Self-assembling Organogels Loaded with Tenoxicam for Local Intensive Pain and Inflammation Cure: In Vitro and In Vivo Correlation.

Due to tenoxicam (TX)'s poor aqueous solubility (0.072 mg/ml), it is poorly absorbable in the GIT, and the long-term oral administration of TX may cause severe GIT disturbances. Topical administration of TX can help in bypassing the GIT adverse effects. Therefore, in the present work, we constructed different pluronic/lecithin organogels (PLOs) for topical delivery of TX. PLO was constructed simply via direct mixing of an aqueous pluronic solution with lecithin solution. The prepared PLO formulations were characterized for their physicochemical properties including pH, drug content, visual inspection, viscosity, and spreadability. Also, the in vitro release and kinetic studies were carried out to investigate the mechanism of drug release. Moreover, the in vivo studies were carried out by investigating the anti-inflammatory and analgesic activities using albino male rats. The results showed that the modified PLOs have good physicochemical properties. The viscosity of the modified gels is a direct proportionality with both lecithin and pluronic concentrations. Also, subsequently, the drug release rate is directly proportional to gel viscosity. Moreover, the in vivo studies showed that the modified PLOs (F19) showed a significant ( < 0.05%) paw edema inhibition and pain analgesia compared with other investigated groups. Also, the results indicated that the increase in dose is accompanied by higher activity and a longer duration of action which extended to 12 h. Hence, the modified PLOs are promising safe candidates or vehicles for effective TX loading with sustained delivery behavior.

Chitosan nanoparticles as a smart nanocarrier for gefitinib for tackling lung cancer: Design of experiment and in vitro cytotoxicity study.

Due to its poor solubility and systemic side effects, gefitinib (Gef) has limited application in treatment of lung cancer. In this study, we used design of experiment (DOE) tools to gain the necessary knowledge for the synthesis of high-quality gefitinib loaded chitosan nanoparticles (Gef-CSNPs) capable of delivering and concentrating Gef at A549 cells, thereby increasing therapeutic effectiveness while decreasing adverse effects. The optimized Gef-CSNPs were characterized by SEM, TEM, DSC, XRD, and FTIR analyses. The optimized Gef-CSNPs had a particle size of 158±3.6 nm, an entrapment efficiency of 93±1.2 %, and a release of 97±0.6 % after 8 h. The in vitro cytotoxicity of the optimized Gef-CSNPs was found to be significantly higher than pure Gef (IC50 = 10.08 ± 0.76 µg/mL and IC50 = 21.65 ± 0.32 µg/mL), respectively. In the A549 human cell line, the optimized Gef-CSNPs formula outperformed pure Gef in terms of cellular uptake (3.286 ± 0.12 µg/mL and 1.777 ± 0.1 µg/mL) and apoptotic population (64.82 ± 1.25 % and 29.38 ± 1.11 %), respectively. These findings explain why researchers are so interested in using natural biopolymers to combat lung cancer, and they paint an optimistic picture of their potential as a promising tool in the fight against lung cancer.

Recent Advances in the Pharmaceutical and Biomedical Applications of Cyclodextrin-Capped Gold Nanoparticles.

The real problem in pharmaceutical preparation is drugs' poor aqueous solubility, low permeability through biological membranes, and short biological t1/2. Conventional drug delivery systems are not able to overcome these problems. However, cyclodextrins (CDs) and their derivatives can solve these challenges. This article aims to summarize and review the history, properties, and different applications of cyclodextrins, especially the ability of inclusion complex formation. It also refers to the effects of cyclodextrin on drug solubility, bioavailability, and stability. Moreover, it focuses on preparing and applying gold nanoparticles (AuNPs) as novel drug delivery systems. It also studies the uses and effects of cyclodextrins in this field as novel drug carriers and targeting devices. The system formulated from AuNPs linked with CD molecules combines the advantages of both CD and AuNPs. Cyclodextrins benefit in increasing aqueous drug solubility, loading capacity, stability, and size control of gold NPs. Also, AuNPs are applied as diagnostic and therapeutic agents because of their unique chemical properties. Plus, AuNPs possess several advantages such as ease of detection, targeted and selective drug delivery, greater surface area, high loading efficiency, and higher stability than microparticles. In the present article, we tried to present the potential pharmaceutical applications of CD-derived AuNPs in biomedical applications including antibacterial, anticancer, gene-drug delivery, and various targeted drug delivery applications. Also, the article highlighted the role of CDs in the preparation and improvement of catalytic enzymes, the formation of self-assembling molecular print boards, the fabrication of supramolecular functionalized electrodes, and biosensors formation.

Injectable Hydrogels Based on Cyclodextrin/Cholesterol Inclusion Complexation and Loaded with 5-Fluorouracil/Methotrexate for Breast Cancer Treatment.

Breast cancer is the second most common cancer in women worldwide. Long-term treatment with conventional chemotherapy may result in severe systemic side effects. Therefore, the localized delivery of chemotherapy helps to overcome such a problem. In this article, self-assembling hydrogels were constructed via inclusion complexation between host ß-cyclodextrin polymers (8armPEG20k-CD and pß-CD) and the guest polymers 8-armed poly(ethylene glycol) capped either with cholesterol (8armPEG20k-chol) or adamantane (8armPEG20k-Ad) and were loaded with 5-fluorouracil (5-FU) and methotrexate (MTX). The prepared hydrogels were characterized by SEM and rheological behaviors. The in vitro release of 5-FU and MTX was studied. The cytotoxicity of our modified systems was investigated against breast tumor cells (MCF-7) using an MTT assay. Additionally, the histopathological changes in breast tissues were monitored before and after their intratumor injection. The results of rheological characterization indicated the viscoelastic behavior in all cases except for 8armPEG-Ad. In vitro release results showed a variable range of release profiles from 6 to 21 days, depending on the hydrogel composition. MTT findings indicated the inhibition ability of our systems against the viability of cancer cells depending on the kind and concentration of the hydrogel and the incubation period. Moreover, the results of histopathology showed the improvement of cancer manifestation (swelling and inflammation) after intratumor injection of loaded hydrogel systems. In conclusion, the obtained results indicated the applicability of the modified hydrogels as injectable vehicles for both loading and controlled release of anticancer therapies.

Gefitinib-loaded starch nanoparticles for battling lung cancer: Optimization by full factorial design and in vitro cytotoxicity evaluation.

Lung cancer is the number one killer among all cancer types. For decades, clinicians have been using conventional chemotherapeutics, but they can't rely on them alone anymore, because they poison bad cells and good cells as well. Researchers exploited nanotechnology as a potential tool to develop a platform for drug delivery to improve therapeutic efficiency. A quality by design synthesis of gefitinib-loaded starch nanoparticles (Gef-StNPs) has emerged as an essential tool to study and optimize the factors included in their synthesis. Therefore, we applied design of experiment (DOE) tools to attain the essential knowledge for the synthesis of high-quality Gef-StNPs that can deliver and concentrate the gefitinib (Gef) at A549 cells, thereby improving therapeutic efficacy and minimizing adverse effects. The in vitro cytotoxicity after exposing the A549 human lung cancer cells to the optimized Gef-StNPs was found to be much higher than that of the pure Gef (IC50 = 6.037 ± 0.24 and 21.65 ± 0.32 µg/mL, respectively). The optimized Gef-StNPs formula showed superiority over the pure Gef regarding the cellular uptake in A549 human cell line (3.976 ± 0.14 and 1.777 ± 0.1 µg/mL) and apoptotic population (77.14 ± 1.43 and 29.38 ± 1.11 %), respectively. The results elucidate why researchers have a voracious appetite for using natural biopolymers to combat lung cancer and paint an optimistic picture of their potential to be a promising tool in battling lung cancer.

A Novel Approach for the Availability and Ocular Delivery of Tenoxicam Potassium: Synthesis, Characterization, and In Vivo Application.

Tenoxicam (TX) is a non-steroidal anti-inflammatory agent that can be used to control pain in various ophthalmic lesions like cataracts, refractive surgery, and corneal abrasion. TX has a very slightly aqueous solubility of 0.072 mg/mL resulting in difficulty to be formulated in ophthalmic solutions. This study aims to improve TX solubility by converting it into its potassium salt to achieve a target of 10 mg/mL (1%w/v) concentration of TX in the desired aqueous medium for the formulation of aqueous ophthalmic solutions. The synthesized TX salt was characterized by different evaluation parameters such as solubility studies, 1H NMR, IR, and elemental analyses. Different TX potassium solutions were formulated at concentrations of 0.5% and 1% w/v using different viscosity-imparting agents. The prepared solutions were characterized for their physicochemical properties including visual inspection, pH, rheological, in vitro release, and kinetic behavior. Also, the formulations were biologically evaluated in vivo using male albino rabbits. The obtained results showed the successful synthesis of TX salt, as indicated by IR and NMR, and elemental analysis. The solubility study showed that the solubility of TX was improved hugely to 18 mg/mL (250-fold). In addition, the results showed that the prepared formulations showed acceptable physicochemical properties. The highest release rate was obtained with formula F1, which contains no viscosity-imparting agents. While as, the lowest release rate was obtained in the case of formula F9, composed of Pluronic F127 (12% w/v). The in vivo results showed that TX optimized ophthalmic solutions F8 and F9 inhibited the redness and edema in an extended or sustained manner.

Silver Nanoparticles Stabilized by Poly (Vinyl Pyrrolidone) with Potential Anticancer Activity towards Prostate Cancer.

Tumor necrosis factor (TNF-α) and inflammatory cytokine (IL-6) play a vital role in various cellular incidents such as the proliferation and death of cells during carcinogenesis. Hence, regulation of these biomarkers could be a promising tool for controlling tumor progression using nanoformulations. Silver nanoparticles-poly (vinyl pyrrolidone) (AgNPs-PVP) were prepared using the reduction of silver nitrate and stabilized with PVP. They are characterized through yield percentage, UV-VIS, FT-IR, size, charge, and morphology. The obtained AgNPs were tested for anticancer activity against prostate cancer (PC 3) and human skin fibroblast (HFS) cell lines. Moreover, biomarker-based confirmations like TNF-α and IL-6 were estimated. The synthesized AgNPs-PVP were stable, spherical in shape, with particle sizes of 122.33 ± 17.61 nm, a polydispersity index of 0.49 ± 0.07, and a negative surface charge of -19.23 ± 0.61 mV. In vitro cytotoxicity testing showed the AgNPs-PVP exhibited antiproliferation properties in PC3 in a dose-dependent manner. In addition, when compared to control cells, AgNPs-PVP has lower TNF-α with a significant value ( ∗ p < 0.05); the value reached 16.84 ± 0.71 pg/ml versus 20.81 ± 0.44 pg/ml, respectively. In addition, HSF cells showed a high level of reduction ( ∗∗∗ p < 0.001) in IL-6 production. This study suggested that AgNPs-PVP could be a possible therapeutic agent for human prostate cancer and anti-IL-6 in cancerous and noncancerous cells. Further studies will be performed to investigate the effect of AgNPs-PVP in different types of cancer.

Therapeutic Intervention with Dietary Chitosan Nanoparticles Alleviates Fish Pathological and Molecular Systemic Inflammatory Responses against Infections.

Marine bio-sourced chitosan nanoparticles (CSNP) are antimicrobial and immunomodulatory agents beneficial for fish medicine. Herein, dietary CSNP was investigated for the amelioration of the systemic inflammatory responses of an induced fish model. One hundred and forty-four rainbow trout were assigned to one pathogen-free and non-supplemented group (negative control), and three challenged groups: non-supplemented (positive control), CSNP-preventive, and CSNP-therapeutic. After a feeding experiment extended for 21 days, the organosomatic indices (OSI) and molecular aspects were assessed. After a challenge experiment extended for further 28 days, CSNP-therapeutic intervention was assessed on fish survival and systemic inflammatory responses on pathology, histo-morphology, and molecular aspects. With CSNP administration, OSI nonsignificantly decreased and the relative expression of targeted inflammatory-mediator genes was significantly increased. The CSNP-therapeutic fish showed an RPS of 80% as compared to the positive control group, and CSNP-therapeutic administration retained the highest gene expression augmentation up to 28 days after the challenge. Notably, the splenic reticulin fibers framework of the CSNP-therapeutic group retained the highest integrity among the groups during the infection. After recovery, reticulin fibers density in the CSNP-therapeutic samples was significantly higher than in the negative control group, which indicates high innate immunity. Thus, CSNP showed promising biotherapeutic features enhancing fish resistance against infections.

Polymerized ß-Cyclodextrin-Based Injectable Hydrogel for Sustained Release of 5-Fluorouracil/Methotrexate Mixture in Breast Cancer Management: In Vitro and In Vivo Analytical Validations.

An inclusion complexation, between polymerized ß-cyclodextrin and cholesterol end-capping branched polyethylene glycol, was utilized for constructing a self-assembled hydrogel. The physicochemical properties, the in vitro release profiles of 5-Fluorouracil/methotrexate (anticancer drugs), and the surface morphology of the resulting hydrogel were studied. Moreover, in vivo studies were carried out on female rats bearing breast cancer. The results revealed that the prepared systems were white in color, rubbery, and homogenous. The in vitro release studies showed an efficient ability of the modified system for drug loading and release in a sustained release manner for 14 days. The surface morphology was spongy porous. Moreover, the tumors' healing was indicated from the analysis of tumor volume, plasma tumor markers, and histopathological analysis, compared to the controlled rats. The pharmacokinetic parameters appeared significant differences (p < 0.05) in the Cmax and Tmax of the medicated hydrogel samples, as compared with sole or combined saline-injected samples. The whole AUC of each drug in the medicated hydrogel samples was five-fold more than the mixture administrated in PBS. In conclusion, the proposed work delivered a hydrogel system that has a convenient ability for localized sustained release of breast cancer management.

Current and Future Prospective of Injectable Hydrogels-Design Challenges and Limitations.

Injectable hydrogels (IHs) are smart biomaterials and are the most widely investigated and versatile technologies, which can be either implanted or inserted into living bodies with minimal invasion. Their unique features, tunable structure and stimuli-responsive biodegradation properties make these IHs promising in many biomedical applications, including tissue engineering, regenerative medicines, implants, drug/protein/gene delivery, cancer treatment, aesthetic corrections and spinal fusions. In this review, we comprehensively analyze the current development of several important types of IHs, including all those that have received FDA approval, are under clinical trials or are available commercially on the market. We also analyze the structural chemistry, synthesis, bonding, chemical/physical crosslinking and responsive release in association with current prospective research. Finally, we also review IHs' associated future prospects, hurdles, limitations and challenges in their development, fabrication, synthesis, in situ applications and regulatory affairs.

Smart Injectable Chitosan Hydrogels Loaded with 5-Fluorouracil for the Treatment of Breast Cancer.

The treatment of breast cancer requires long chemotherapy management, which is accompanied by severe side effects. Localized delivery of anticancer drugs helps to increase the drug concentration at the site of action and overcome such a problem. In the present study, chitosan hydrogel was prepared for local delivery of 5-Fluorouracil. The in vitro release behavior was investigated and the anticancer activity was evaluated against MCF-7 cells using MTT assay. The in vivo studies were investigated via intra-tumoral injection of a 5-FU loaded hydrogel into breast cancer of female rats. The results indicated that the modified hydrogel has excellent physicochemical properties with a sustained in vitro release profile matching a zero-order kinetic for one month. In addition, the hydrogel showed superior inhibition of cell viability compared with the untreated control group. Moreover, the in vivo studies resulted in antitumor activity with minor side effects. The tumor volume and level of tumor markers in blood were inhibited significantly by applying the hydrogel compared with the untreated control group. In conclusion, the designed injectable hydrogels are potential drug delivery systems for the treatment of breast cancer with a controlled drug release profile, which could be suitable for decreasing the side effects of chemotherapy agents.

Cyclodextrin/Adamantane-Grafted Polyethylene Glycol-Based Self-assembling Constructs for Topical Delivery of Ketorolac Tromethamine: Formulation, Characterization, and In Vivo Studies.

Topical formulation of non-steroidal anti-inflammatory drugs (NSAIDs) exhibits many advantages over the oral administration route, such as avoiding the direct effect on GIT and avoiding the poor oral bioavailability of such drugs. Our study aims to develop a new self-assembling construct based on the hydrophobic interaction between adamantane terminated poly (ethylene glycol) polymers and polymerized ß-cyclodextrin. The viscous constructs were developed from direct mixing of host and guest polymer solutions, indicating spontaneous formation without cross-linkers. The modified system was evaluated by different analyses, including X-ray diffractometry, electron microscopy, isothermal titration calorimetry, and rheological analysis. Moreover, such a system's ability for drug loading and release was investigated via the in vitro release of ketorolac tromethamine (KT) as a model of NSAIDs. Finally, the prepared formulas were applied on a rat paw edema model to prove the enhanced anti-inflammatory activities. The obtained results indicated that the modified constructs have a rubbery porous structure with an amorphous nature. Also, from rheological results, the modified system exhibited a viscous behavior with higher loss modulus (G″) compared with storage (G'). The inclusion complexation between cyclodextrin and adamantane moieties was proved by the recorded high binding constants with a 1:1 stoichiometric ratio. Furthermore, the results showed the successful KT incorporation into the modified system and quantitatively released through a semi-permeable membrane in a sustained fashion (over 24 h). Finally, the in vivo results of the medicated constructs showed a significant inhibition of the induced inflammation and swelling, indicating that the modified construct has a great utility for safe non-irritating topical delivery applications.

In Vitro Release of 5-Fluorouracil and Methotrexate from Different Thermosensitive Chitosan Hydrogel Systems.

5-Fluorouracil is a member of cytotoxic drugs with poor selectivity to cancer cells. Currently, systemic administration of this anti-cancer drug (oral or injection) exposes normal tissues to the drug-induced toxicity. Nowadays, attention has been greatly directed towards in situ gel-forming systems that can be injected into the affected tissues in its sol form with a minimally invasive technique. More specifically, chitosan hydrogel systems were in focus due to their antibacterial effect as well as their biodegradable, biocompatible, and mucoadhesive properties. In the present work, 5-fluorouracil was loaded on various thermosensitive chitosan hydrogel systems cross linked with different linking agents like ß-glycerophosphate, pluronic F127, and hydroxyapatite. Also, methotrexate was added to 5-fluorouracil in order to gain its previously reported synergistic effects. Firstly, a compatibility study was performed using UV-spectrophotometric, infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) techniques to exclude the possibility of any physical or chemical interactions between the selected drugs and excipients. The prepared hydrogel systems were characterized for their physicochemical properties including organoleptic, pH, syringeability and injectability, viscosity, and gelation temperature (Tgel) by various analysis techniques. Moreover, the in vitro release behavior of 5-fluorouracil and methotrexate was determined with a modified analytical method. The results indicated that chitosan hydrogel system cross-linked with a combination of ß- glycerophosphate, and 10 % pluronicF127 (F4) showed the most suitable physicochemical properties and release profile. Accordingly, this formula can be considered as a missionary system for localized sustained delivery of cytotoxic drugs.

Self-Assembling Organogels Based on Pluronic and Lecithin for Sustained Release of Etodolac: In Vitro and In Vivo Correlation.

BACKGROUND: Etodolac, a member of non steroidal anti-inflammatory drugs (NSAIDs), has a poor aqueous solubility. Long term administration of etodolac causes severe gastrointestinal disturbances such as peptic ulcer and bleeding. These disturbances could be overcome by alternative routes such as a topical administration. METHOD: In the present study, pluronic lecithin organogels (PLOs) were prepared by simple mixing of pluronic solution with lecithin solution. Etodolac was loaded into the prepared gels or added during the gel formation. The physicochemical properties of the modified organogels were investigated by different analysis including visual inspection, pH determination, viscosity, spreadability and extrudability. Also, the in vitro release studies of etodolac in the presence of different penetration enhancers were carried out. The anti-inflammatory behavior of the prepared etodolac organogel was investigated using carrageenan induced paw edema test. RESULTS: The results indicated that the prepared organogels showed good physicochemical properties. The organogels, containing a combination of tween 80 and oleic acid as penetration enhancers, showed the highest percentage of drug release. CONCLUSION: All tested organogels showed a significant oedema inhibition compared with oral indomethacin ® and Voltaren® as a topical marketed anti-inflammatory drug. Moreover, the increase of drug concentration from 1% to 5% w/w is accompanied with a longer duration of action up to 12 hrs. Therefore, the formulated organogels are considered as a promising vehicle for controlled topical delivery of etodolac.

Physically cross-linked hydrogels of ß -cyclodextrin polymer and poly(ethylene glycol)-cholesterol as delivery systems for macromolecules and small drug molecules.

An injectable hydrogel based on the inclusion complexation of polymerized ß-cyclodextrin (pß-CD) and cholesterol terminated poly(ethylene glycol) (PEG-chol) was developed and used as a delivery system for both macromolecules and small drugs. The hydrogel was characterized by different analyses including X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. The effects of pß-CD/PEG-chol ratio and PEG-chol architecture on the hydrogel properties were also investigated. Cytotoxicity of the hydrogel was evaluated in NIH 3T3 fibroblasts using MTS assay. The hydrogel had an elastic behavior even at high temperature since the gelation temperature was observed at 68 °C. The highest hydrogel strength and stability were observed for the 8-armed PEG-chol at a pß-CD/PEG-chol ratio of 1:1, w/w. Hydrogel degradation in phosphate buffered saline occurred by gradual erosion over the course of two months. IgG, a model hydrophilic macromolecule and riluzole, a model hydrophobic small drug were incorporated into the hydrogel and quantitatively released in a sustained fashion. The released IgG maintained its bioactivity confirming the absence of deleterious effects on protein structure during loading and release. The hydrogels showed no toxicity on NIH 3T3 fibroblasts confirming their biocompatibility. These results confirm the potential of pß-CD/PEG-chol hydrogel as a versatile delivery system for drugs of different molecular weights and nature.