ABSTRACT
Thermosensitive hydrogels based on chitosan are of great interests for injectable implant drug delivery. The poly(ethylene glycol)-grafted-chitosan (PEG-g-CS) hydrogel was reported as a potential thermosensitive system. The objective of the present study is to evaluate the cytotoxicity, in vivo degradation and drug release of PEG-g-CS hydrogel. Cytotoxicity was evaluated using L929 murine fibrosarcoma cell line. Degradation and drug release in vivo were investigated by subcutaneous injection of the hydrogel into Sprague-Dawley rats. PEG-g-CS polymer exhibits no significant cytotoxicity when its concentration is less than 3 mg mL(-1). After being implanted, PEG-g-CS hydrogel maintains its integrity for two weeks and collapses, merging into the tissue, in the third week. It causes moderate inflammatory response but no fibrous encapsulation around the hydrogel is found. The hydrogel presents a three-week sustained release of cyclosporine A with no significant burst release in vitro and produces the effective drug concentration in blood for more than five weeks in vivo, performing almost the same bioavailability to chitosan/glycerophosphate hydrogel. Further modifications of PEG-g-CS hydrogel might be necessary to modulate the degradation and to mitigate the fluctuations in blood drug concentration.
Subject(s)
Chitosan/chemistry , Drug Carriers/chemistry , Drug Carriers/toxicity , Drug Implants/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate/toxicity , Polyethylene Glycols/chemistry , Animals , Biocompatible Materials/chemistry , Biocompatible Materials/toxicity , Cell Line, Tumor , Cyclosporine/chemistry , Male , Mice , Rats , Rats, Sprague-Dawley , TemperatureABSTRACT
OBJECTIVE: Paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles incorporated with galactose-carrying polymer poly(vinyl benzyllactonamide) (PVLA) were prepared to facilitate the hepatocyte cell targeted delivery of paclitaxel via ligand-receptor mediated endocytosis. The factors impacting nanoparticle properties, drug release and cellular uptake efficiency were evaluated in vitro. METHOD: Paclitaxel-loaded nanoparticles incorporated with PVLA were prepared by emulsion solvent evaporation method with polyvinyl alcohol (PVA) as co-emulsifier. The presence of PVLA on the particle surface was investigated through the change of ζ potential and surface hydrophobicity. Cellular uptake and cytotoxic activity, involving factors concerned with them, were evaluated by HepG2 cells in vitro. RESULTS: The presence of PVLA led to the increase of ζ potential, reduction of the particle surface hydrophobicity, slight promotion of paclitaxel encapsulation efficiency and more homogeneous particle size, but excessive PVLA accelerated the burst release. With enhanced attachment and cellular uptake efficiency, the PVLA incorporated nanoparticles exhibited significant cytotoxicity to HepG2 cells, and particles with higher PVLA-to-PLGA ratio, although had larger size and almost the same cellular uptake efficiency, performed much higher cytotoxic activity due to the larger drug capacity and faster release rate.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Drug Delivery Systems , Hepatocytes/drug effects , Lactose/analogs & derivatives , Liver Neoplasms/drug therapy , Nanoparticles/chemistry , Paclitaxel/administration & dosage , Polystyrenes/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Survival/drug effects , Drug Compounding , Emulsifying Agents/chemistry , Endocytosis/drug effects , Galactose/chemistry , Hep G2 Cells , Hepatocytes/metabolism , Humans , Hydrophobic and Hydrophilic Interactions , Kinetics , Lactose/chemistry , Paclitaxel/chemistry , Paclitaxel/pharmacology , Particle Size , Polyvinyl Alcohol/chemistry , Solubility , Surface PropertiesABSTRACT
Thermosensitive hydrogel composed of chitosan and glycerophosphate (CS/GP) is proposed to be the potential candidate of in situ gel-forming implant for long-term drug delivery. The present study was focused on the body response and induced structural and componential variations of the hydrogel, which were considered to impact on the drug delivery significantly but were scarcely reported. The body response was investigated by histological examination. It showed that the hydrogel caused an inflammatory response immediately after being implanted into Sprague-Dawley (SD) rats. The inflammatory response was mainly exhibited as inflammatory cell surrounding and infiltrating, tissue encapsulating, and vascularization in tissue. The effects of the inflammatory response on the structure and component of the CS/GP hydrogel were extensively explored through analyzing the hydrogel samples taken by surgery. The tissue encapsulation and osmotic pressure caused the water loss of the hydrogel and the compaction of the hydrogel network, and resulted in the porosity decreasing. The cell surrounding and infiltrating spawned big pores in the network and generated the subdivision of the network. All these structural and componential variations of the hydrogel in vivo were quite different from those in vitro and were supposed to exert significantly effects on drug release kinetics.
Subject(s)
Chitosan/pharmacology , Drug Delivery Systems/methods , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate/pharmacology , Implants, Experimental , Animals , Calorimetry, Differential Scanning , Chitosan/administration & dosage , Freeze Drying , Glycerophosphates/pharmacology , Hydrogel, Polyethylene Glycol Dimethacrylate/administration & dosage , Hydrogen-Ion Concentration/drug effects , Injections , Microscopy, Electron, Scanning , Porosity/drug effects , Prosthesis Implantation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Time Factors , Viscosity/drug effects , WaterABSTRACT
A novel monolithic osmotic tablet composed of solid dispersion of water-insoluble 10-hydroxycamptothecin (HCPT) was prepared. The tablet core was made of a suspending agent, polyethylene oxide, an osmotic agent, sodium chloride, and a solid dispersion consisting of polyethylene glycol 6000 and HCPT. Optimized formulation was able to deliver HCPT at the constant rate of 1.21 mg/hour for 12 hours with cumulative release above 90% in vitro, independent of environmental media and stirring rate, and the release rate is co-controlled by osmotic pressure, suspending effect, and drug solubility in solid dispersion. The monolithic osmotic tablet containing solid dispersion has great potential in the controlled delivery of water-insoluble drugs.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/chemistry , Camptothecin/analogs & derivatives , Drug Delivery Systems , Technology, Pharmaceutical/methods , Camptothecin/administration & dosage , Camptothecin/chemistry , Cellulose/analogs & derivatives , Cellulose/chemistry , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Delayed-Action Preparations , Excipients/chemistry , Osmosis , Polyethylene Glycols/chemistry , Sodium Chloride/chemistry , Solubility , Tablets , X-Ray DiffractionABSTRACT
The simultaneity nitrification and denitrification (SND) was studied in a loop reactor. In the experiment, the research of biological nutrients removal was carried by changing carbon source and the method of adding carbon source, and the concentration of NOx(-)-N and the dissolved oxygen (DO) level were also inspected. The results indicated that the removal of NH4+-N could be enhanced by adding carbon source with COD 800 mg/L + 800 mg/L. And the concentration of NH4+-N in outlet was lower than 3 mg/L; Lower DO level in the reactor could be made easily by using difficultly reduced carbon source. It was useful to improve the biological nutrients removal. When using ethanol or glycerol as carbon source, the removal efficiency of NH4+-N was better than using glucose.
