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Background: Ligustrazine and chalcones have been reported previously for various biological activities including anticancer effects. Objectives: Based on the multitargeted biological activities approach of ligustrazine-based chalcones, in the current study 18 synthetic ligustrazine-containing α, β-unsaturated carbonyl-based 1, 3- Diphenyl-2-propen-1-one derivatives were evaluated for their inhibitory effects on the growth of five different types of cancer cells. Methods: All the compounds were evaluated for anticancer effects on various cancer cell lines by propidium iodide fluorescence assay and various other assays were performed for mechanistic studies. Results: A majority of compounds exhibited strong inhibition of cancer cells, especially synthetic compounds 4a and 4b, bearing 1-Pyridin-3-yl-ethanone as a ketone moiety in the main structural backbone were found to be most powerful inhibitors of cancer cell growth. Nine most active compounds among the whole series were selected for further studies related to different cancer targets, including EGFR TK kinases, tubulin polymerization, KAF and BRAFV600E. Conclusion: Synthetic derivatives, including 4a-b and 5a-b showed a multitarget approach and strong inhibitory effects on EGFR, FAK and BRAF while three compounds, including 3e bearing methoxy substitution, 4a and 4b with 1-pyridin-3-yl-ethanone moiety showed the inhibition of tubulin polymerization.

Purpose: To assess the prevalence of handwritten prescription errors in Rafha Central Hospital in Saudi Arabia, and to determine the most predominant type of prescription error. Methods: A cross-sectional study was carried out on randomly selected samples of hand-written prescriptions in out-patient and in-patient pharmacies of Rafha Central Hospital over a five-month period (October 2016 to February 2017). A data collection sheet specially designed for this purpose was used to collect relevant information. The collected prescriptions were analyzed for the presence of prescription errors based on prescription parameters defined by the World Health Organization (WHO) and current guidelines published in British National Formulary (BNF). Descriptive statistics and Microsoft Office were used for processing and analyzing the data collected. Results: Overall, 1019 prescription errors were identified. More than half of the total errors (610; 60 %) were associated with missing patient's information. Moreover, the parameters related to drug and prescriber information were absent in 204 (20 %) and 5 (0.4 %) prescriptions, respectively. In addition, 200 (19 %) miscellaneous errors related to date, legible handwriting and directions for patients were identified. Conclusion: This study discovered errors in hand-written prescriptions. A majority of the prescriptions did not adhere to accepted guidelines. The most common errors are absence of generic names of drugs, non-indication of duration of therapy or prescriber’s contact address, and absence of patient’s weight. Moreover, illegible handwriting was obvious in a substantial number of prescriptions.

Every year millions of new cases of various types of cancers are diagnosed, leading to an alarming rate of fatalities. Mitoxantrone is an anthracenedione antineoplastic agent which is used in the treatment of various types of cancer, mostly acute myeloid leukemia and prostate cancer. In spite of its therapeutic applications, it possesses numerous limitations and side effects including specific targeting and systemic toxicity. Sodium alginate is a biodegradable, mucoadhesive and biocompatible polymer commonly used in drug delivery applications. Glutaraldehyde is a saturated dialdehyde and is used as a polymer cross linker. In this study, mitoxantrone-loaded glutaraldehyde-sodium alginate nanoparticles were developed by ionic gelation method and characterized (determination of particle size, drug entrapment efficiency, drug release and its kinetics) for the delivery of anticancer drugs. The nanoparticles mean particle size was found to be within the acceptable range. The entrapment efficiency was also on the higher side with sustained drug release. The findings of this study reveal promising potential of delivery system and project the way forward for further in vitro and in vivo investigations.

Nanotechnology facilitated drug delivery has been used to enhance the drug bioavailability, efficacy, reduce toxicity and improve patient compliance aiming to targetthe cells and tissues to produce anticipated pharmacological action. The aim of the present study was to formulate and evaluate rivastigmine (RT) loaded chitosan (CS) nanoparticles for sustained release. RT is a short actingreversible acetylcholinesterase inhibitor used for the treatment of mild to moderate Alzheimer's and Parkinson's disease. In current research RT loaded CS-tripolyphosphate (TPP) nanoparticles were prepared by usingionic gelation method in fourdifferent polymer concentrations (0.1%,0.2%,0.3%,0.4%). The prepared nanoparticles were evaluated by Zeta sizer in order to determine particle size, PDI and zeta potential. Further, drug entrapment efficiency and in vitro release studies were carried out. The results showed that particle size decreased by loading drug within nanoparticles when compared with unloaded nanoparticles. The particle size of RT loaded CS nanoparticles ranged from 125.9 ± 2.5 to 356.0 ± 7.9 by varying CS concentration from 0.1% to 0.4% w/v. Among different ratios studied, 0.4% ratio showed highest drug entrapment efficiency (80%). In vitro release studies showed that RT loaded CS nanoparticles could sustain release the drug.In conclusion, the current research results showed that the chitosan nanoparticles can be used as a potential carrier for providing sustained delivery of RT.

Introduction Organ transplantation is a critically important procedure, which requires immune modulation by using immunosuppressants. Development of nanoparticles is an emerging and beneficial engineering process to increase the dissolution rate of poorly soluble immunosuppressants as well as to provide controlled release for better therapeutic outcomes. Method Currently, the nanoprecipitation method was employed to fabricate β-cyclodextrin (βCD) facilitated mycophenolate mofetil (MMF)-loaded solid lipid nanoparticles (SLNPs). The prime objectives of the study included, improvement of the dissolution profile of poorly aqueous soluble drug and controlled release from the SLNs to provide steady state drug concentration. Drug release from the prepared SLNs was assessed in two different media, ie, acidic buffer at pH 1.2 and phosphate buffer at pH 7.2 using USP dissolution apparatus for 12 h, followed by the evaluation of drug release mechanism and pattern by applying kinetic models. Results Justifiably, in acidic medium, the release was found to be 12% more (68%) in comparison to that in basic medium (56%). However, in both dissolution media, drug release was independent of initial concentration (R2>0.95) with non-Fickian type of diffusion mechanism. The outcomes of the study have exhibited that prepared formulations were in nanosized range (80-170 nm) with a net charge of ±23 charge on their surface. They possessed fairly uniform surface with acceptable polydispersity index (0.23±0.09). Scanning electron microscopy (SEM) analysis illustrated that the nanoparticles had uniform particle size and shape. Discussion The findings show potential applications of the nanoparticles and the method for the development of SLNPs in controlled release of MMF for better therapeutic outcomes. Conclusively, the prepared SLNPs were well designed in nanosized ranges and justifying the once daily controlled release formulation dose of MMF to enhance patient compliance.

Background Bisphosphonates have very low bioavailability and cause irritation of the esophagus and stomach. This study was planned to improve the oral bioavailability of ibandronate through the formation of a raft in the stomach. Bisphosphonate-induced irritation of the esophagus and stomach is prevented by the formation of a raft. Materials and methods The nanostructured raft was developed through the use of nanosized citrus pectin (NCP). The particle size of NCP was measured by zeta sizer and SEM. The percentage of NCP and the neutralization profile of raft was studied. The ibandronate, polymers, and the developed formulation were characterized by FTIR, XRD, TGA, and DSC. The release of ibandronate was studied in 0.1 N HCl, 0.5 N HCl, 1 N HCl, and simulated gastric fluid (SGF) and a cell viability study was performed using Caco-2 cells. The PPR5 formulation and Bonish 150 mg tablets were selected as test and reference formulations, respectively, for pharmacokinetic study. Twelve healthy albino rats were taken and divided into two groups using a Latin square crossover design, and the blood samples were collected for 24 hours. Results The SEM image showed that the particle size of NCP was 159 nm. The raft of PPR5 showed 94% NCP and 45 minutes duration of neutralization. The FTIR and XRD showed chemical stability and a uniform distribution of ibandronate in the raft. The TGA and DSC indicated the thermal stability of formulation. The release of 99.87% ibandronate at 20 minutes was observed in the SGF. The values of C max for the reference and test formulations were 493±0.237 ng/mL and 653±0.097 ng/mL, respectively. The AUC(0-t) of the reference and test formulations was 3708.25±3.418 ng/mL.h and 6899.25±3.467 ng/mL.h, respectively. Conclusion The NCP has been successfully prepared from citrus pectin and has shown effective porous raft formation. The bioavailability of the ibandronate from newly developed PPR5 was higher than the already marketed formulation.

Background: Statins perceived to have favorable safety profile. Although many people on statin therapy do well but no drug is without potential for side effects. Awareness about risks as well as benefits of drugs is needed particularly drugs which are used on wide scale like statins because even uncommon side effects can have significant health impact. Objectives of the Study: To determine side effects occurrence among Saudi patients taking statins and to evaluate drug-drug interactions in Saudi patients taking statins. Methodology: Self administered cross sectional study conducted during a period of four months from October 2018 to January 2019 in Turaif general hospital, Saudi Arabia on random sample of 500 Saudi patients out of which 330 participants were included in the study which were taking different types of statins medication using self-administered questionnaire in Arabic language specially designed for the research purpose after obtaining verbal consent and the data analyzed by SPSS program. Results: A total of 330 patients; 128 (39%) females and 202 (61%) males—participated in the study. The majority 165 (50%) were in the age-group of 50 – 59 years. Simvastatin was the most commonly used statin among study participants 136 (41%) followed by rosuvastatin 114 (35%). Among the participants, there were some patients who take drugs which have drug interactions with statins; there were 64 (19%) take Amlodipine with simvastatin, 13 (4%) and 6 (2%) take esomeprazole and ompeprazole respectively with statins. Only 9 (3%) reported that they were advised by pharmacist to avoid grape fruit. Majority of participants 309 (94%) reported neck pain, difficulty in walking, frequently fatigue after starting on statin. Also majority of participants 320 (97%) suffer from muscle pain after starting statins medications. Conclusion: The percentage of statin related side effects in this study population is high especially myopathy. Also some patients in this study taking medications that have drug interaction with statins, Counseling to patient regarding statin therapy appear to be insufficient. So, this study indicate that there's a need for more efforts from the physicians and pharmacist to avoid prescribing or dispensing medication that have drug-drug interaction with statins and provide counseling to patients regarding their statin therapy.

Introduction: Analgesics are substances which work in various ways to relieve different types of pain experienced in the body. Non-prescription over-the-counter (OTC) drugs are widely used by patients to control pain and fever. Study Objective: To evaluate of knowledge, attitudes and practices about analgesic and their side effects. Methods: A cross-sectional study conducted during a period of three months from September to December 2017 in Rafha and Riyadh - Saudi Arabia on a random sample of 237 Saudi people, the data was collected by using a self-administered questionnaire in the Arabic language. Statistical analysis was done by using MS EXCEL using descriptive statistics and chi-square test. Results: A total of 237 participants out of 260 consented to be interviewed and completed the questionnaire with a response rate (91%). Their ages ranged between 18 years and 54 years with a mean (28) and standard deviation (7.9). Majority of participants were females (92%) and about two thirds (66%) were highly educated. A quarter of study participants (25%) do not read leaflet of analgesic before use. About one-fifth of respondents (20%) reported that they cannot stop taking analgesic even if the pain is mild. 12% and 36% of respondents always and sometimes, respectively, use more than one type of analgesic for pain relief. 10% of respondents reported the occurrence of side effects from analgesic. The respondents use analgesic mainly for headache (43%) and toothache (25%). The chronic disease for which participants take analgesic were mainly arthritis (39%) and migraine (30%). About three-quarters of respondents (74%) were aware that the use of analgesic is accompanied by side effects. The respondents believed that the reasons for analgesic misuse are that analgesic easily obtained without a medical prescription (40%) and there is no educational or awareness program regarding analgesic use (33%). Majority of participants believed that there is no sufficient awareness about analgesic. The source of information about analgesic for participants is physician (24%). Panadol analgesic is the most commonly used analgesic (48%) reported by participants. Results showed that there is a significant statistical difference between male and female regard analgesic use (P=0.048) and between different level of educations and analgesic use (P=0.334). Also, there is a highly significant statistical difference between male and female regard reading the leaflet before taking analgesic (P=0.0001) and between the educational level of participants regarding reading the leaflet before analgesic use (P=0.0008). Conclusion: The over-the-counter (OTC) analgesic drugs are commonly used and many patients are unaware of their side effects. The findings of this study showed that people's knowledge, attitudes and practices regarding analgesic use is poor. Also, it is important to improve people's knowledge, attitudes and practices regarding analgesic use to reduce the misconceptions and misguided expectations contributing to inappropriate analgesic use. Therefore, health professional practice should play a major role in people's awareness of the appropriate use of OTC analgesic drugs.

The purpose of the current studies was to develop ocular insert of betaxolol hydrochloride (BXH), using arabinoxylan (AX) as a film former. The inserts were prepared by sandwiching I mg of BXH between two films of AX. Six different formulations of ocular inserts were prepared in such a way that first three formulations contained varying concentrations of AX along with glycerol as plasticizer, whereas, rest of the formulations were added with 0.5mg of sodium alginate, sandwiched between two films of AX along with 1mg of BXH. Chemical compatibilities of the ingredients were assessed by using FTIR. Prepared ocular inserts were subjected to various physicochemical characterizations. The dissolution studies showed that ocular inserts containing sodium alginate with the AX showed sustained release effect better than the formulations with AX alone. Addition of sodium alginate resulted in inhibition of sudden release in initial phase and further sustained the release of drug from ocular inserts. Ocular inserts were pH compatible to the eyes as well as there was no interaction among the drug and excipients, suggesting that the selected excipients were suitable for the development of sustained release ocular inserts of BXH.

The purpose of this study was to develop liposome-enriched Ketoprofen liposomal hydrogels and carry out in vitro release profile experiment. The aim was to achieve sustained topical drug delivery for extended time interval from liposomal gels. Phosphatidylcholine, Cholesterol and Ketoprofen were dissolved in chloroform/methanol (2:1, v/v) mixture and subsequently transferred to a flask attached to rotavapor. The liposomes were assessed for particle size and percent drug entrapment. F-7 and F-8 batches were found to be optimized batches having optimum sizes, drug entrapment efficiencies and cumulative drug releases. F-8 batch was further evaluated for stability. The results show that the prepared liposomes of Ketoprofen might turn out to be potential candidates for effective and safe sustained drug delivery thereby resulting in the reduction of dosing frequency.

Background: Nature has always been considered as the primary source of pharmaceutical ingredients. A variety of hemicelluloses, as well as their modified forms, have been under investigation. Herein, a study was designed to explore the biocompatibility of hemicellulose and its modified form (thiolated hemicellulose) as well as its potential as a pharmaceutical excipient.Method: For thiol modification thiourea was used as the thiol donor, HCl as the catalytic reagent, and methanol was used for washing purposes. Modified polymers were characterized for physicochemical characteristics, including surface morphology, the amorphous or crystalline nature of the particles, modification of polymer by FTIR, and biocompatibilities. For acute oral toxicity study, a single dose of 2 g/kg was administered to albino rats of 200 g average weight (n = 3). Polymers were evaluated as pharmaceutical excipients by preparing compressed tablets of antiplatelet drug (Ticagrelor), followed by various quality control tests, such as swelling index, thickness and diameter, disintegration, and in-vitro drug release.Results: From the results, it was observed that thiol modification has been successfully accomplished as characteristic peaks belonging to –SH group appeared at 2667.7691 cm−1 in FTIR scan. The modified polymer was found safe in the use concentration range, confirming their safe use for in vivo analysis. No significant effect has been observed in the behavior, biological fluid (blood), or on vital organs. Thiolated hemicellulose was found to be an excellent drug retarding polymer as 8 h of dissolution studies showed that 67.08% of the drug has been released.Conclusion: Conclusively, incorporation of thiol moiety made the polymer more mucoadhesive with, and a worthy carrier of, the drug with good biocompatibilities.

Migraine is a throbbing condition, usually associated with nausea and vomiting and requires concurrent administration of anti-migraine along with anti-emetic therapy. The current study was undertaken with an aim to fabricate fast dissolving oral strips (FDOSs) containing Sumatriptan succinate (anti-migraine) and Metoclopramide HCl (anti-emetic) in combination without involving any superdisintegrant. Hydrophilic polymer polyvinyl alcohol (PVA) was used alone with three concentrations of 100, 125, and 150 mg using variable concentrations of glycerol. The solvent casting technique was employed to formulate FDOSs and were evaluated for surface morphology, mechanical properties, surface pH, % moisture content, disintegration time (DT), total dissolving time (TDT), drug contents, and dissolution profile. PVA (150 mg) with 5% glycerol concentration gave best formulation results. FDOSs have exhibited good tensile strength with smooth and uniform surface morphology. DT was ranged from 7.7 to 28 s; while TDT was from 26.4 to 77.6 s. Both polymer and plasticizer concentrations were found to be influencing the characteristics of the strips. Dissolution studies were carried out in distilled water for 15 min and all the formulations have shown released more than 50% drug within first 2 min thereby highlighting the usefulness of FDOSs for the delivery of both drugs in combination significantly. Optimized combination of ingredients was found to be suitable for the formulation of FDOSs for simultaneous delivery of Metoclopramide HCl and Sumatriptan succinate.

Background:The complication of Alzheimer’s disease (AD) has made the development of its therapeutic a challenging task. Even after decades of research, we have achieved no more than a few years of symptomatic relief. The inability to diagnose the disease early is the major hurdle behind its treatment. Several studies have aimed to identify potential biomarkers that can be detected in body fluids (CSF, blood, urine, etc.) or assessed by neuroimaging (i.e., PET and MRI). However, the clinical implementation of these biomarkers is incomplete as they cannot be validated.Method:This study aimed to overcome the limitation of using artificial intelligence along with technical tools that have been extensively investigated for AD diagnosis. For developing a promising artificial intelligence strategy that can diagnose AD early, it is critical to supervise neuropsychological outcomes and imaging-based readouts with a proper clinical review.Conclusion:Profound knowledge, a large data pool, and detailed investigations are required for the successful implementation of this tool. This review will enlighten various aspects of early diagnosis of AD using artificial intelligence.

Background: Rosuvastatin Calcium and Ezetimibe are used to control cholesterol level while Perindopril Erbumine is used to treat hypertension. Hepatic metabolism reduces the therapeutic effect of these drugs. Objective: Instant release buccal films (IRBFs) could possibly be a solution to this issue. The objective of the study was to formulate IRBFs of Rosuvastatin Calcium, Perindopril Erbumine and Ezetimibe using solvent casting technique. Methods: Polymers used to prepare IRBFs included hydroxypropyl methylcellulose (HPMC E5), PEG 400 (as plasticizer) and Tween 80 (as surfactant). Solvent casting technique was used to fabricate the films, followed by their in-vitro analysis including high performance liquid chromatography (HPLC), X-ray diffraction (XRD), fourier transform infrared evaluation (FTIR), In-vitro dissolution, In-vitro disintegration, stability tests, scanning electron microscopy (SEM), folding fortitude, thickness evaluation, surface pH, tensile strength, weight variation and percentage moisture content. Results: Optical microscopy as well as SEM analysis displayed that the surfaces of IRBFs were smooth with uniform mixing of ingredients. IRBFs disintegrated within 15 seconds while on dissolution they exhibited instant drug release i.e. 100% release in 2 minutes. Conclusions: The results show promising potential of IRBFs in drug delivery.

In the current study, a series of new ligustrazine-based chalcones was synthesized. For insertion of tetramethylpyrazine (TMP, also designated as ligustrazine) in chemical backbone of chalcone, a new ligustrazine-based aldehyde was prepared. New ketones were synthesized for inclusion of quinazolin-4-yl amino and pyrazin-2-yl amino moieties. The newly synthesized compounds were screened for acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases (MAO) inhibitory activities and also for in vitro cytotoxicity on PC12 cells. The effect of these compounds against amyloid β-induced cytotoxicity and aggregation was also investigated. The synthesized compounds effectively inhibited the related enzymes and also exhibited neuroprotective effects. Most of the compounds displayed better inhibitory potencies against Aβ aggregation than reference compounds. Some compounds such as 11e and 16b showed very potent effects on multiple targets exhibiting behavior as multifunctional anti-Alzheimer agents.

Transdermal patches loaded with ramipril and repaglinide were prepared with the ambition to develop matrix-type transdermal drug delivery system for enhanced permeability and hence improved bioavailability. Different formulations were designed by intermittent concentrations of hydroxypropyl methylcellulose K4M as hydrophilic polymer and ethyl cellulose as hydrophobic polymer. Solvent casting method was used for the fabrication of transdermal patches. Oleic acid and propylene glycol were used to enhance permeability along with polyethylene glycol 400 as plasticizer. Newly designed patches were then evaluated for various physicochemical and mechanical properties. Compatibility studies were performed by Fourier transformed infrared spectroscopy which did not reveal any interaction between drug and polymers. Crystalline nature of drugs was confirmed when they were subjected to X-ray diffraction study and surface morphological studies using scanning electron microscopy. Transdermal patches were of good...

Current study was designed with the aim to employ quasi emulsification, and double emulsification techniques for the development of Flurbiprofen (FLB) loaded micro sponges, followed by their physicochemical evaluation. FTIR interpretations exhibited compatibility of ingredients, while crystallographic analysis revealed crystalline nature of pure drug, which was masked upon incorporation into microsponges. Optical microscope and SEM have exposed spherical and spongy surfaces of prepared micro sponges. Micromeritics suggested that the flow properties are excellent and microsponges have remarkable drug entrapment efficiency (98.55±0.08%). In-vitro dissolution studies demonstrated good control over release of FLB until 8th h from the prepared microsponges. However, a difference in cumulated amount of released drug was noticed i.e. EC based formulation has released about 99.3±0.10%, while XG facilitated EC based formulations offered 92.7±2.1% release of the drug. Zeta potential indicated access of negative charge while zeta sizer has described the range of the particle size between 2.6 to 3.5μm. Conclusively the results have advocated the suitability of selected ingredients for incorporation of FLB into microsponges for its sustained delivery.

Present work was conducted to improve the bioavailability of Tizanidine HCl (TZN) by formulating mucoadhesive buccal films (MBFs) using novel thiolated arabinoxylan (TAX) as film former. MBF's were prepared by solvent casting technique followed by their evaluation for surface morphology and folding endurance. Moreover, pharmacokinetic parameters including C

This study was schemed to comprehend the latest kaleidoscopic trends of bacterial resistance in neonatal pathogens against all those antibiotics commonly employed as empirical therapy in neonates. The methodological approach included; isolation and subsequent identification of those pathogens having caused bacterial infections in neonates, application of antibiotic sensitivity testing and finally construing the conclusion depicting patterns of antibiotic resistance by various pathogens, isolated from neonatal biological samples. Antibiotic resistance patterns was evident in gram-positive as well as in gram-negative bacteria in all the eight species identified in this study. Even antibiotic drugs which are being commonly relied upon for treating multi-resistant bacterial infections, found to be in effective against many newly emerged resistant bacteria, when used alone. Resistance Antibiotics drugs against which most prominent resistance pattern emerged include; Amikacin sulphate, Linezolid, Piperacillin / Tazobactam, Amoxicillin / Clavulanic acid, Vencomycin, Cefoperazone / Sulbactam, Ceftriaxone sodium, Ciprofloxacin, Cefixime trihydrate and Imipenem. The inferred upshot suggests that antibiotic resistance is emerging fast and ever-changing phenomenon of antibiotic resistance has significantly reduced the therapeutic space to maneuver, particularly, in treating neonatal infections.

The drug research and development nowadays is focusing on multi-target drugs. In the treatment of cancer, therapies using drugs inhibiting one numerous targets signify a novel viewpoint. In comparison with traditional therapy, multi-targeted drugs directly aim cell subpopulations which are involved in progression of tumor. The current study comprises the synthesis of 34 novel ligustrazine-containing α, β-unsaturated carbonyl-based compounds and oximes. The growth of 5 various cancer cell types was strongly inhibited by ligustrazine-containing oximes as revealed by biological evaluation. A strong SAR was provided by the antiproliferative activity. The mechanistic effects of most active antiproliferative compounds on tubulin polymerization, EGFR TK kinases, KAF and BRAFV600E were investigated, followed by in vitro investigation of reversal of efflux-based resistance developed by cancer cells. EGFR was strongly inhibited by two oximes 7e and 8o. Out of all linkers including positive control, 1-isopropyl-piperidin-4-one linker-bearing compounds showed best inhibition of FAK. The strongest inhibitory activity of BRAFV600E was showed by compound 5e with an IC50 of 0.7 μM. Analogs such as 5 and 7 (b,e,f) exhibited a dual role as anticancer as well as MDR reversal agents. For understanding the target protein integrations with new compounds, molecular docking studies were also carried out.

The incidence of cancer can be decreased by chemoprevention using either natural or synthetic agents. Apart from synthetic compounds, numerous natural products have exhibited promising potential to inhibit carcinogenesis in vivo. In this study, α, β-unsaturated carbonyl-based anticancer compounds were used as starting materials to synthesize new oxime analogs. The findings from the antiproliferative assay using seven different human cancer cell lines provided a clear picture of structure-activity relationship. The oxime analogs namely 7a and 8a showed strong antiproliferative activity against the cell lines. The mechanistic effects of compounds on EGFR-TK kinases and tubulin polymerization and BRAFV600E were investigated. In addition, the efficacy of compounds in reversing the efflux-mediated resistance developed by cancer cells was also studied. The compounds 5a and 6a displayed potent activity on various targets such as BRAFV600E and EGFR-TK kinases and also exhibited strong antiproliferative activity against different cell lines hence showing potential of multifunctional anticancer agents.

Penetration and distribution of drug through the avascular regions of human solid tumors after extravasation are crucial concerns for antitumor efficacy. To address this issue, anin vitrosolid tumor model of multicellular layers (MCLs) of human colorectal cancer cells (DLD-1) was established. In an attempt to deliver Dicer substrate small interfering RNA (DsiRNA), chitosan (CS) nanoparticles have been developed for targeting vascular endothelial growth factor (VEGF) gene for tumor growth inhibition. The DsiRNA-CS nanoparticles prepared by ionic gelation method had provided maximal protection of DsiRNA in full human serum up to 48 h incubation. RT-PCR studies revealed significant concentration- and time-dependent knock-down ofVEGFmRNA and its product due to uniform penetration of DsiRNA-CS nanoparticles throughout MCLs. Taken together, this study also demonstrated that DsiRNA-CS nanoparticles could effectively knock downVEGFgene as therapeutic target in monolayer culture or in solid tumor model for potential treatment of human colorectal carcinoma.

Recently, a newly discovered Dicer-substrate siRNA (DsiRNA) demonstrates higher potency in gene silencing than siRNA but both suffer from rapid degradation, poor cellular uptake and chemical instability. Therefore, Tat-peptide was exploited to protect and facilitate their delivery into cells. In this study, Tat-peptide was complexed with siRNA or DsiRNA through simple complexation. The physicochemical properties (particle size, surface charge and morphology) of the complexes formed were then characterized. The ability of Tat-peptide to carry and protect siRNA or DsiRNA was determined by UV-Vis spectrophotometry and serum protection assay, respectively. Cytotoxicity effect of these complexes was assessed in V79 cell line. siRNA-Tat complexes had particle size ranged from 186 ± 17.8 to 375 ± 8.3 nm with surface charge ranged from -9.3 ± 1.0 to +13.5 ± 1.0 mV, depending on the Tat-to-siRNA concentration ratio. As for DsiRNA-Tat complexes, the particle size was smaller than the ones complexed with siRNA, ranging from 176 ± 8.6 to 458 ± 14.7 nm. Their surface charge was in the range of +27.1 ± 3.6 to +38.1 ± 0.9 mV. Both oligonucleotide (ON) species bound strongly to Tat-peptide, forming stable complexes with loading efficiency of more than 86%. These complexes were relatively non cytotoxic as the cell viability of ∼90% was achieved. In conclusion, Tat-peptide has a great potential as siRNA and DsiRNA vector due to the formation of stable complexes with desirable physical characteristics, low toxicity and able to carry high amount of siRNA or DsiRNA.

Recently, Dicer-substrate small interfering RNA (DsiRNA) has gained attention owing to its greater potency over small interfering RNA (siRNA). However, the use of DsiRNA is restricted by its rapid degradationin vitro. To address this issue, chitosan nanoparticulate deliver yplatform for the Dicer-substrate siRNA (DsiRNA) was developed and characterized. Nanoparticles were prepared by simple complexation and ionic gelation methods. The mean particle size of DsiRNA-adsorbed chitosan nanospheres (DsiRNA-CS NPs) prepared by the ionic gelation method ranged from 225 to 335 nm, while simple complexation yielded DsiRNA-chitosan complexes (DsiRNA-CS complexes) ranging from 270 to 730 nm. The zeta potential of both types of nanoparticles ranged from +40 to +65 mV. TEM and AFM micrographs revealed spherical and irregular morphology of DsiRNA-CS NPs and DsiRNA-CS complexes. ATR-FTIR spectroscopy confirmed the presence of DsiRNA in the CS NPs/complexes. Both types of nanoparticles exhibited sustained release and high binding and encapsulation (100%) efficiency of DsiRNA. DsiRNA-CS NPs/complexes showed low, concentration-dependent cytotoxicityin vitro. DsiRNA-CS NPs showed better stability than the complexes when stored at 4 and 25°C. Thus, it is anticipated that CS NPs are promising vectors for DsiRNA delivery due to their stability, safety, and cost-effectiveness.