New metal-organic framework coated sodium alginate for the delivery of curcumin as a sustainable drug delivery and cancer therapy system.

The utilization of biocompatible drug delivery systems with extended drug release capabilities is highly advantageous in cancer therapy, as they can mitigate adverse effects. To establish such a biocompatible system with prolonged drug release behavior, researchers developed an innovative drug carrier. In this study, a sustainable approach was employed to synthesize a new zinc-based metal-organic framework (Zn-MOF) through the reaction between synthesized Schiff base ligands and zinc ions. Comprehensive analyses, including FT-IR, XRD, SEM, BET surface area, and TGA techniques, were employed to thoroughly characterize the frameworks. Following comprehensive characterization, curcumin (CUR) was loaded onto the Zn-MOF, resulting in CUR entrapment efficiency and loading capacity of 79.23 % and 26.11 %, respectively. In vitro evaluations of CUR release from CUR@MOF exhibited controlled release patterns, releasing 78.9 % and 50.0 % of CUR at pH 5.0 and pH 7.4, respectively. To mitigate initial burst release, a coating of the biopolymer sodium alginate (SA) was applied to CUR@Zn-MOF. In vitro CUR release tests indicated that SA/CUR@Zn-MOF outperformed pristine CUR@Zn-MOF. The release of CUR conformed to the Korsmeyer-Peppas model, displaying non-Fickian diffusion. Furthermore, an in vitro cytotoxicity study clearly demonstrated the potent anti-tumor activity of the synthesized CUR@Zn-MOF attributed to its controlled release of CUR. This led to the induction of apoptotic effects and cell death across HeLa, HEK293, and SH-SY5Y cell lines. These findings strongly suggest that the developed pH-sensitive carriers hold remarkable potential as targeted vehicles for drug delivery in cancer therapy.

The green synthesis and applications of biological metal-organic frameworks for targeted drug delivery and tumor treatments.

Biological metal-organic frameworks (bio-MOFs) constitute a growing subclass of MOFs composed of metals and bio-ligands derived from biology, such as nucleobases, peptides, saccharides, and amino acids. Bio-ligands are more abundant than other traditional organic ligands, providing multiple coordination sites for MOFs. However, bio-MOFs are typically prepared using hazardous or harmful solvents or reagents, as well as laborious processes that do not conform to environmentally friendly standards. To improve biocompatibility and biosafety, eco-friendly synthesis and functionalization techniques should be employed with mild conditions and safer materials, aiming to reduce or avoid the use of toxic and hazardous chemical agents. Recently, bio-MOF applications have gained importance in some research areas, including imaging, tumor therapy, and targeted drug delivery, owing to their flexibility, low steric hindrances, low toxicity, remarkable biocompatibility, surface property refining, and degradability. This has led to an exponential increase in research on these materials. This paper provides a comprehensive review of updated strategies for the synthesis of environmentally friendly bio-MOFs, as well as an examination of the current progress and accomplishments in green-synthesized bio-MOFs for drug delivery aims and tumor treatments. In conclusion, we consider the challenges of applying bio-MOFs for biomedical applications and clarify the possible research orientation that can lead to highly efficient therapeutic outcomes.

Modeling and simulation of smart magnetic self-assembled nanomicelle trajectories in an internal thoracic artery flow for breast cancer therapy.

Magnetic drug targeting (MDT) is one of the most modern techniques in cancer therapy for its ability to reduce the side effects of chemotherapy experienced by systemic drug administration. In this study, a comprehensive mathematical model has been developed to predict the drug particle trajectories of anticancer dasatinib magnetic nanomicelles (DAS-MNM) released in an internal thoracic artery (ITA) blood flow for breast cancer therapy using an external magnetic field. Several factors are investigated in regard to the efficiency of MDT through the ITA, including magnetic field strength (MFS), relative magnetic permeability, magnet size, drug particle size, and initial position of drug particle. The drug particle trajectory results confirmed the successful MDT using an external magnetic field with a capture efficiency of more than 90%. This was achieved by employing a wide range of particle sizes of DAS-MNM close to the external magnetic field source at the arterial wall than in other positions. Moreover, the results showed that the number of trapped particles increased with increasing both MFS and drug particle diameter within the target tissue, while the drug particle permeability did not have a considerable effect on the particle retention. In addition, for achieving a successful drug/cargo delivery through the arteries, the magnetic field, the particle size, and the initial release locations should be adjusted simultaneously. The present work offers insights into the critical factors in MDT with a significant impact on breast cancer therapy, tissue engineering, and regenerative medicine. Magnetic drug targeting model of anticancer dasatinib magnetic nanomicelles (DAS-MNM) released in an internal thoracic artery blood flow for breast cancer therapy.

Controlled Drug Release of Smart Magnetic Self-Assembled Micelle, Kinetics and Transport Mechanisms.

Magnetic nanocarriers have been extensively used as a potential drug release system for breast cancer therapy. This work investigates drug release kinetics and transport mechanisms of dasatinib (DAS) anticancer drugs encapsulated in nanomagnetic self-assembled micelles. The drug release kinetics of DAS from the nanomagnetic micelles (NMM) was predicted by fitting the drug release experimental data to four different empirical models at pH values 7.4 and 5. Moreover, a simple mathematical model that can predict the drug release from bulk eroding polymer matrices has been developed using the COMSOL Multiphysics® program. The diffusional egress of the DAS release through the NMM was carried out by evaluating the diffusion coefficients inside NMM using Fick's second law and diffusion coefficients in the solution utilizing the Stokes-Einstein equation. The results revealed that NMM exhibited a superior sustained drug release rate in acidic conditions compared to the neutral state. The Peppas-Sahlin and COMSOL models gave the best fitting for the experimental drug release data and eroding matrices obtained from free DAS, DAS-micelles, and DAS-magnetic micelles at both pH values with correlation coefficients reached to 0.99. The transport mechanisms results showed a Fickian diffusion mechanism controlled with the highest diffusion coefficients of NMM in acidic conditions, while a significant relaxation contribution was observed at the neutral state.

Influence of phosphorus on the NH3-SCR performance of CeO2-TiO2 catalyst for NOx removal from co-incineration flue gas of domestic waste and municipal sludge.

Domestic waste and municipal sludge are two major solid hazardous substances generated from human daily life. Co-incineration technology is regarded as an effective method for the treatment of them. However, the emitted NOx-containing exhaust with high content of phosphorus should purified strictly. CeO2-TiO2 is a promising catalyst for removal of NOx by NH3-SCR technology, but the effect of phosphorous in the exhaust is ambiguous. Therefore, the effect of phosphorus on NH3-SCR performance and physicochemical properties of CeO2-TiO2 catalyst was investigated in our present work. It was found that phosphorus decreased the NH3-SCR activity below 300 °C. Interestingly, it suppressed the formation of NOx and N2O caused by NH3 over-oxidation above 300 °C. The reason might be that phosphorus induced Ti4+ to migrate from CeO2-TiO2 solid solution and form crystalline TiO2, which led to the destruction of Ti-O-Ce structure in the catalyst. So, the transfer of electrons between Ti and Ce ions, the relative contents of Ce3+, and surface adsorbed oxygen, as well as the redox performance were limited, which further inhibited the over-oxidation of NH3. In addition, phosphorus weakened the NH3 adsorption on Lewis acid sites and the adsorption performance of NO + O2, while increased the Brønsted acid sites. Finally, the reaction mechanism over CeO2-TiO2 catalyst did not change after introducing phosphorus, L-H and E-R mechanisms co-existed on the surface of the catalysts.

Recent advances in electrospun nanofibers for some biomedical applications.

Nanofibers provide multiple merits for the delivery of many therapeutic agents with versatile biomedical applications. With the fast recent advancement in nanotechnology, nanofibers could be easily fabricated with tunable morphologies and release profiles. Here, we review the most recent approaches in the fabrication of electrospun nanofibers incorporating some natural ingredients for their wound healing potential. In addition, electrospun nanofibers for treatment of skin carcinoma and delivery of different growth factors for tissue regeneration will also be highlighted in this review. Nanofibers incorporating different active therapeutical agents are very promising drug delivery platforms.

On-Chip Preparation of Amphiphilic Nanomicelles-in-Sodium Alginate Spheroids as a Novel Platform Against Triple-Negative Human Breast Cancer Cells: Fabrication, Study of Microfluidics Flow Hydrodynamics and Proof of Concept for Anticancer and Drug Delivery Applications.

Spheroidal microparticles versatility as a drug carrier makes it a real workhorse in drug delivery applications. Despite of their long history, few research publications emphasize on how to improve their potential targeting ability, production rate, and dissolution characteristics. The current research presents an example of the combined state of the art of nano- and microparticles development technologies. Here in a novel on-chip, microfluidics approach is developed for encapsulating amphiphilic nanomicelles-in-sodium alginate spheroid. The designed nano-in-micro drug delivery system revealed a superior cytotoxicity against triple-negative human breast cancer cell line (MDA-MB-231), besides, a more sustained release of the drug. Hydrodynamics of the designed microchip was also investigated as a function of different flow rates with an insight on the dimensionless numbers; capillary number and Weber number throughout the microchannels. Our study confirmed the efficient encapsulation of nanomicelles within the alginate shell. The current microfluidics approach can be efficiently applied for uniform production of nano-in-microparticles with potential anticancer capability.

Magnetically Guided Self-Assembled Protein Micelles for Enhanced Delivery of Dasatinib to Human Triple-Negative Breast Cancer Cells.

Magnetic nanocarriers are useful in targeted cancer therapy. Dasatinib (DAS)-loaded magnetic micelles were prepared for magnetically guided drug delivery. The magnetic nanoplatform is composed of hydrophobic oleic acid-coated magnetite (Fe3O4) core along with DAS encapsulated in amphiphilic zein-lactoferrin self-assembled polymeric micelles. Transmission electron microscope analysis manifested formation of these magnetic micelles with a mean diameter of about 100 nm. In addition, drug-loaded magnetic micelles displayed a saturation magnetization of about 10.01 emu.g-1 with a superparamagnetic property. They also showed good in vitro serum stability and hemocompatibility accompanied with a sustained release of DAS in acidic pH. More importantly, they exhibited 1.35-fold increase in their in vitro cytotoxicity against triple-negative human breast cancer cell line (MDA-MB-231) using an external magnetic field compared to drug-loaded magnetic micelles in the absence of a magnetic field. Enhanced inhibition of p-c-Src protein expression level and in vitro cellular migration under the effect of magnetic field was noted owing to the dual-targeting strategy offered by the presence of a magnetic sensitive core, as well as the active targeting property of lactoferrin corona. Taken all together, these results suggest that DAS-loaded magnetic micelles possess a great potential for targeted therapy of breast cancer.

Improved Resolution of 4-Chloromandelic Acid and the Effect of Chlorine Interactions Using (R)-(+)-Benzyl-1-Phenylethylamine as a Resolving Agent.

In order to avoid the disadvantage of commonly used resolving agent 1-phenylethylamine (hereafter: PEA), which is soluble in water, (R)-(+)-benzyl-1-phenylethylamine ((R)-(+)-BPA) was used to resolve 4-chloromandelic acid (4-ClMA) in this study. The optimal resolution conditions were determined: absolute ethanol as a solvent, the molar ratio of 4-ClMA to (R)-(+)-BPA as 1:1, the filtration temperature as 15 °C, and the amount of solvent as 1.6 mL/1 mmol 4-ClMA. Thermophysical properties, such as melting point, heat of fusion, and solubility, exhibited significant differences between the less and more soluble salts. The single crystals for the pair of diastereomeric salts were cultivated and their crystal structures were examined thoroughly. In addition to commonly observed interactions like hydrogen bonding and CH/π interactions. The chlorine…chlorine interaction was observed in the less soluble salt presenting as Cl…Cl between adjacent hydrogen network columns, while the Cl/π interaction was observed in the more soluble salt. It was found that halogen interactions played an important role in chiral recognition of 4-ClMA by (R)-(+)-BPA.

Self-assembled amphiphilic zein-lactoferrin micelles for tumor targeted co-delivery of rapamycin and wogonin to breast cancer.

Protein-based micelles have shown significant potential for tumor-targeted delivery of anti-cancer drugs. In this light, self-assembled nanocarriers based on GRAS (Generally recognized as safe) amphiphilic protein co-polymers were synthesized via carbodiimide coupling reaction. The new nano-platform is composed of the following key components: (i) hydrophobic zein core to encapsulate the hydrophobic drugs rapamycin (RAP) and wogonin (WOG) with high encapsulation efficiency, (ii) hydrophilic lactoferrin (Lf) corona to enhance the tumor targeting, and prolong systemic circulation of the nanocarriers, and (iii) glutaraldehyde (GLA)-crosslinking to reduce the particle size and improve micellar stability. Zein-Lf micelles showed relatively rapid release of WOG followed by slower diffusion of RAP from zein core. This sequential release may aid in efflux pump inhibition by WOG thus sensitizing tumor cells to RAP action. Interestingly, these micelles showed good hemocompatibility as well as enhanced serum stability owing to the brush-like architecture of Lf shell. Moreover, this combined nano-delivery system maximized synergistic cytotoxicity of RAP and WOG in terms of tumor inhibition in MCF-7 breast cancer cells and Ehrlich ascites tumor animal model as a result of enhanced active targeting. Collectively, GLA-crosslinked zein-Lf micelles hold great promise for combined RAP/WOG delivery to breast cancer with reduced drug dose, minimized side effects and maximized anti-tumor efficacy.

Investigation on polymorphic behavior of progesterone and stabilization by co-crystallization: a review.

Progesterone, extensively used in human as well as veterinary medicines is a progestogen type of hormone. With the aim for hunting the stable polymorph, this review examines polymorphic behavior of progesterone and stabilization of less stable form by co-crystallization. An overview of two monotropically related forms of progesterone--form-I and form-II, synthetic enantiomer, ent-progesterone and racemic progesterone is provided. Different methods reported in the literature for the formation of polymorphs of progesterone are discussed here. After extensive manual screening it has been found that, though there are few methods mentioned in the literature for the formation of form-II, there is a lack of reproducibility in the recipes. This contribution also briefly reviews three other forms of progesterone (form-III, form-IV and form-V) which appear only in equilibrium melt and cannot be structurally characterized. Finally, comparison of different physical properties of form-I and form-II are also addressed.

Cubic magnetically guided nanoaggregates for inhalable drug delivery: in vitro magnetic aerosol deposition study.

The present work describes the in vitro aerosol deposition and enhanced deaggregation behavior of superparamagnetic iron oxide nanoaggregates (SPIONs). SPIONs were surface-coated with amine functionalized polyrotaxane and were proposed as a carrier for inhalation dry powders. Polyrotaxane is primarily composed of beta cyclodextrin rings which are spontaneously threaded on the block copolymer, poly(propylene glycol) bis(2-aminopropylether). Variable concentrations of surface coating polymers showed controlled manipulation of the crystal size and morphology. Magnetic nanoaggregates fabricated with low concentration of polyrotaxane showed cubic crystal morphology. However, these nanoaggregates exhibited rhombic dodecahedron crystal structure upon increasing the coating polymer concentration. In comparison to the spherical uncoated magnetic nanoparticles, cubic phase magnetic nanoaggregates demonstrated an enhanced in vitro aerosol deposition using magnetic field alignment. This enhancement can be accomplished at low inhalation flow rates (15 and 30 L/min). However, transformation to the cubic crystal structure was observed to be associated with a reduction in the powder geometric standard deviation. Using a mathematical modeling approach, we noted significant enhancement in the deaggregation behavior of inhalation dry powders; that can be achieved with small amounts of magnetic nanoaggregates. Aggregates of cubic nanoparticles showed promise for targeted pulmonary deposition of anticancer drugs.

Controlled release of 5-fluorouracil and progesterone from magnetic nanoaggregates.

BACKGROUND: The potential use of magnetic nanoparticles in biomedical applications has witnessed an exponential growth in recent years. METHODS: In this study, we used nanoaggregates of magnetic nanoparticles as carriers for controlled drug delivery. The nanoaggregates are formed due to the presence of the block copolymer of polyethylene oxide-polypropylene oxide (Pluronic F-68) and beta-cyclodextrin that surround the magnetic core of the nanoparticles. The administration of the drug carriers occurs by inhalation, and the drug is delivered systemically via the pulmonary route. We tested the delivery of 5-fluorouracil and progesterone, which are used as models of hydrophilic and hydrophobic drugs, respectively. RESULTS: The estimated nanoaggregates' diameters are between 293 nm ± 14.65 nm and 90.2 nm ± 4.51 nm, respectively. In-situ and post-synthesis techniques are two approaches for drug loading. The polymer composition of nanoaggregates and initial drug concentration showed a significant effect on both the drug entrapment efficiency and release kinetics. Average drug entrapment efficiencies ranged between 16.11% and 83.25%. In-situ loaded samples showed significantly slower release rates. The drug release mechanism is investigated by mathematical curve fitting to different drug release kinetics models. In most cases, the Peppas model has shown good correlations (coefficients of correlation, R(2), between 0.85 and 0.99) with the examined release profiles. The estimated release indices are below 0.5, which indicates the Fickian diffusion mechanism. For samples with an initial burst effect, the modified Peppas model can provide a better understanding of the drug release mechanism, both in the samples loaded with progesterone, or those high polymer concentrations. CONCLUSION: Our work showed prolonged delivery of drugs (5-fluorouracil and progesterone) by diffusion from nanoaggregates, with the potential to reduce dose-related adverse effects.

Resolution of 2-chloromandelic acid with (R)-(+)-N-benzyl-1-phenylethylamine: chiral discrimination mechanism.

During the resolution of 2-chloromandelic acid with (R)-(+)-N-benzyl-1-phenylethylamine, the crystals of the less soluble salt were grown, and their structure were determined and presented. The chiral discrimination mechanism was investigated by examining the weak intermolecular interactions (such as hydrogen bond, CH/π, and van der Waals interactions) and molecular packing mode in crystal structure of the less soluble diastereomeric salt. A one-dimensional double-chain hydrogen-bonding network and a "lock-and-key" supramolecular packing mode are disclosed. The investigation demonstrates that hydrophobic layers with corrugated surfaces can fit into the grooves of one another to realize a compact packing, when the molecular structure of resolving agent is much larger than that of the racemate. This "lock-and-key" assembly is recognized to be another characteristic of molecular packing contributing to the chiral discrimination, in addition to the well-known sandwich-like packing by hydrophobic layers with planar boundary surfaces.

Chiral discrimination in diastereomeric salts of chlorine-substituted mandelic acid and phenylethylamine.

The crystal structures of diastereomeric salts of chloromandelic acid and phenylethylamine were determined and are presented herein. The structure comparison between less soluble salts and more soluble salts shows that weak interactions such as CH/pi interactions and van der Waals gain importance and contribute to chiral recognition when the hydrogen bonding patterns are very similar.

Crystallization of progesterone for pulmonary drug delivery.

The purpose of this study is to investigate the suitability of the crystallization process to produce microcrystals of progesterone for respiratory drug delivery. Crystallization of progesterone was carried out from water-isopropanol (IPA) mixture. The antisolvent (water) was added at two different addition rates (10 and 100 mL/min). The mass percentage of antisolvent was varied between (50% and 75%), and the initial drug concentration was adjusted at (0.5 and 1 g/L). The effect of crystallization method (antisolvent precipitation or combined cooling and antisolvent) was also examined. These operating conditions were investigated in a 2(4) factorial design in an effort to optimize the process. Different solid-state and surface characterization techniques were applied in conjunction with measurements of powder flow properties using aerodynamic particle sizer (APS). Powder dispersibility and aerosol performance were analyzed using Anderson Cascade Impactor (ACI). Antisolvent addition rate, initial drug concentration and dynamic solvent composition are shown to have a significant effect on the aerosol characteristics of progesterone microcrystals. An increase of 38.73% in the fine particle fraction (FPF) was demonstrated for some powders produced by combined cooling and antisolvent crystallization. In conclusion, it was possible to control particle size and hence, pulmonary deposition using process parameters alone, and produce particles with a narrow particle size distribution and a mean particle size of 5 microm with nearly no particles larger than 10 microm by direct crystallization. The suitability of deep pulmonary deposition was proved by the platelet-like morphology of processed microcrystals and greater surface-to-volume ratio than spherical particles.

Diastereomeric resolution of p-chloromandelic acid with (R)-phenylethylamine.

The optical resolution of p-chloromandelic acid using (R)-alpha-phenylethylamine as resolving agent was presented. The effect of solvents, molar ratio of racemate to the resolving agent, filtration temperature as well as the amount of solvent on resolution was investigated by orthogonal experimentation. The binary melting point phase diagram and crystal structure analysis of diastereomeric salts rationalized the success of the resolution.

Identification and characterization of solid-state nature of 2-chloromandelic acid.

The racemate and enantiomers of 2-chloromandelic acid were characterized by SS-NMR, XRPD, and FTIR. The binary melting point phase diagram was constructed by DSC (differential scanning calorimetry). The solid-state nature of 2-chloromandelic acid was identified to be a racemic compound. The crystal structure of racemic compound was determined to be monoclinic P2(1)/c.

Experimental study of the GAS process for producing microparticles of beclomethasone-17,21-dipropionate suitable for pulmonary delivery.

In this study the micronization of beclomethasone-17,21-dipropionate (BECD), used as an inhaled steroid for the treatment of asthma, was studied using the gas-antisolvent (GAS) process as a "green" alternative to pharmaceutical recrystallization. A systematic investigation of the influence of the key GAS process parameters: antisolvent addition rate (1, 50, 75 and 100 ml/min), temperature (25, 32.5, 40 and 52.5 degrees C), solute concentration (5, 25, 70 and 100%), and agitation rate (500, 1000, 2000 and 3000 rpm) were investigated on particle morphology, size distribution, and crystallinity. It was found using scanning electron microscopy (SEM) and laser diffraction, that increasing the antisolvent addition rate and the agitation rate, while decreasing the temperature and solute concentration, led to a decrease in the steroids mean particle diameter. These parameters could be tuned to give a mean particle diameter of 1.8 microm, and an average mass median aerodynamic diameter (MMAD) of 7.9 microm. High-performance liquid chromatography (HPLC) results showed the recrystallized BECD was purer than the non-processed material. The role of the solvent (acetone, methanol and ethanol) in the BECD crystal structure was investigated using X-ray diffraction (XRD), which showed acetone gave a more crystalline structure, hence having lower incorporation into the crystal structure. These results showed that the GAS process has the potential to produce steroid with powder properties suitable for inhalation therapy.