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.

Formulation of chitosan coated nanoliposomes for the oral delivery of colistin sulfate: in vitro characterization, 99mTc-radiolabeling and in vivo biodistribution studies.

Colistin sulfate is a very important antibiotic for the treatment of multidrug-resistant Gram-negative infections. Unfortunately, it has low oral bioavailability and several side effects following parenteral administration. The present study aims to develop chitosan-coated colistin nanoliposomes to improve the stability in the gastrointestinal tract and to enhance the oral delivery of colistin. The chitosan-coated colistin nanoliposomes were obtained via thin-film evaporation and electrostatic deposition methods using either Span 60, Tween 65 or Tween 80 as surfactants with different cholesterol: surfactant: soya lecithin ratios. The influence of systems variables was further characterized by vesicle size analysis, zeta potential (ZP), poly dispersibility index (PDI), and also their entrapment efficiency percentage (EE %) was evaluated. Various systems were formed with vesicle sizes in the nano-range, 155.64 ± 12.53 nm to 315.64 ± 15.90 nm, and EE % of 45.2 ± 2.9% to 81.8 ± 2.9%. Moreover, the ZP value of the prepared nanoliposomes switched from a negative to a positive value after chitosan coating. To track the released colistin in vivo, technetium 99m (99mTc) was incorporated into the optimum system (S-3) system via direct coupling with colistin. Chitosan-coated 99mTc-colistin nanoliposome, 99mTc-colistin suspension, and 99mTc-chitosan-coated nanoliposomes (placebo) were administered orally into bacterial infection (Escherichia coli) bearing mice. The biodistribution results showed that chitosan-coated nanoliposome significantly enhanced the bioavailability of colistin compared to colistin suspension (the commercially available). Moreover, the system effectively improved the localization of colistin at the infected muscle. In conclusion, this approach offers a promising tool for enhanced oral delivery of colistin.

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.

Evaluation of radioiodinated ethopabate as a potential tumor targeting agent.

Overexpression of folate synthesis and folate receptor in a wide variety of tumors was reported. As a result, folate derivatives have emerged as a potential candidate for tumor imaging and therapy. Ethopabate is a structural analogue of para-aminobenzoic acid (PABA), a precursor of folic acid. Ethopabate was radiolabeled with radioiodine-131 (131I) via direct electrophilic substitution reaction. Several factors that might affect the radiolabeling yield were studied. Paper chromatography was utilized for testing and evaluation of [131I]iodoethopabate, and HPLC was used as a co-chromatographic tool to confirm the radiochemical yield. The biodistribution of [131I]iodoethopabate in normal and tumor-bearing mice was investigated. The radioiodination of ethopabate resulted in a radiochemical yield of 93.70 ± 0.19%. The biodistribution data revealed that [131I]iodoethopabate was taken up by tumors with promising target/non-target (T/NT) ratios. Where, the tumor to-blood ratios were 3.30 ± 0.40 and 4.06 ± 0.10 at 1 and 4 h post injection, respectively. As a result of these findings, [131I]iodoethopabate appears to have excellent tumor uptake and adequate stability to be used for diagnostic purpose in the future.

Radio-iodination and biological evaluation of pentoxifylline as a novel probe for diagnosis of intermittent claudication.

The diagnosis of intermittent claudication (IC) is challenging. Imaging with radiopharmaceuticals provides a new method for detecting acute IC. Pentoxifylline improves blood flow to ischemic tissues via increasing erythrocyte elasticity and inhibiting platelet aggregation. Pentoxifylline was radio-iodinated with radioiodine-131 (131I) through a direct electrophilic substitution reaction. Furthermore, various factors that might influence the radiolabeling strategy were investigated. The radiochemical yield of [131I]iodopentoxiphyline was evaluated by using paper chromatography and HPLC methods. The biodistribution pattern of [131I]iodopentoxiphyline was studied, where Swiss albino mice was used as a model of acute limb ischemia-reperfusion. The maximum radiochemical yield of pentoxifylline was found to be 94.11 ± 2.35%. The biodistribution findings revealed that [131I]iodopentoxiphyline was significantly deposited at the ischemic site (left hind limbs), with encouraging target/non-target (T/NT) ratios. At 0.25 and 1 h post injection, the uptake of [131I]iodo-pentoxifylline was 5.30 ± 0.30 and 9.98 ± 1.12%, respectively. Also, the maximum T/NT ratio for [131I]iodo-pentoxifylline (9.45 ± 0.26) was obtained at 0.25 h post injection. Due to safety and selectivity, [131I]iodo-pentoxifylline may be a good prospective diagnostic tool for early identification of IC. Moreover, the outcome of this study can be expected to apply to I-123 as well.

Radioiodination and in vivo assessment of the potential of newly synthesized pyrrolizine-5-carboxamides derivative in tumor model.

Recently, pyrrolizine derivatives have been reported to possess numerous anticancer activities. In a previous study, (EZ)-6-((4-chlorobenzylidene)-amino)-7-cyano-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine carboxamide (EZPCA) compound was synthesized and the cytotoxic activity of EZPCA toward COX-2 enzyme (overexpressed in cancer cells) was reported. In order to assess the suitability of this compound as a promising pilot structure for in vivo applications, EZPCA was radiolabeled with radioiodine-131 (131I) and various factors affecting radiolabeling process were studied. Quality control studies of [131I]iodo-EZPCA were performed using paper chromatography and HPLC was used as a co-chromatographic technique for confirming the radiochemical yield. Biodistribution studies of [131I]iodo-EZPCA were undertaken in normal and tumor bearing mice. The radiochemical yield percentage of [131I]iodo-EZPCA was 94.20 ± 0.12%. The biodistribution results showed evident tumor uptake of [131I]iodo-EZPCA with promising target/non-target (T/NT) ratios. As a conclusion, these data suggest that [131I]iodo-EZPCA had high binding efficiency, high tumor uptake and sufficient stability to be used be used in diagnostic studies.

Design and development of microemulsion systems of a new antineoplaston A10 analog for enhanced intravenous antitumor activity: In vitro characterization, molecular docking, 125I-radiolabeling and in vivo biodistribution studies.

A10, (3-phenylacetylamino-2,6-piperidinedione), is a natural peptide with broad antineoplastic activity. Recently, in vitro antitumor effect of a new A10 analog [3-(4-methoxybenzoylamino)-2,6-piperidinedione] (MPD) has been verified. However, poor aqueous solubility represents an obstacle towards intravenous formulation of MPD and impedes successful in vivo antitumor activity. To surmount such limitation, MPD microemulsion (MPDME) was developed. A 3122 full factorial design using Design-Expert® software was adopted to study the influence of different parameters and select the optimum formulation (MPDME1). Transmission electron microscopy (TEM) displayed spherical droplets of MPDME1. The cytotoxicity of MPDME1 in Michigan Cancer Foundation 7 (MCF-7) breast cancer cell line exceeded that of MPD solution (MPDS) and tamoxifen. Compatibility with injectable diluents, in vitro hemolytic studies and in vivo histopathological examination confirmed the safety of parenteral application of MPDME1. Molecular docking results showed almost same binding affinity of A10, MPD and 125I-MPD with histone deacetylase 8 (HDAC8) receptor. Accordingly, radioiodination of MPDME1 and MPDS was done via direct electrophilic substitution reaction. Biodistribution of 125I-MPDME1 and 125I-MPDS in normal and tumor (ascites and solid) bearing mice showed high accumulation of 125I-MPDME1 in tumor tissues. Overall, the results proved that MPDME represents promising parenteral delivery system capable of improving antineoplastic activity of MPD.

Improved Targeting and Tumor Retention of a Newly Synthesized Antineoplaston A10 Derivative by Intratumoral Administration: Molecular Docking, Technetium 99m Radiolabeling, and In Vivo Biodistribution Studies.

BACKGROUND: Recently, the direct intratumoral (i.t.) injection of anticancer agents has been investigated. A newly synthesized Antineoplaston A10 analog 3-(4-methoxybenzoylamino)-2,6-piperidinedione (MPD) showed an antitumor activity in human breast cancer cell line. Unfortunately, MPD suffered from poor water solubility. MATERIALS AND METHODS: Pseudoternary phase diagram of oil (isopropyl myristate), surfactant (Tween 80), cosurfactant (ethanol), and water was plotted. MPD microemulsion (MPDME) was developed and characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and morphology (transmission electron microscopy). MPDME and MPD solution (MPDS) were radiolabeled with technetium 99m (99mTc) using stannous chloride dihydrate (SnCl2.2H2O). Molecular docking of MPD and 99mTc-MPD was performed to study the interaction with DNA. RESULTS: The impacts of intravenous (i.v.) and i.t. injections of 99mTc-MPDME and 99mTc-MPDS on biodistribution were studied. The developed MPDME showed spherical droplets with mean PS (74.00 ± 5.69 nm), PDI (0.25 ± 0.03), and ZP (33.90 ± 0.90 mV). Labeling yield of 99mTc-MPDME and 99mTc-MPDS was 97.00% ± 0.60% and 92.02% ± 0.45%, respectively. MPD and 99mTc-MPD showed almost same binding affinity with DNA binding site. Biodistribution results showed that i.t. injection of 99mTc-MPDME significantly enhanced tumor retention compared to i.v. route. CONCLUSIONS: Herein, the authors concluded that microemulsion could be used as i.t. injectable delivery vehicle to improve targeting and tumor retention of MPD.

Molecular Docking, Pharmacophore, and 3D-QSAR Approach: Can Adenine Derivatives Exhibit Significant Inhibitor Towards Ebola Virus?

INTRODUCTION: Ebola Virus Disease (EVD) is caused by Ebola virus, which is often accompanied by fatal hemorrhagic fever upon infection in humans. This virus has caused the majority of deaths in human. There are no proper vaccinations and medications available for EVD. It is pivoting the attraction of scientist to develop the potent vaccination or novel lead to inhibit Ebola virus. METHODS & MATERIALS: In the present study, we developed 3D-QSAR and the pharmacophoric model from the previous reported potent compounds for the Ebola virus. RESULTS & DISCUSSION: Results & Discussion: The pharmacophoric model AAAP.116 was generated with better survival value and selectivity. Moreover, the 3D-QSAR model also showed the best r2 value 0.99 using PLS factor. Thereby, we found the higher F value, which demonstrated the statistical significance of both the models. Furthermore, homological modeling and molecular docking study were performed to analyze the affinity of the potent lead. This showed the best binding energy and bond formation with targeted protein. CONCLUSION: Finally, all the results of this study concluded that 3D-QSAR and Pharmacophore models may be helpful to search potent lead for EVD treatment in future.

Pharmacophore, 3D-QSAR Models and Dynamic Simulation of 1,4-Benzothiazines for Colorectal Cancer Treatment.

AIM AND OBJECTIVE: Interleukin-6 has become an attractive protein target. This is found in the progression of colon cancer. It performs various functions in the colon cancer cells such as inflammation, activates various cell types signaling and also promotes proliferation in colon cancer cells. It is a valid target to develop anticolon cancer drug. The purpose of our study is to develop the Three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models, pharmacophore modeling and docking study as well as MD simulation to find out the novel potent inhibitors that bind with Interleukin-6 in colon cancer treatment. MATERIAL AND METHODS: In this study, common pharmacophore models and atom-based 3D-QSAR studies were carried out by using 1,4-benzothiazine derivatives with their experiential GI50values towards HT-29 human colon cancer cell line. RESULTS: The common pharmacophore model (ADHR26) was developed and the survival score was found to be 3.828. The generated pharmacophore-based alignment was used to develop a predictive atom-based 3D-QSAR model by using Partial Least Square (PLS) method. Phase predictable activity and LogGI50 also exhibited the most significant atomic position in the backbone structure of ligands for anticolon cancer activity. Molecular dynamic and docking studies for the IL-6 target provide key framework of ligand for the anticolon cancer activity. CONCLUSION: Finally, results generated from the work data, that exhibited the pharmacophore models and 3D-QSAR hypothesis might be a path of milestone in the area of medicinal chemistry to researchers for further design of new and potent IL-6 inhibitors.