milk fortification with PDF resulted in better growth with increase in weight 16.8 and 13.78 g/kg/day (P=0.0430), length 0.76 and 0.58 cm/week (P=0.0027), and head circumference of 0.59 and 0.5 cm/week (P=0.0217) in cases and controls respectively. Duration of hospital stay was less in cases (22.76 versus 28.52 days in Controls), P=0.02. No significant changes were found in serum electrolytes, BUN, or Alb between both groups. Hemoglobin was significantly higher in Cases, P=0.04. There were no significant clinical complications. Our feeding protocol of fortification of human milk with PDF in preterm very low birth weight newborns resulted in better growth and decrease in length of hospital stay. The use of PDF could be an alternative option for fortification of mothers' milk for preterm VLBW infants in developing countries with low resources.