Development of Liposomal Gemcitabine with High Drug Loading Capacity

Liposomes are widely used for systemic delivery of chemotherapeutic agents to reduce their nonspecific side effects. Gemcitabine (Gem) makes a great candidate for liposomal encapsulation due to the short half-life and nonspecific side effects; however, it has been difficult to achieve liposomal Gem with high drug loading capacity. Remote loading, which uses a transmembrane pH gradient to induce an influx of drug and locks the drug in the core as a sulfate complex, does not serve Gem as efficiently as doxorubicin (Dox) due to the low pKa value of Gem. Existing studies have attempted to improve Gem loading capacity in liposomes by employing lipophilic Gem derivatives or creating a high-concentration gradient for active loading into the hydrophilic cores (small volume loading). In this study, we combine the remote loading approach and small volume loading or hypertonic loading, a new approach to induce the influx of Gem into the preformed liposomes by high osmotic pressure, to achieve a Gem loading capacity of 9.4–10.3 wt % in contrast to 0.14–3.8 wt % of the conventional methods. Liposomal Gem showed a good stability during storage, sustained-release over 120 h in vitro, enhanced cellular uptake, and improved cytotoxicity as compared to free Gem. Liposomal Gem showed a synergistic effect with liposomal Dox on Huh7 hepatocellular carcinoma cells. A mixture of liposomal Gem and liposomal Dox delivered both drugs to the tumor more efficiently than a free drug mixture and showed a relatively good anti-tumor effect in a xenograft model of hepatocellular carcinoma. This study shows that bioactive liposomal Gem with high drug loading capacity can be produced by remote loading combined with additional approaches to increase drug influx into the liposomes

Exploration of the Safety and Solubilization, Dissolution, Analgesic Effects of Common Basic Excipients on the NSAID Drug Ketoprofen

Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with three basic excipients: tris, L-lysine, and L-arginine, and investigated their ability to improve water solubility and reduce ulcerogenic potential. The complexation/salt formation of ketoprofen and the basic excipients was prepared using physical mixing and coprecipitation methods. The prepared mixtures were studied for solubility, docking, dissolution, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vivo evaluation for efficacy (the writhing test), and safety (ulcerogenic liability). Phase solubility diagrams were constructed, and a linear solubility (AL type) curve was obtained with tris. Docking studies suggested a possible salt formation with L-arginine using Hirshfeld surface analysis. The order of enhancement of solubility and dissolution rates was as follows: L-arginine > L-lysine > tris. In vivo analgesic evaluation indicated a significant enhancement of the onset of action of analgesic activities for the three basic excipients. However, safety and gastric protection indicated that both ketoprofen arginine and ketoprofen lysine salts were more favorable than ketoprofen tris

Captopril Polyvinyl Alcohol/Sodium Alginate/Gelatin-Based Oral Dispersible Films (ODFs) with Modified Release and Advanced Oral Bioavailability for the Treatment of Pediatric Hypertension

Hypertension can begin in childhood; elevated blood pressure in children is known as pediatric hypertension. Contrary to adult hypertension, there is a scarcity of commercial medications suitable for the treatment of pediatric hypertension. The aim of this study was to develop orally dispersible films (ODFs) loaded with captopril for the treatment of hypertension in children. Captopril-loaded ODFs were composed of different blends of synthetic polymers, such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone, and natural polymers, such as sodium alginate (SA) and gelatin. The ODFs were characterized based on their mechanical and thermal properties, drug content, surface morphology, in vitro disintegration, in vitro release, and bioavailability. A novel HPLC method with precolumn derivatization was developed to precisely and selectively determine captopril levels in plasma. A low concentration of PVA and a high concentration of SA generated ODFs with faster hydration and disintegration rates. SA-based films exhibited fast disintegration properties (1–2 min). The optimized modified-release film (F2) showed significant (p ® tablets (701 ng min/mL). While the plasma concentration peaking was in favor of the immediate-release tablet, Tmax was significantly prolonged by 5.4 times for the optimized ODF (3.59 h) compared with that of the tablets (0.66 h). These findings indicate uniform and sustained plasma concentrations, as opposed to the pulsatile and rapid plasma peaking of captopril from the immediate-release tablets. These findings suggest that the modified release of oral films could offer more favorable plasma profiles and better control of hypertension than the conventional release tablets

A Novel C@Fe@Cu Nanocomposite Loaded with Doxorubicin Tailored for the Treatment of Hepatocellular Carcinoma

High mortality and morbidity rates are related to hepatocellular carcinoma (HCC), which is the most prevalent type of liver cancer. A new vision for cancer treatment and cancer cell targeting has emerged with the application of nanotechnology, which reduces the systemic toxicity and adverse effects of chemotherapy medications while increasing their effectiveness. It was the goal of the proposed work to create and investigate an anticancer C@Fe@Cu nanocomposite (NC) loaded with Doxorubicin (DOX) for the treatment of HCC. Scanning and transmission electron microscopes (SEM and TEM) were used to examine the morphology of the produced NC. The formulation variables (DOX content, C@Fe@Cu NC weight, and stirring speed) were analyzed and optimized using Box-Behnken Design (BBD) and Response Surface Methodology (RSM). Additionally, X-ray diffraction patterns (XRD) and Fourier Transform Infrared (FTIR) were investigated. Doxorubicin and DOX- loaded C@Fe@Cu NC (DOX-C@Fe@Cu NC) were also assessed against HEPG2 cells for anticancer efficacy (Hepatic cancer cell line). The results revealed the formation of C@Fe@Cu NC with a mean size of 7.8 nm. A D-R model with a mean size of 24.1 nm best fits the adsorption behavior of DOX onto the C@Fe@Cu NC surface. DOX-C@Fe@Cu NC has also been demonstrated to have a considerably lower IC50 and higher cytotoxicity than DOX alone in an in vitro investigation. Therefore, DOX-C@Fe@Cu NC is a promising DOX delivery vehicle for the full recovery of HCC

Novel Green Biosynthesis of 5-Fluorouracil Chromium Nanoparticles Using Harpullia pendula Extract for Treatment of Colorectal Cancer

Colorectal cancer (CRC) is the third highest major cause of morbidity and mortality worldwide. Hence, many strategies and approaches have been widely developed for cancer treatment. This work prepared and evaluated the antitumor activity of 5-Fluorouracil (5-Fu) loaded chromium nanoparticles (5-FuCrNPs). The green biosynthesis approach using Harpullia (H) pendula aqueous extract was used for CrNPs preparation, which was further loaded with 5-Fu. The prepared NPs were characterized for morphology using scanning and transmission electron microscopes (SEM and TEM). The results revealed the formation of uniform, mono-dispersive, and highly stable CrNPs with a mean size of 23 nm. Encapsulation of 5-Fu over CrNPs, with a higher drug loading efficiency, was successful with a mean size of 29 nm being produced. In addition, Fourier transform infrared (FTIR) and X-ray diffraction pattern (XRD) were also used for the investigation. The drug 5-Fu was adsorbed on the surface of biosynthesized CrNPs in order to overcome its clinical resistance and increase its activity against CRC cells. Box–Behnken Design (BBD) and response surface methodology (RSM) were used to characterize and optimize the formulation factors (5-Fu concentration, CrNP weight, and temperature). Furthermore, the antitumor activity of the prepared 5-FuCrNPs was tested against CRC cells (CACO-2). This in vitro antitumor study demonstrated that 5-Fu-loaded CrNPs markedly decreased the IC50 of 5-Fu and exerted more cytotoxicity at nearly all concentrations than 5-Fu alone. In conclusion, 5-FuCrNPs is a promising drug delivery system for the effective treatment of CRC

Tailoring of Novel Azithromycin-Loaded Zinc Oxide Nanoparticles for Wound Healing

Skin is the largest mechanical barrier against invading pathogens. Following skin injury, the healing process immediately starts to regenerate the damaged tissues and to avoid complications that usually include colonization by pathogenic bacteria, leading to fever and sepsis, which further impairs and complicates the healing process. So, there is an urgent need to develop a novel pharmaceutical material that promotes the healing of infected wounds. The present work aimed to prepare and evaluate the efficacy of novel azithromycin-loaded zinc oxide nanoparticles (AZM-ZnONPs) in the treatment of infected wounds. The Box–Behnken design and response surface methodology were used to evaluate loading efficiency and release characteristics of the prepared NPs. The minimum inhibitory concentration (MIC) of the formulations was determined against Staphylococcus aureus and Escherichia coli. Moreover, the anti-bacterial and wound-healing activities of the AZM-loaded ZnONPs impregnated into hydroxyl propyl methylcellulose (HPMC) gel were evaluated in an excisional wound model in rats. The prepared ZnONPs were loaded with AZM by adsorption. The prepared ZnONPs were fully characterized by XRD, EDAX, SEM, TEM, and FT-IR analysis. Particle size distribution for the prepared ZnO and AZM-ZnONPs were determined and found to be 34 and 39 nm, respectively. The mechanism by which AZM adsorbed on the surface of ZnONPs was the best fit by the Freundlich model with a maximum load capacity of 160.4 mg/g. Anti-microbial studies showed that AZM-ZnONPs were more effective than other controls. Using an experimental infection model in rats, AZM-ZnONPs impregnated into HPMC gel enhanced bacterial clearance and epidermal regeneration, and stimulated tissue formation. In conclusion, AZM -loaded ZnONPs are a promising platform for effective and rapid healing of infected wounds