ABSTRACT
Thermo-sensitive polymer-modified liposomes are able to achieve site-specific delivery of drugs. In this work, thermo-sensitive polymers were synthesized by atomic transfer radical polymerization of N-isopropyl acrylamide (NIPAAm) and N,N-dimethyl acrylamide (DMAAm) using bromoisobutyryl distearoyl phosphoethanolamine (DSPE-Br) as initiator. The resulting PNIPAAm-DSPE and P(NIPAAm-DMAAm)-DSPE polymers were characterized using proton nuclear magnetic resonance, Fourier transform infrared, and ultraviolet-visible spectroscopy. PNIPAAm-DSPE and P(NIPAAm-DMAAm)-DSPE exhibit a lower critical solution temperature of 34.0 and 46.9°C in water, and 29.8 and 38.8°C in phosphate buffered saline, respectively. Paclitaxel-loaded thermo-sensitive liposomes were prepared using film hydration method, followed by post-insertion of P(NIPAAm-DMAAm)-DSPE into the liposome bilayer. Drug release of traditional and thermosensitive liposomes was comparatively studied at 37 and 40°C. The total release and release rate of thermosensitive liposomes at 40°C were much higher than those at 37°C. And drug release is higher for thermosensitive liposomes than for traditional liposomes because insertion of thermo-sensitive polymer chains affects the system's stability. MTT assay showed that thermo-sensitive liposomes present no cytotoxicity to L929 cells at the tested concentrations, and paclitaxel-loaded liposomes have significant cytotoxicity against A549 cancer cells. Therefore, it is concluded that P(NIPAAm-DMAAm)-DSPE modified thermo-sensitive liposomes could be promising as nano-carrier of antitumor drugs.
Subject(s)
Antineoplastic Agents , Liposomes , Hydrophobic and Hydrophilic Interactions , Polymers , TemperatureABSTRACT
PTMC-PEG-PTMC triblock copolymers were prepared by ring-opening polymerization of trimethylene carbonate (TMC) in the presence of dihydroxylated poly(ethylene glycol) (PEG) with Mn of 6000 and 10,000 as macro-initiator. The copolymers with different PTMC block Lengths and the two PEGs were end functionalized with acryloyl chloride. The resulting diacrylated PEG-PTMC-DA and PEG-DA were characterized by using NMR, GPC and DSC. The degree of substitution of end groups varied from 50.0 to 65.1%. Hydrogels were prepared by photo-crosslinking PEG-PTMC-DA and PEG-DA in aqueous solution using a water soluble photo-initiator under visible light irradiation. The effects of PTMC and PEG block lengths and degree of substitution on the swelling and weight loss of hydrogels were determined. Higher degree of substitution leads to higher crosslinking density, and thus to lower degree of swelling and weight loss. Similarly, higher PTMC block length also leads to lower degree of swelling and weight loss. Freeze dried hydrogels exhibit a highly porous structure with pore sizes from 20 to 100 µm. The biocompatibility of hydrogels was evaluated by MTT assay, hemolysis test, and dynamic clotting time measurements. Results show that the various hydrogels present outstanding cyto- and hemo-compatibility. Doxorubicin was taken as a model drug to evaluate the potential of PEG-PTMC-DA and PEG-DA hydrogels as drug carrier. An initial burst release was observed in all cases, followed by slower release up to more than 90%. The release rate is strongly dependent on the degree of swelling. The higher the degree of swelling, the faster the release rate. Finally, the effect of drug loaded hydrogels on SKBR-3 tumor cells was evaluated in comparison with free drug. Similar cyto-toxicity was obtained for drug loaded hydrogels and free drug at comparable drug concentrations. Therefore, injectable PEG-PTMC-DA hydrogels with outstanding biocompatibility and drug release properties could be most promising as bioresorbable carrier of hydrophilic drugs.
ABSTRACT
Nanotubes were prepared by self-assembly of the copolymer using co-solvent evaporation method. The biocompatibility of the nanotubes was assessed in comparison with spherical micelles and filomicelles prepared from poly(ethylene glycol)-poly(L-lactide-co-glycolide) (PEG-PLGA) and poly(ethylene glycol)-poly(L-lactide) (PEG-PLA), respectively. Several aspects of biocompatibility of the aggregates were considered, including agar diffusion and MTT assay, release of cytokines, hemolysis, protein adsorption, dynamic clotting in vitro, and Zebrafish embryonic compatibility in vivo. The nanotubes present good cell compatibility and blood compatibility in vitro, and almost no toxicity towards Zebrafish embryos development in vivo. Furthermore, dual-loading of hydrophilic cisplatin and hydrophobic paclitaxel was achieved in the nanotubes with high loading content and loading efficiency. The release of both drugs was slower from dual-loaded nanotubes than from single-loaded ones, but the total amount of released drugs in higher for dual-loaded nanotubes than from single-loaded ones. Cellular uptake and inhibition tests showed that the nanotubes were successfully taken up by tumor cells and effectively inhibited cell growth. It is thus concluded that PEG-PLA-PEG nanotubes with outstanding biocompatibility could be promising for co-delivery of hydrophilic and hydrophobic agents in combination cancer therapy.
