ABSTRACT
In this work, biodegradable PCL-PEG-PCL (PCEC) triblock copolymers were successfully synthesized at one-step. Aqueous solution of PCEC copolymer displayed thermosensitive sol-gel-sol transition behavior, which is flowing sol at low temperature and turns into non-flowing gel at body temperature. The cytotoxicity of PCEC copolymer was evaluated by cell viability assay using HEK293 and WISH cells. In vivo gel-formation, degradation test, acute toxicity tests, and histopathological study of PCEC hydrogels were performed in BALB/c mice by subcutaneous administration. In acute toxicity test, the mice were observed continuously for 21 days. For histopathologic study, samples including heart, liver, spleen, lung, kidneys, and tissue of injection site were histochemical prepared and stained with hematoxylin-eosin. No mortality or significant signs of acute toxicity was observed during the whole observation period and there is no significant lesion to be shown in histopathologic study of major organs and tissue of injection site. The maximum tolerance dose (MTD) of PCEC hydrogel (20 wt%) by subcutaneous administration was calculated to be higher than 25 g/kg b.w. The results indicated that the obtained PCEC hydrogel was non-toxic after subcutaneous administration, and could be a safe candidate for in situ gel-forming controlled drug delivery system.
Subject(s)
Hydrogels/chemistry , Hydrogels/toxicity , Polyesters/chemistry , Polyesters/toxicity , Polyethylene Glycols/chemistry , Polyethylene Glycols/toxicity , Animals , Body Weight/drug effects , Cell Line , Cell Survival/drug effects , Chromatography, Gel , Delayed-Action Preparations , Drug Delivery Systems , Female , Glucose/chemistry , Humans , Injections, Intraperitoneal , Magnetic Resonance Spectroscopy , Male , Maximum Tolerated Dose , Mice , Mice, Inbred BALB C , Solutions , Spectroscopy, Fourier Transform InfraredABSTRACT
In this work, a biodegradable poly(ethylene glycol)-poly(epsilon-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG, PECE) triblock copolymer was successfully synthesized. The aqueous solution of such PECE copolymer displayed special sol-gel-sol transition as temperature increase, which is a flowing sol at low-temperature and turns into a nonflowing gel at body temperature. The cytotoxicity of PECE copolymer was evaluated by cell viability assay using HEK 293 cells. In vivo gel formation and degradation test based on intraperitoneal and subcutaneous administration was conducted, respectively. The acute toxicity test and histopathological study were performed in BALB/c mice by intrapleural, intraperitoneal, or subcutaneous administration of PECE hydrogel (30 Wt %), respectively. The dose of intrapleural, intraperitoneal, or subcutaneous administration was up to 10 g/kg body weight (b.w.), 25 g/kg b.w., and 25 g/kg b.w., respectively, and the mice were observed continuously for 14 days. For histopathologic study, samples including heart, liver, lung, kidneys, spleen, stomach, intestine, and tissue of injection site were prepared for histochemical analysis and were stained with hematoxylin-eosin. No mortality or significant signs of acute toxicity was observed during the whole observation period and there is no significant lesion to be shown in histopathologic study of major organs. Therefore, the maximum tolerance dose of PECE hydrogel by intrapleural, intraperitoneal, or subcutaneous administration was calculated to be higher than 10 g/kg b.w., 25 g/kg b.w., and 25 g/kg b.w., respectively. The results indicated that the prepared PECE hydrogel was nontoxic after intrapleural, intraperitoneal, or subcutaneous administration, and it could be a safe candidate for in situ gel-forming controlled drug delivery system.
Subject(s)
Biocompatible Materials , Drug Carriers , Drug Delivery Systems , Hydrogel, Polyethylene Glycol Dimethacrylate , Polyesters , Polyethylene Glycols , Absorbable Implants , Animals , Biocompatible Materials/chemistry , Biocompatible Materials/toxicity , Cell Line , Drug Carriers/chemistry , Drug Carriers/toxicity , Female , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate/toxicity , Infusions, Subcutaneous , Male , Materials Testing , Mice , Mice, Inbred BALB C , Molecular Structure , Phase Transition , Polyesters/chemistry , Polyesters/toxicity , Polyethylene Glycols/chemistry , Polyethylene Glycols/toxicityABSTRACT
In this article, biodegradable and low molecular weight poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) triblock copolymers were successfully synthesized. Aqueous solution of the obtained PECE copolymers underwent sol-gel-sol transition as temperature increased which was flowing sol at room temperature and then turned into nonflowing gel at body temperature. Sol-gel-sol phase transition behaviors of aqueous PECE solutions were studied using rheometry and test tube-inverting method, which were affected by many factors, including the heating/cooling procedure and different additives in copolymers aqueous solution. In vitro drug release behavior was studied using bovine serum albumin (BSA) and Vitamin B(12) (VB(12)) as model drugs, and the PECE hydrogel could protect BSA from acidic degradation for 1 week at least. Therefore, PECE hydrogel is believed to be promising for injectable in situ gel-forming controlled drug delivery system due to their great thermosensitivity and biodegradability.
Subject(s)
Drug Delivery Systems , Hydrogels/chemistry , Polyesters/chemistry , Polyethylene Glycols/chemistry , Acids/chemistry , Chromatography, Gel , Delayed-Action Preparations , Hot Temperature , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Microscopy, Electron, Scanning , Molecular Weight , Rheology , Serum Albumin, Bovine/administration & dosage , Serum Albumin, Bovine/chemistry , Sodium Chloride/chemistry , Spectroscopy, Fourier Transform Infrared , Temperature , Vitamin B 12/administration & dosage , Vitamin B 12/chemistryABSTRACT
In this paper, biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL) triblock copolymer was synthesized, and was characterized by FTIR, 1H-NMR and GPC. The PCL-PEG-PCL/dimethyl sulfoxide (DMSO) solution displayed in situ gelling behavior when subcutaneously injected into the body. Toxicity tests and a histopathological study were performed in BALB/c mice. We focused mainly on acute organ toxicity of BALB/c mice by subcutaneous injection. In the acute toxicity test, the dose of subcutaneous injection was 5 g/kg body weight (b.w.), and the mice were observed continuously for 14 days. For the histopathological study, samples including heart, lung, liver, kidneys, spleen, stomach and intestine were histochemically prepared and stained with hematoxylin-eosin for histopathological examination. No mortality or significant signs of toxicity were observed during the whole observation period, and there is no significant lesion to be shown in histopathological study of major organs in the mice. Therefore, the maximal tolerance dose of dimethyl sulfoxide (DMSO) solution of PCL-PEG-PCL copolymer by subcutaneous injection was calculated to be higher than 5 g/kg b.w. Therefore, the PCL-PEG-PCL/DMSO system was thought to be non-toxic after subcutaneous injection, and it might be a candidate for an in situ gelling controlled drug delivery system.
Subject(s)
Absorbable Implants , Biocompatible Materials/chemistry , Drug Delivery Systems , Polyesters/chemistry , Polyethylene Glycols/chemistry , Polymers/chemistry , Animals , Body Weight , Chromatography, Gas/methods , Dimethyl Sulfoxide/chemistry , Magnetic Resonance Spectroscopy/methods , Mice , Mice, Inbred BALB C , Polyesters/toxicity , Polyethylene Glycols/toxicity , Polymers/toxicity , Spectroscopy, Fourier Transform Infrared/methods , Tissue DistributionABSTRACT
BACKGROUND: Most conventional methods for delivering chemotherapeutic agents fail to achieve therapeutic concentrations of drugs, despite reaching toxic systemic levels. Novel controlled drug delivery systems are designed to deliver drugs at predetermined rates for predefined periods at the target organ and overcome the shortcomings of conventional drug formulations therefore could diminish the side effects and improve the life quality of the patients. Thus, a suitable controlled drug delivery system is extremely important for chemotherapy. RESULTS: A novel biodegradable thermosensitive composite hydrogel, based on poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) and Pluronic F127 copolymer, was successfully prepared in this work, which underwent thermosensitive sol-gel-sol transition. And it was flowing sol at ambient temperature but became non-flowing gel at body temperature. By varying the composition, sol-gel-sol transition and in vitro drug release behavior of the composite hydrogel could be adjusted. Cytotoxicity of the composite hydrogel was conducted by cell viability assay using human HEK293 cells. The 293 cell viability of composite hydrogel copolymers were yet higher than 71.4%, even when the input copolymers were 500 microg per well. Vitamin B12 (VB12), honokiol (HK), and bovine serum albumin (BSA) were used as model drugs to investigate the in vitro release behavior of hydrophilic small molecular drug, hydrophobic small molecular drug, and protein drug from the composite hydrogel respectively. All the above-mentioned drugs in this work could be released slowly from composite hydrogel in an extended period. Chemical composition of composite hydrogel, initial drug loading, and hydrogel concentration substantially affected the drug release behavior. The higher Pluronic F127 content, lower initial drug loading amount, or lower hydrogel concentration resulted in higher cumulative release rate. CONCLUSION: The results showed that composite hydrogel prepared in this paper were biocompatible with low cell cytotoxicity, and the drugs in this work could be released slowly from composite hydrogel in an extended period, which suggested that the composite hydrogel might have great potential applications in biomedical fields.
