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Fulltext Fe/Mg-Modified Carbonate Apatite with Uniform Particle Size and Unique Transport Protein-Related Protein Corona Efficiently Delivers Doxorubicin into Breast Cancer Cells

Haque ST, Karim ME, Abidin SAZ, Othman I, Holl MMB, Chowdhury EH

Nanomaterials (Basel), 2020 Apr 27;10(5).
PMID: 32349272 DOI: 10.3390/nano10050834

Breast cancer is the abnormal, uncontrollable proliferation of cells in the breast. Conventional treatment modalities like chemotherapy induce deteriorating side effects on healthy cells. Non-viral inorganic nanoparticles (NPs) confer exclusive characteristics, such as, stability, controllable shape and size, facile surface modification, and unique magnetic and optical properties which make them attractive drug carriers. Among them, carbonate apatite (CA) particles are pH-responsive in nature, enabling rapid intracellular drug release, but are typically heterogeneous with the tendency to self-aggregate. Here, we modified the nano-carrier by partially substituting Ca2+ with Mg2+ and Fe3+ into a basic lattice structure of CA, forming Fe/Mg-carbonate apatite (Fe/Mg-CA) NPs with the ability to mitigate self-aggregation, form unique protein corona in the presence of serum and efficiently deliver doxorubicin (DOX), an anti-cancer drug into breast cancer cells. Two formulations of Fe/Mg-CA NPs were generated by adding different concentrations of Fe3+ and Mg2+ along with a fixed amount of Ca2+ in bicarbonate buffered DMEM (Dulbecco's Modified Eagle's Medium), followed by 30 min incubation at 37 °C. Particles were characterized by turbidity analysis, z-average diameter and zeta potential measurement, optical microscopy, field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), energy dispersive X-ray (EDX), flame atomic absorption spectroscopy (FAAS), pH dissolution, drug binding, cellular uptake, thiazolyl blue tetrazolium bromide (MTT) assay, stability analysis, and protein corona study by LCMS (Liquid chromatography-mass spectrometry). Both formulations of Fe/Mg-CA displayed mostly uniform nano-sized particles with less tendency to aggregate. The EDX and FAAS elemental analysis confirmed the weight (%) of Ca, Fe and Mg, along with their Ca/P ratio in the particles. A constant drug binding efficiency was noticed with 5 μM to 10 μM of initial DOX concentration. A pH dissolution study of Fe/Mg-CA NPs revealed the quick release of DOX in acidic pH. Enhancement of cytotoxicity for the chemotherapy drug was greater for Fe/Mg-CA NPs as compared to CA NPs, which could be explained by an increase in cellular internalization as a result of the small z-average diameter of the former. The protein corona study by LCMS demonstrated that Fe/Mg-CA NPs exhibited the highest affinity towards transport proteins without binding with opsonins. Biodistribution study was performed to study the effect of DOX-loaded Fe/Mg-CA NPs on the tissue distribution of DOX in Balb/c 4T1 tumor-bearing mice. Both formulations of Fe/Mg-CA NPs have significantly increased the accumulation of DOX in tumors. Interestingly, high Fe/Mg-CA NPs exhibited less off-target distribution compared to low Fe/Mg-CA NPs. Furthermore, the blood plasma analysis revealed prolonged blood circulation half-life of DOX-loaded low and high Fe/Mg-CA NPs compared to free DOX solution. Modifying CA NPs with Fe3+ and Mg2+, thereby, led to the generation of nano-sized particles with less tendency to aggregate, enhancing the drug binding efficiency, cellular uptake, and cytotoxicity without hampering drug release in acidic pH, while improving the circulation half-life and tumor accumulation of DOX. Therefore, Fe/Mg-CA which predominantly forms a transport protein-related protein corona could be a proficient carrier for therapeutic delivery in breast cancer.

Matched MeSH terms: Drug Liberation
Preparation of aerogel beads and microspheres based on chitosan and cellulose for drug delivery: A review

Shi W, Ching YC, Chuah CH

Int J Biol Macromol, 2021 Feb 15;170:751-767.
PMID: 33412201 DOI: 10.1016/j.ijbiomac.2020.12.214

Spherical aerogels are not easily broken during use and are easier to transport and store which can be used as templates for drug delivery. This review summarizes the possible approaches for the preparation of aerogel beads and microspheres based on chitosan and cellulose, an overview to the methods of manufacturing droplets is presented, afterwards, the transition mechanisms from sol to a spherical gel are reviewed in detail followed by different drying processes to obtain spherical aerogels with porous structures. Additionally, a specific focus is given to aerogel beads and microspheres to be regarded as drug delivery carriers. Furthermore, a core/shell architecture of aerogel beads and microspheres for controlled drug release is described and subjected to inspire readers to create novel drug release system. Finally, the conclusions and outlooks of aerogel beads and microspheres for drug delivery are summarized.

Matched MeSH terms: Drug Liberation
Cyclodextrin- and dendrimer-conjugated graphene oxide as a nanocarrier for the delivery of selected chemotherapeutic and photosensitizing agents

Siriviriyanun A, Tsai YJ, Voon SH, Kiew SF, Imae T, Kiew LV, et al.

Mater Sci Eng C Mater Biol Appl, 2018 Aug 01;89:307-315.
PMID: 29752102 DOI: 10.1016/j.msec.2018.04.020

In this study, nanohybrid materials consisting of graphene oxide (GO), β‑cyclodextrin (CD) and poly(amido amine) dendrimer (DEN) were successfully prepared by covalent bonding. GO-CD and GO-CD-DEN were found to be potential nanocarriers for anticancer drugs including chemotherapeutics (doxorubicin (DOX), camptothecin (CPT)) and photosensitizer (protoporphyrin IX (PpIX)). GO-CD possessed 1.2 times higher DOX-loading capacity than GO due to inclusion of additional DOX to the CD. The drug loading on GO-CD-DEN increased in the order: DOX drugs were loaded in GO-CD and GO-CD-DEN. Functionalization of GO with CD and CD-DEN increased the uptake in cancer cells, and both GO-CD and GO-CD-DEN nanohybrids remained in the cytoplasm and were not uptaken into the nucleus, as shown in the flow cytometry and high-content screening study.

Matched MeSH terms: Drug Liberation
Controlled delivery of the antiprotozoal agent (tinidazole) from intravaginal polymer matrices for treatment of the sexually transmitted infection, trichomoniasis

Fernando HV, Chan LL, Dang N, Santhanes D, Banneheke H, Nalliah S, et al.

Pharm Dev Technol, 2019 Mar;24(3):348-356.
PMID: 29799300 DOI: 10.1080/10837450.2018.1481430

Microporous polymeric matrices prepared from poly(ɛ-caprolactone) [PCL] were evaluated for controlled vaginal delivery of the antiprotozoal agent (tinidazole) in the treatment of the sexually transmitted infection, trichomoniasis. The matrices were produced by rapidly cooling co-solutions of PCL and tinidazole in acetone to -80 °C to induce crystallisation and hardening of the polymer. Tinidazole incorporation in the matrices increased from 1.4 to 3.9% (w/w), when the drug concentration in the starting PCL solution was raised from 10 to 20% (w/w), giving rise to drug loading efficiencies up to 20%. Rapid 'burst release' of 30% of the tinidazole content was recorded over 24 h when the PCL matrices were immersed in simulated vaginal fluid. Gradual drug release occurred over the next 6 days resulting in delivery of around 50% of the tinidazole load by day 7 with the released drug retaining antiprotozoal activity at levels almost 50% that of the 'non-formulated' drug in solution form. Basic modelling predicted that the concentration of tinidazole released into vaginal fluid in vivo from a PCL matrix in the form of an intravaginal ring would exceed the minimum inhibitory concentration against Trichomonas vaginalis. These findings recommend further investigation of PCL matrices as intravaginal devices for controlled delivery of antiprotozoal agents in the treatment and prevention of sexually transmitted infections.

Matched MeSH terms: Drug Liberation
Formulation strategies for achieving high delivery efficiency of thymoquinone-containing Nigella sativa extract to the colon based on oral alginate microcapsules for treatment of inflammatory bowel disease

Samak YO, Santhanes D, El-Massik MA, Coombes AGA

J Microencapsul, 2019 Mar;36(2):204-214.
PMID: 31164027 DOI: 10.1080/02652048.2019.1620356

Nigella sativa extract (NSE) was incorporated in alginate microcapsules using aerosolisation and homogenisation methods, respectively, with the aim of delivering high concentrations of the active species, thymoquinone (TQ), directly to sites of inflammation in the colon following oral administration. Encapsulation of NSE was accomplished either by direct loading or diffusion into blank microparticles. Microcapsules in the size range 40-60 µm exhibited significantly higher NSE loading up to 42% w/w and encapsulation efficiency (EE) up to 63% when the extract was entrapped by direct encapsulation compared with 4.1 w/w loading, 6.2% EE when NSE was incorporated by diffusion loading. Sequential exposure of samples to simulated intestinal fluids (SIFs) revealed that the microcapsules suppressed NSE release in simulated gastric fluid (SGF) for 2 h and SIF for 4 h and liberated most of the NSE content (80%) in simulated colonic fluid (SCF) over 18 h. NSE released in SCF at 12 h exhibited antioxidant activity, when measured using the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay at levels comparable with the activity of unencapsulated extract. These findings demonstrate the potential of oral alginate microcapsules as highly efficient, targeted carriers for colonic delivery of NSE in the treatment of inflammatory bowel disease.

Matched MeSH terms: Drug Liberation
Process evaluation and in vitro selectivity analysis of aptamer-drug polymeric formulation for targeted pharmaceutical delivery

Tan KX, Lau SY, Danquah MK

Biomed Pharmacother, 2018 May;101:996-1002.
PMID: 29635910 DOI: 10.1016/j.biopha.2018.03.052

Targeted drug delivery is a promising strategy to promote effective delivery of conventional and emerging pharmaceuticals. The emergence of aptamers as superior targeting ligands to direct active drug molecules specifically to desired malignant cells has created new opportunities to enhance disease therapies. The application of biodegradable polymers as delivery carriers to develop aptamer-navigated drug delivery system is a promising approach to effectively deliver desired drug dosages to target cells. This study reports the development of a layer-by-layer aptamer-mediated drug delivery system (DPAP) via a w/o/w double emulsion technique homogenized by ultrasonication or magnetic stirring. Experimental results showed no significant differences in the biophysical characteristics of DPAP nanoparticles generated using the two homogenization techniques. The DPAP formulation demonstrated a strong targeting performance and selectivity towards its target receptor molecules in the presence of non-targets. The DPAP formulation demonstrated a controlled and sustained drug release profile under the conditions of pH 7 and temperature 37 °C. Also, the drug release rate of DPAP formulation was successfully accelerated under an endosomal acidic condition of ∼pH 5.5, indicating the potential to enhance drug delivery within the endosomal micro-environment. The findings from this work are useful to understanding polymer-aptamer-drug relationship and their impact on developing effective targeted delivery systems.

Matched MeSH terms: Drug Liberation
Fulltext The Effect of Cross-linking Efficiency of Drug-Loaded Novel Freeze Gelated Chitosan Templates for Periodontal Tissue Regeneration

Qasim SSB, Nogueria LP, Fawzy AS, Daood U

AAPS PharmSciTech, 2020 Jun 16;21(5):173.
PMID: 32548717 DOI: 10.1208/s12249-020-01708-x

Innovative strategies for periodontal regeneration have been the focus of research clusters across the globe for decades. In order to overcome the drawbacks of currently available options, investigators have suggested a novel concept of functionally graded membrane (FGM) templates with different structural and morphological gradients. Chitosan (CH) has been used in the past for similar purpose. However, the composite formulation of composite and tetracycline when cross-linked with glutaraldehyde have received little attention. Therefore, the purpose of the study was to investigate the drug loading and release characteristics of novel freeze gelated chitosan templates at different percentages of glutaraldehyde. These were cross-linked with 0.1 and 1% glutaraldehyde and loaded with doxycycline hyclate. The electron micrographs depicted porous morphology of neat templates. After cross-linking, these templates showed compressed ultrastructures. Computerized tomography analysis showed that the templates had 88 to 92% porosity with average pore diameter decreased from 78 to 44.9 μm with increasing concentration. Fourier transform infrared spectroscopy showed alterations in the glycosidic segment of chitosan fingerprint region which after drug loading showed a dominant doxycycline spectral composite profile. Interestingly, swelling profile was not affected by cross-linking either at 0.1 and 1% glutaraldehyde and template showed a swelling ratio of 80%, which gained equilibrium after 15 min. The drug release pattern also showed a 40 μg/mL of release after 24 h. These doxycycline-loaded templates show their tendency to be used in a functionally graded membrane facing the defect site.

Matched MeSH terms: Drug Liberation
Fulltext Antibacterial efficacy and drug-release behavior study of β-tricalcium phosphate micro-granules against staphylococcus aureus and Escherichia coli

Nor Hazliana Harun, Rabiatul Basria S.M.N. Mydin, Khairul Anuar Shariff, Nur Adila Rosdi, Davamunisvari Rames

Malaysian Journal of Medicine and Health Sciences, 2020;16(3):202-206.
MyJurnal

Introduction: This study aims to investigate different residue sizes of β-tricalcium phosphate (β-TCP) micro-granules as carriers to assess antibacterial activity and drug-control release behavior of ampicillin (AMP-) and antimycotic (AMC-). Incorporation of antibiotic into the β-TCP micro-granules and it sustain release behavior could be used as alternative solution to reduce the risk of osteomyelitis and bone infections risks. Methods: Three different residue sizes (less than 300 µm, 300 µm and 600 µm) were prepared and coated with antibiotics solution (20 µg/µl of ampi- cillin and 100X antimycotic solution) by using two methods; dip and stream coating. After 72 h, 1.5 mL of distilled water was added to the treated (β-TCP) micro-granules at two different pH value (5.0 and 7.4). The extracted solution was further analyzed by Kirby Bauer disc diffusion test and spectrophotometer assay. Results: The solution con- taining AMC-(β-TCP) micro-granules with the size of 300 µm residue produced the largest inhibition zones against Escherichia coli (E. coli). All residue sizes coated with AMP- showed no antibacterial activity against both strains; Staphylococcus aureus (S. aureus) and E.coli. Additionally, the release behavior of AMC-(β-TCP) micro-granules was found not depending on the pH, but on the size of residue. Complete drug release was rapidly observed within 48
h. Conclusion: Based on this findings, it showed AMC-(β-TCP) micro-granules had an antibacterial activity against Gram-negative strain. Specifically, it can reduced the growth rate of E. coli and the rapid release behavior of AMC- (β-TCP) micro-granules help in minimizing the risk-infections in early stage of implantation.

Matched MeSH terms: Drug Liberation
Preparation, characterization, and in vitro release studies of insulin-loaded double-walled poly(lactide-co-glycolide) microspheres

Ansary RH, Rahman MM, Awang MB, Katas H, Hadi H, Doolaanea AA

Drug Deliv Transl Res, 2016 06;6(3):308-18.
PMID: 26817478 DOI: 10.1007/s13346-016-0278-y

The purpose of this study was to fabricate insulin-loaded double-walled and single-polymer poly(lactide-co-glycolide) (PLGA) microspheres using a fast degrading glucose core, hydroxyl-terminated poly(lactide-co-glycolide) (Glu-PLGA), and a moderate degrading carboxyl-terminated PLGA polymers. A modified water-in-oil-in-oil-in-water (w/o/o/w) emulsion solvent evaporation technique was employed to prepare double-walled microspheres, whereas single-polymer microspheres were fabricated by a conventional water-in-oil-in-water (w/o/w) emulsion solvent evaporation method. The effect of fabrication techniques and polymer characteristics on microspheres size, morphology, encapsulation efficiency, in vitro release, and insulin stability was evaluated. The prepared double-walled microspheres were essentially non-porous, smooth surfaced, and spherical in shape, whereas single-polymer microspheres were highly porous. Double-walled microspheres exhibited a significantly reduced initial burst followed by sustained and almost complete release of insulin compared to single-polymer microspheres. Initial burst release was further suppressed from double-walled microspheres when the mass ratio of the component polymers was increased. In conclusion, double-walled microspheres made of Glu-PLGA and PLGA can be a potential delivery system of therapeutic insulin.

Matched MeSH terms: Drug Liberation
Fulltext Encapsulation of Black Seed Oil in Alginate Beads as a pH-Sensitive Carrier for Intestine-Targeted Drug Delivery: In Vitro, In Vivo and Ex Vivo Study

Azad AK, Al-Mahmood SMA, Chatterjee B, Wan Sulaiman WMA, Elsayed TM, Doolaanea AA

Pharmaceutics, 2020 Mar 02;12(3).
PMID: 32131539 DOI: 10.3390/pharmaceutics12030219

Black seed oil (BSO) has been used for various therapeutic purposes around the world since ancient eras. It is one of the most prominent oils used in nutraceutical formulations and daily consumption for its significant therapeutic value is common phenomena. The main aim of this study was to develop alginate-BSO beads as a controlled release system designed to control drug release in the gastrointestinal tract (GIT). Electrospray technology facilitates formulation of small and uniform beads with higher diffusion and swelling rates resulting in process performance improvement. The effect of different formulation and process variables was evaluated on the internal and external bead morphology, size, shape, encapsulation efficiency, swelling rate, in vitro drug release, release mechanism, ex vivo mucoadhesive strength and gastrointestinal tract qualitative and quantitative distribution. All the formulated beads showed small sizes of 0.58 ± 0.01 mm (F8) and spherical shape of 0.03 ± 0.00 mm. The coefficient of weight variation (%) ranged from 1.37 (F8) to 3.93 (F5) ng. All formulations (F1-F9) were studied in vitro for release characteristics and swelling behaviour, then the release data were fitted to various equations to determine the exponent (ns), swelling kinetic constant (ks), swelling rate (%/h), correlation coefficient (r2) and release kinetic mechanism. The oil encapsulation efficiency was almost complete at 90.13% ± 0.93% in dried beads. The maximum bead swelling rate showed 982.23 (F8, r2 = 0.996) in pH 6.8 and the drug release exceeded 90% in simulated gastrointestinal fluid (pH 6.8). Moreover, the beads were well distributed throughout various parts of the intestine. This designed formulation could possibly be advantageous in terms of increased bioavailability and targeted drug delivery to the intestine region and thus may find applications in some diseases like irritable bowel syndrome.

Matched MeSH terms: Drug Liberation
Fulltext Solubility enhancement studies on lurasidone hydrochloride using mixed hydrotropy

Madan JR, Pawar KT, Dua K

Int J Pharm Investig, 2015 Apr-Jun;5(2):114-20.
PMID: 25838997 DOI: 10.4103/2230-973X.153390

Low aqueous solubility is a major problem faced during formulation development of new drug molecules. Lurasidone HCl (LRD) is an antipsychotic agent specially used in the treatments of schizophrenia and is a good example of the problems associated with low aqueous solubility. Lurasidone is practically insoluble in water, has poor bioavailability and slow onset of action and therefore cannot be given in emergency clinical situations like schizophrenia. Hence, purpose of this research was to provide a fast dissolving oral dosage form of Lurasidone. This dosage form can provide quick onset of action by using the concept of mixed hydrotropy. Initially, solubility of LRD was determined individually in nicotinamide, sodium citrate, urea and sodium benzoate at concentration of 10, 20, 30 and 40% w/v solutions using purified water as a solvent. Highest solubility was obtained in 40% sodium benzoate solution. In order to decrease the individual hydrotrope concentration mixed hydrotropic agents were used. Highest solubility was obtained in 15:20:5 ratio of Nicotinamide + sodium benzoate + sodium citrate. This optimized combination was utilized in the preparation of solid dispersions by using distilled water as a solvent. Solid dispersions were evaluated for X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared to show no drug-hydrotropes interaction has occurred. This solid dispersion was compressed to form fast dissolving tablets. Dissolution studies of prepared tablets were done using USP Type II apparatus. The batch L3 tablets show 88% cumulative drug release within 14 min and in vitro dispersion time was 32 min. It was concluded that the concept of mixed hydrotropic solid dispersion is novel, safe and cost-effective technique for enhancing the bioavailability of poorly water-soluble drugs. The miraculous enhancement in solubility and bioavailability of Lurasidone is clear indication of the potential of mixed hydrotropy to be used in future for other poorly water-soluble drugs in which low bioavailability is a major concern.

Matched MeSH terms: Drug Liberation
Central composite designed formulation, characterization and in vitro cytotoxic effect of erlotinib loaded chitosan nanoparticulate system

Pandey P, Chellappan DK, Tambuwala MM, Bakshi HA, Dua K, Dureja H

Int J Biol Macromol, 2019 Dec 01;141:596-610.
PMID: 31494160 DOI: 10.1016/j.ijbiomac.2019.09.023

The most common cause of deaths due to cancers nowadays is lung cancer. The objective of this study was to prepare erlotinib loaded chitosan nanoparticles for their anticancer potential. To study the effect of formulation variables on prepared nanoparticles using central composite design. Erlotinib loaded chitosan nanoparticles were prepared by ionic gelation method using probe sonication technique. It was found that batch NP-7 has a maximum loading capacity and entrapment efficiency with a particle size (138.5 nm) which is ideal for targeting solid tumors. Analysis of variance was applied to the particle size, entrapment efficiency and percent cumulative drug release to study the fitting and the significance of the model. The batch NP-7 showed 91.57% and 39.78% drug release after 24 h in 0.1 N hydrochloric acid and Phosphate Buffer (PB) pH 6.8, respectively. The IC50 value of NP-7 evaluated on A549 Lung cancer cells was found to be 6.36 μM. The XRD of NP-7 displayed the existence of erlotinib in the amorphous pattern. The optimized batch released erlotinib slowly in comparison to the marketed tablet formulation. Erlotinib loaded chitosan nanoparticles were prepared successfully using sonication technique with suitable particle size, entrapment efficiency and drug release. The formulated nanoparticles can be utilized for the treatment of lung cancer.

Matched MeSH terms: Drug Liberation
Oral Nanoemulsion of Fenofibrate: Formulation, Characterization, and In Vitro Drug Release Studies

Gulati N, Kumar Chellappan D, M Tambuwala M, A A Aljabali A, Prasher P, Kumar Singh S, et al.

Assay Drug Dev Technol, 2021 05 14;19(4):246-261.
PMID: 33989048 DOI: 10.1089/adt.2021.012

Nanoemulsions (NMs) are one of the most important colloidal dispersion systems that are primarily used to improve the solubility of poorly water soluble drugs. The main objectives of this study were, first, to prepare an NM loaded with fenofibrate using a high shear homogenization technique and, second, to study the effect of variable using a central composite design. Twenty batches of fenofibrate-loaded NM formulations were prepared. The formed NMs were subjected to droplet size analysis, zeta potential, entrapment efficiency, pH, dilution, polydispersity index, transmission electron microscopy (TEM), Fourier transform infrared spectrophotometry, differential scanning calorimetry (DSC), and in vitro drug release study. Analysis of variance was used for entrapment efficiency data to study the fitness and significance of the design. The NM-7 batch formulation demonstrated maximum entrapment efficiency (81.82%) with lowest droplet size (72.28 nm), and was thus chosen as the optimized batch. TEM analysis revealed that the NM was well dispersed with droplet sizes <100 nm. Incorporation of the drug into the NM was confirmed with DSC studies. In addition, the batch NM-7 also showed the maximum in vitro drug release (87.6%) in a 0.05 M sodium lauryl sulfate solution. The release data revealed that the NM followed first-order kinetics. The outcomes of the study revealed the development of a stable oral NM containing fenofibrate using the high shear homogenization technique. This approach may aid in further enhancing the oral bioavailability of fenofibrate, which requires further in vivo studies.

Matched MeSH terms: Drug Liberation
Fulltext Development and evaluation of Ketoprofen sustained release matrix tablet using Hibiscus rosa-sinensis leaves mucilage

Kaleemullah M, Jiyauddin K, Thiban E, Rasha S, Al-Dhalli S, Budiasih S, et al.

Saudi Pharm J, 2017 Jul;25(5):770-779.
PMID: 28725150 DOI: 10.1016/j.jsps.2016.10.006

Currently, the use of natural gums and mucilage is of increasing importance in pharmaceutical formulations as valuable drug excipient. Natural plant-based materials are economic, free of side effects, biocompatible and biodegradable. Therefore, Ketoprofen matrix tablets were formulated by employing Hibiscus rosa-sinensis leaves mucilage as natural polymer and HPMC (K100M) as a synthetic polymer to sustain the drug release from matrix system. Direct compression method was used to develop sustained released matrix tablets. The formulated matrix tablets were evaluated in terms of physical appearance, weight variation, thickness, diameter, hardness, friability and in vitro drug release. The difference between the natural and synthetic polymers was investigated concurrently. Matrix tablets developed from each formulation passed all standard physical evaluation tests. The dissolution studies of formulated tablets revealed sustained drug release up to 24 h compared to the reference drug Apo Keto® SR tablets. The dissolution data later were fitted into kinetic models such as zero order equation, first order equation, Higuchi equation, Hixson Crowell equation and Korsmeyer-Peppas equation to study the release of drugs from each formulation. The best formulations were selected based on the similarity factor (f2) value of 50% and more. Through the research, it is found that by increasing the polymers concentration, the rate of drug release decreased for both natural and synthetic polymers. The best formulation was found to be F3 which contained 40% Hibiscus rosa-sinensis mucilage polymer and showed comparable dissolution profile to the reference drug with f2 value of 78.03%. The release kinetics of this formulation has shown to follow non-Fickian type which involved both diffusion and erosion mechanism. Additionally, the statistical results indicated that there was no significant difference (p > 0.05) between the F3 and reference drug in terms of MDT and T50% with p-values of 1.00 and 0.995 respectively.

Matched MeSH terms: Drug Liberation
Preparation of letrozole dispersed pHEMA/AAm-g-LDPE drug release system: In-vitro release kinetics for the treatment of endometriosis

Siddiqa AJ, Shrivastava NK, Ali Mohsin ME, Abidi MH, Shaikh TA, El-Meligy MA

Colloids Surf B Biointerfaces, 2019 Jul 01;179:445-452.
PMID: 31005739 DOI: 10.1016/j.colsurfb.2019.04.014

This paper focuses on the development of a drug delivery system for systemically controlled release of a poorly soluble drug, letrozole. The work meticulously describes the preparation and characterizations of 2-hydroxyethyl methacrylate (HEMA) polymerization onto hydrophilic acrylamide grafted low-density polyethylene (AAm-g-LDPE) surface for targeted drug release system. The surface morphology and thickness measurement of coated pHEMA layer were measured using scanning electron microscopy (SEM). The swelling study was done in deionized (DI) water and simulated uterine fluid (SUF, pH = 7.6). In vitro release of letrozole from the system was performed in SUF. Further, the release kinetics of letrozole from the system was studied using different mathematical models. The results, suggest that the rate of drug release can be altered by varying the concentrations of cross-linker in pHEMA. The optimized sample released 72% drug at the end of 72 h of measurement.

Matched MeSH terms: Drug Liberation*
Graphene oxide as a nanocarrier for controlled release and targeted delivery of an anticancer active agent, chlorogenic acid

Barahuie F, Saifullah B, Dorniani D, Fakurazi S, Karthivashan G, Hussein MZ, et al.

Mater Sci Eng C Mater Biol Appl, 2017 May 01;74:177-185.
PMID: 28254283 DOI: 10.1016/j.msec.2016.11.114

We have synthesized graphene oxide using improved Hummer's method in order to explore the potential use of the resulting graphene oxide as a nanocarrier for an active anticancer agent, chlorogenic acid (CA). The synthesized graphene oxide and chlorogenic acid-graphene oxide nanocomposite (CAGO) were characterized using Fourier transform infrared (FTIR) spectroscopy, thermogravimetry and differential thermogravimetry analysis, Raman spectroscopy, powder X-ray diffraction (PXRD), UV-vis spectroscopy and high resolution transmission electron microscopy (HRTEM) techniques. The successful conjugation of chlorogenic acid onto graphene oxide through hydrogen bonding and π-π interaction was confirmed by Raman spectroscopy, FTIR analysis and X-ray diffraction patterns. The loading of CA in the nanohybrid was estimated to be around 13.1% by UV-vis spectroscopy. The release profiles showed favourable, sustained and pH-dependent release of CA from CAGO nanocomposite and conformed well to the pseudo-second order kinetic model. Furthermore, the designed anticancer nanohybrid was thermally more stable than its counterpart. The in vitro cytotoxicity results revealed insignificant toxicity effect towards normal cell line, with a viability of >80% even at higher concentration of 50μg/mL. Contrarily, CAGO nanocomposite revealed enhanced toxic effect towards evaluated cancer cell lines (HepG2 human liver hepatocellular carcinoma cell line, A549 human lung adenocarcinoma epithelial cell line, and HeLa human cervical cancer cell line) compared to its free form.

Matched MeSH terms: Drug Liberation
Fulltext Morphological Changes and Cellular Uptake of Functionalized Graphene Oxide Loaded with Protocatechuic Acid and Folic Acid in Hepatocellular Carcinoma Cancer Cell

Buskaran K, Hussein MZ, Mohd Moklas MA, Fakurazi S

Int J Mol Sci, 2020 Aug 16;21(16).
PMID: 32824281 DOI: 10.3390/ijms21165874

The development of nanocomposites has swiftly changed the horizon of drug delivery systems in defining a new platform. Major understanding of the interaction of nanocomposites with cells and how the interaction influences intracellular uptake is an important aspect to study in order to ensure successful utilisation of the nanocomposites. Studies have suggested that the nanocomposites' ability to permeate into biological cells is attributable to their well-defined physicochemical properties with nanoscale size, which is relevant to the nanoscale components of biology and cellular organelles. The functionalized graphene oxide coated with polyethylene glycol, loaded with protocatechuic acid and folic acid (GOP-PCA-FA) nanocomposite intracellular uptake was analysed using transmission electron microscope. The accumulation of fluorescent-labelled nanocomposites in the HepG2 cell was also analysed using a fluorescent microscope. In vitro cellular uptake showed that there was uptake of the drug from 24 h into the cells and the release study using fluorescently tagged nanocomposite demonstrated that release and accumulation were observed at 24 h and 48 h. Moreover, the migration ability of tumor cells is a key step in tumor progression which was observed 48 h after treatment. The GOP serves as a potential nanocarrier system which is capable of improving the therapeutic efficacy of drugs and biomolecules in medical as well as pharmaceutical applications through the enhanced intracellular release and accumulation of the encapsulated drugs. Nonetheless, it is essential to analyse the translocation of our newly developed GOP-PCA-FA, and its efficiency for drug delivery, effective cellular uptake, and abundant intracellular accumulation would be compromised by possible untoward side effects.

Matched MeSH terms: Drug Liberation
Fulltext Synthesis and properties of magnetic nanotheranostics coated with polyethylene glycol/5-fluorouracil/layered double hydroxide

Ebadi M, Saifullah B, Buskaran K, Hussein MZ, Fakurazi S

Int J Nanomedicine, 2019;14:6661-6678.
PMID: 31695362 DOI: 10.2147/IJN.S214923

Background: Cancer treatments are being continually developed. Increasingly more effective and better-targeted treatments are available. As treatment has developed, the outcomes have improved.
Purpose: In this work, polyethylene glycol (PEG), layered double hydroxide (LDH) and 5-fluorouracil (5-FU) were used as a stabilizing agent, a carrier and an anticancer active agent, respectively.
Characterization and methods: Magnetite nanoparticles (Fe3O4) coated with polyethylene glycol (PEG) and co-coated with 5-fluorouracil/Mg/Al- or Zn/Al-layered double hydroxide were synthesized by co-precipitation technique. Structural, magnetic properties, particle shape, particle size and drug loading percentage of the magnetic nanoparticles were investigated by XRD, TGA, FTIR, DLS, FESEM, TEM, VSM, UV-vis spectroscopy and HPLC techniques.
Results: XRD, TGA and FTIR studies confirmed the formation of Fe3O4 phase and the presence of iron oxide nanoparticles, polyethylene glycol, LDH and the drug for all the synthesized samples. The size of the nanoparticles co-coated with Mg/Al-LDH is about 27 nm compared to 40 nm when they were co-coated with Zn/Al-LDH, with both showings near uniform spherical shape. The iron oxide nanoparticles retain their superparamagnetic property when they were coated with polyethylene glycol, polyethylene glycol co-coated with Mg/Al-LDH and polyethylene glycol co-coated with Zn/Al-LDH with magnetic saturation value of 56, 40 and 27 emu/g, respectively. The cytotoxicity study reveals that the anticancer nanodelivery system has better anticancer activity than the free drug, 5-FU against liver cancer HepG2 cells and at the same time, it was found to be less toxic to the normal fibroblast 3T3 cells.
Conclusion: These are unique core-shell nanoparticles synthesized with the presence of multiple functionalities are hoped can be used as a multifunctional nanocarrier with the capability of targeted delivery using an external magnetic field and can also be exploited as hypothermia for cancer cells in addition to the chemotherapy property.

Matched MeSH terms: Drug Liberation
Fulltext Graphene Oxide Loaded with Protocatechuic Acid and Chlorogenic Acid Dual Drug Nanodelivery System for Human Hepatocellular Carcinoma Therapeutic Application

Buskaran K, Hussein MZ, Moklas MAM, Masarudin MJ, Fakurazi S

Int J Mol Sci, 2021 May 28;22(11).
PMID: 34071389 DOI: 10.3390/ijms22115786

Hepatocellular carcinoma or hepatoma is a primary malignant neoplasm that responsible for 75-90% of all liver cancer in humans. Nanotechnology introduced the dual drug nanodelivery method as one of the initiatives in nanomedicine for cancer therapy. Graphene oxide (GO) loaded with protocatechuic acid (PCA) and chlorogenic acid (CA) have shown some anticancer activities in both passive and active targeting. The physicochemical characterizations for nanocomposites were conducted. Cell cytotoxicity assay and lactate dehydrogenase were conducted to estimate cell cytotoxicity and the severity of cell damage. Next, nanocomposite intracellular drug uptake was analyzed using a transmission electron microscope. The accumulation and localization of fluorescent-labelled nanocomposite in the human hepatocellular carcinoma (HepG2) cells were analyzed using a fluorescent microscope. Subsequently, Annexin V- fluorescein isothiocyanate (FITC)/propidium iodide analysis showed that nanocomposites induced late apoptosis in HepG2 cells. Cell cycle arrest was ascertained at the G2/M phase. There was the depolarization of mitochondrial membrane potential and an upregulation of reactive oxygen species when HepG2 cells were induced by nanocomposites. In conclusion, HepG2 cells treated with a graphene oxide-polyethylene glycol (GOP)-PCA/CA-FA dual drug nanocomposite exhibited significant anticancer activities with less toxicity compared to pristine protocatechuic acid, chlorogenic acid and GOP-PCA/CA nanocomposite, may be due to the utilization of a folic acid-targeting nanodrug delivery system.

Matched MeSH terms: Drug Liberation
Gelatin Hydrogels Loaded with Lactoferrin-Functionalized Bio-Nanosilver as a Potential Antibacterial and Anti-Biofilm Dressing for Infected Wounds: Synthesis, Characterization, and Deciphering of Cytotoxicity

Suleman Ismail Abdalla S, Katas H, Chan JY, Ganasan P, Azmi F, Fauzi MB

Mol Pharm, 2021 05 03;18(5):1956-1969.
PMID: 33822631 DOI: 10.1021/acs.molpharmaceut.0c01033

Gelatin hydrogels are attractive for wound applications owing to their well-defined structural, physical, and chemical properties as well as good cell adhesion and biocompatibility. This study aimed to develop gelatin hydrogels incorporated with bio-nanosilver functionalized with lactoferrin (Ag-LTF) as a dual-antimicrobial action dressing, to be used in treating infected wounds. The hydrogels were cross-linked using genipin prior to loading with Ag-LTF and characterized for their physical and swelling properties, rheology, polymer and actives interactions, and in vitro release of the actives. The hydrogel's anti-biofilm and antibacterial performances against S. aureus and P. aeruginosa as well as their cytotoxicity effects were assessed in vitro, including primary wound healing gene expression of human dermal fibroblasts (HDFs). The formulated hydrogels showed adequate release of AgNPs and LTF, with promising antimicrobial effects against both bacterial strains. The Ag-LTF-loaded hydrogel did not significantly interfere with the normal cellular functions as no alteration was detected for cell viability, migration rate, and expression of the target genes, suggesting the nontoxicity of Ag-LTF as well as the hydrogels. In conclusion, Ag-LTF-loaded genipin-cross-linked gelatin hydrogel was successfully synthesized as a new approach for fighting biofilms in infected wounds, which may be applied to accelerate healing of chronic wounds.

Matched MeSH terms: Drug Liberation

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