Agar Graft Modification with Acrylic and Methacrylic Acid for the Preparation of pH-Sensitive Nanogels for 5-Fluorouracil Delivery.

Agar, a naturally occurring polysaccharide, has been modified by grafting it with acrylic (AcA) and methacrylic (McA) acid monomers, resulting in acrylic or methacrylic acid grafted polymer (AA-g-AcA or AA-g-McA) with pH-sensitive swelling behavior. Different ratios between agar, monomers, and initiator were applied. The synthesized grades of both new polymer series were characterized using FTIR spectroscopy, NMR, TGA, DSC, and XRD to ascertain the intended grafting. The percentage of grafting (% G), grafting efficiency (% GE), and % conversion (% C) were calculated, and models with optimal characteristics were further characterized. The swelling behavior of the newly synthesized polymers was studied over time and in solutions with different pH. These polymers were subsequently crosslinked with varying amounts of glutaraldehyde to obtain 5-fluorouracil-loaded nanogels. The optimal ratios of polymer, drug, and crosslinker resulted in nearly 80% loading efficiency. The performed physicochemical characterization (TEM and DLS) showed spherical nanogels with nanometer sizes (105.7-250 nm), negative zeta potentials, and narrow size distributions. According to FTIR analysis, 5-fluorouracil was physically incorporated. The swelling and release behavior of the prepared nanogels was pH-sensitive, favoring the delivery of the chemotherapeutic to tumor cells. The biocompatibility of the proposed nanocarrier was proven using an in vitro hemolysis assay.

Thermosensitive Hydrogel-Functionalized Mesoporous Silica Nanoparticles for Parenteral Application of Chemotherapeutics.

Hydrogels can offer many opportunities for drug delivery strategies. They can be used on their own, or their benefits can be further exploited in combination with other nanocarriers. Intelligent hydrogels that react to changes in the surrounding environment can be utilized as gatekeepers and provide sustained on-demand drug release. In this study, a hybrid nanosystem for temperature- and pH-sensitive delivery was prepared from MCM-41 nanoparticles grafted with a newly synthesized thermosensitive hydrogel (MCM-41/AA-g-PnVCL). The initial particles were chemically modified by the attachment of carboxyl groups. Later, they were grafted with agar (AA) and vinylcaprolactam (VCL) by free radical polymerization. Doxorubicin was applied as a model hydrophilic chemotherapeutic drug. The successful formulation was confirmed by FT-IR and TGA. Transmission electron microscopy and dynamic light scattering analysis showed small particles with negative zeta potential. Their release behaviour was investigated in vitro in media with different pH and at different temperatures. Under tumour simulating conditions (40 °C and pH 4.0), doxorubicin was almost completely released within 72 h. The biocompatibility of the proposed nanoparticles was demonstrated by in vitro haemolysis assay. These results suggest the possible parenteral application of the newly prepared hydrogel-functionalized mesoporous silica nanoparticles for temperature-sensitive and pH-triggered drug delivery at the tumour site.

Doxorubicin and Quercetin Double Loading in Modified MCM-41 Lowered Cardiotoxicity in H9c2 Cardioblast Cells In Vitro.

BACKGROUND: One of the therapeutic limitations of the use of doxorubicin (DOX) as an anticancer drug is its cardiotoxicity. Its hydrophilicity also causes difficulties in achieving sustained release. The simultaneous delivery with the well-known natural antioxidant quercetin could ameliorate its cardiotoxicity. Thus, the main aim of this work is to study the potential of carboxylated and non-carboxylated mesoporous silica MCM-41 nanoparticles for double loading of the hydrophilic doxorubicin hydrochloride and hydrophobic quercetin (Q) in one nanocarrier with a modified release pattern to reduce the cardiotoxic side effects of doxorubicin in vitro. METHODS: The methods included the modification of MCM-41, single and double loading of modified and non-modified MCM-41, physicochemical characterization, in vitro release tests and kinetic study, and in vitro cell viability studies. RESULTS: Doxorubicin and quercetin were successfully double-loaded with encapsulation efficiency (EE) of 43 ± 4.1% and 37 ± 4.5%, respectively, in native MCM-41. The post-synthetic carboxylation led to 49 ± 4.3% EE (DOX) and 36 ± 4.0% (Q) and double lowering of the cardiotoxicity on H9c2 (IC50 = 5.96 µm). Sustained release profiles over 72 h were achieved. CONCLUSIONS: A successful procedure was proposed for the efficient double loading of a hydrophilic drug and a hydrophobic drug. The carboxy-modified double-loaded nanosystems demonstrate a decreased in vitro cardiotoxicity of doxorubicin and can be considered as a potential chemotherapeutic formulation.

Gel Formulations for Topical Treatment of Skin Cancer: A Review.

Skin cancer, with all its variations, is the most common type of cancer worldwide. Chemotherapy by topical application is an attractive strategy because of the ease of application and non-invasiveness. At the same time, the delivery of antineoplastic agents through the skin is difficult because of their challenging physicochemical properties (solubility, ionization, molecular weight, melting point) and the barrier function of the stratum corneum. Various approaches have been applied in order to improve drug penetration, retention, and efficacy. This systematic review aims at identifying the most commonly used techniques for topical drug delivery by means of gel-based topical formulations in skin cancer treatment. The excipients used, the preparation approaches, and the methods characterizing gels are discussed in brief. The safety aspects are also highlighted. The combinatorial formulation of nanocarrier-loaded gels is also reviewed from the perspective of improving drug delivery characteristics. Some limitations and drawbacks in the identified strategies are also outlined and considered within the future scope of topical chemotherapy.

In vitro toxicity evaluation of lomefloxacin-loaded MCM-41 mesoporous silica nanoparticles.

Lomefloxacin (LF) is interesting as a model molecule from a safety point of view because of its high potential for serious adverse drug effects (i.e. phototoxic reactions). In this study, MCM-41 mesoporous silica nanoparticles (MCM-41) were loaded with lomefloxacin, aiming to overcome the drug's intrinsic cytotoxicity. The good biocompatibility of the empty drug carrier (0.1-1.0 mg/ml) was established by the absence of red blood cell lysis (hemolysis assay). The cytotoxicity of empty MCM-41 and lomefloxacin-loaded MCM-41 (LF-MCM-41) was evaluated by using a battery of in vitro cytotoxicity assays: Alamar blue, lactate dehydrogenase release and reactive oxygen species formation by dichlorofluorescein assay. Three cell cultures models: hepatoma HepG2, fibroblasts L929 and endothelial EA.hy926 cells were used to compare the cytotoxicity and reactive oxygen species formation by free drug, empty MCM-41, and LF-MCM-41. The findings from the study indicated that empty MCM-41 (0.1-1.0 mg/ml) showed a low cytotoxic potential in HepG2, followed by L929 and EA.hy926 cells. Lomefloxacin loading in MCM-41 mesoporous silica nanocarrier reduced the cytotoxicity of the free lomefloxacin, especially in the high concentration (1.0 mg/ml MCM-41, containing 120 µg/ml LF). L929 and EA.hy926 cells were more sensitive to the protective effects of LF-MCM-41, compared to HepG2 cells. The results indicate that an improvement in lomefloxacin safety might be expected after incorporation in an appropriate drug delivery system.

Micellar propolis nanoformulation of high antioxidant and hepatoprotective activity

ABSTRACT The present study reports a promising antioxidant protection by a recently developed micellar propolis formulation, against oxidative stress in in vitro and in vivo models of toxicity. The formulation, based on poplar propolis encapsulated in poly(ethylene oxide)-β-poly(propylene oxide)-β-poly(ethylene oxide) triblock copolymer (PEO26-PPO40-PEO26) micelles is characterized by small size (D h = 20 nm), enhances aqueous solubility and good colloidal stability. In vitro, propolis-loaded PEO26-PPO40-PEO26 micelles (20-100 µg/ml) significantly increased the cell viability of human hepatoma HepG2 cells, subjected to H2O2-induced cell injury (0.1 mM, 1 h). Antioxidant activity and protection of the micellar propolis were evaluated in a model of carbon tetrachloride-induced hepatotoxicity in rats (10% CCl4 solution, 1.25 ml/kg, p.o.) by measurement of non-enzyme (malondialdehyde and glutathione) and enzyme (catalase and superoxide dismutase) biomarkers of oxidative stress. Clinic observations, hematological, biochemical parameters and histological analysis were also performed. In vivo, micellar propolis (20 mg/kg b.w., p.o., 14 days) ameliorated CCl4-induced acute liver injury in rats. The oral administration of micellar propolis significantly prevented serum transaminase increases, as well as brought the levels of malondialdehyde, glutathione, and antioxidant enzymes catalase and superoxide dismutase toward the controls levels. Therefore, PEO26-PPO40-PEO26 micelles could be considered as a promising oral delivery system of propolis against oxidative stress injury in liver cells.

Carboxylic modified spherical mesoporous silicas аs drug delivery carriers.

The present study deals with the development and functionalization of mesoporous silica nanoparticles as drug delivery platforms. Spherical MCM-41 and SBA-15 silicas with different pore sizes (2.7 nm and 5.5 nm, respectively) were post-synthesis modified applying a new, two step process. The initial step was the modification with 3-amino-propyltriethoxysilane, and the next was the reaction with succinic anhydride in toluene in order to obtain carboxylic modified mesoporous carriers. The carboxylic-functionalized mesoporous materials were characterized by XRD, nitrogen physisorption, TEM, ATR FT-IR spectroscopy. The successful carboxylic functionalization was proved by the changes of the zeta potential of the mesoporous materials before and after modification. The parent and the carboxylic-modified MCM-41 and SBA-15 materials showed high adsorption capacity (approximately 50 wt.%, except for non-functionalized MCM-41) for sulfadiazine that possesses amino functional groups. Mesoporous structure peculiarities lead to different adsorption capacities on the carriers. In vitro release studies showed slower release rate of sulfadiazine from carboxylic modified MCM-41 and SBA-15 mesoporous particles compared to the non modified ones. Both non loaded and drug-loaded silica materials demonstrated no cytotoxicity on Caco-2 cell line. The functionalized mesoporous systems are appropriate drug delivery platforms due to their biocompatibility and the possibility to modify drug release.