Self-assembled honokiol-loaded micelles based on poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) copolymer.
ABSTRACT Self-assembled polymeric micelles are widely applied in drug delivery system (DDS). In this study, honokiol (HK) loaded micelles were prepared from biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) copolymers. Micelles were prepared by self-assembly of triblock copolymer PCEC in distilled water triggered by its amphiphilic character without any organic solvent. Drug loading and encapsulation efficiency were determined by adjusting the weight ratio of HK and PCEC. The particle size and zeta potential distribution of obtained micelles were determined using Malvern laser particle sizer, and spherical geometry were observed on atomic force microscope (AFM). Otherwise, the thermo-sensitivity of honokiol-loaded micelles was monitored. And the cytotoxicity results of drug loaded micelles showed that the encapsulated honokiol remained potent antitumor effect. Moreover, in vitro release profile demonstrated a significant difference between rapid release of free honokiol and much slower and sustained release of HK-loaded micelles. These results suggested that we have successfully prepared honokiol-loaded micelles in an improved method which is safer and more efficient. The prepared micelles might be potential carriers for honokiol delivery in cancer chemotherapy.
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ABSTRACT: Polymeric micelles, prepared by self-assembly of biodegradable poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG–PCL–PEG, PECE) copolymer in aqueous solution, were proved to be a potential carrier for hydrophobic drug honokiol in our previous contribution. In this study, the safety of blank PECE micelles was evaluated in vitro and in vivo before its further application in biomedical field. The average particle size of obtained micelle was 83.47±0.44nm, and polydisperse index was 0.27±0.01. Also, the zeta potential of prepared micelles was about −0.41±0.02mV. Otherwise, cytotoxicity of PECE micelles was evaluated by cell viability assay using L929 cells, and in vitro hemolytic test was also performed. In vivo acute toxicity evaluation and histopathological study of PECE micelles were conducted in BALB/c mice by intravenous administration. Furthermore, serum chemistry profile and complete blood count test were performed. In acute toxicity test, the mice were observed continuously for 7days. For histopathological study, samples including heart, liver, spleen, lung, and kidneys were histochemical prepared and stained with hematoxylin-eosin (H&E). 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 histopathological study of major organs. The maximal tolerance dose of PECE micelles (100mg/mL) by intravenous administration was calculated to be higher than 10g/kg body weight (b.w.). The results indicated that the obtained PECE micelles was non-toxic after intravenous administration, and could be a safe candidate for hydrophobic drug delivery system. KeywordsBiodegradable–Self-assembly–Micelle–Hemolytic test–Acute toxicity evaluation–Nanomedicine–Health and safetyJournal of Nanoparticle Research 04/2012; 13(2):721-731. · 2.18 Impact Factor
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ABSTRACT: In the present study, six different molecular weight diblock copolymer of methoxy poly (ethylene glycol)-b-poly (ε-caprolactone) (MPEG-PCL) were synthesized and characterized and was used for fabrication of etoposide-loaded micelles by nanoprecipitation technique. The particle size and percentage drug entrapment of prepared micelles were found to be dependent on the molecular weight of PCL block and drug to polymer ratio. The maximum drug loading of 5.32% was found in micellar formulation MPEG5000-PCL10000, while MPEG2000-PCL2000 exhibited 2.73% of maximum drug loading. A variation in the fixed aqueous layer thickness and PEG surface density of micellar formulations was attributed to difference in MPEG molecular weight and interaction of PEG and PCL block of copolymer. The MPEG2000-PCL2000 micelles demonstrated poor in vitro stability among other micellar formulations, due to its interaction with bovine serum albumin and immediate release of drug from micelles. Furthermore, plain etoposide and MPEG2000-PCL2000 micelles exhibited greater extent of hemolysis, due to presence of surfactants and faster release of drug from micelles, respectively. The biodistribution studies carried out on Ehrlich ascites tumor-bearing Balb/C mice confirmed higher accumulation of etoposide-loaded micellar formulation at tumor site compared to plain etoposide due to enhanced permeability and retention effect.Drug Delivery 02/2012; 19(3):155-67. · 2.02 Impact Factor
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ABSTRACT: In this work, we aim to develop a dual drug delivery system (DDDS) of self-assembled micelles in thermosensitive hydrogel composite to deliver hydrophilic and hydrophobic drugs simultaneously for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administered to form micelles or thermosensitive hydrogels, respectively. Therefore, the DDDS was constructed from paclitaxel (PTX) encapsulated PCEC micelles (PTX-micelles) and a fluorouracil (Fu) loaded thermosensitive PCEC hydrogel (Fu-hydrogel). PTX-micelles were prepared by self-assembly of biodegradable PCEC copolymer (M(n) = 3700) and PTX without using any surfactants or excipients. Meanwhile, biodegradable and injectable thermosensitive Fu-hydrogel (M(n) = 3000) with a lower sol-gel transition temperature at around physiological temperature was also prepared. The obtained PTX-micelles in thermosensitive Fu-hydrogel (PTX-micelles-Fu-hydrogel) composite is a free-flowing sol at ambient temperature and rapidly turned into a non-flowing gel at physiological temperature. In addition, the results of cytotoxicity, hemolytic study, and acute toxicity evaluation suggested that the PTX-micelles-Fu-hydrogel was non-toxic and biocompatible. In vitro release behaviors of PTX-micelles-Fu-hydrogel indicated that both PTX and Fu have a sustained release behavior. Furthermore, intraperitoneal application of PTX-micelles-Fu-hydrogel effectively inhibited growth and metastasis of CT26 peritoneal carcinomatosis in vivo (p < 0.001), and induced a stronger antitumor effect than that of Taxol® plus Fu (p < 0.001). The pharmacokinetic study indicated that PTX-micelles-Fu-hydrogel significantly increased PTX and Fu concentration and residence time in peritoneal fluids compared with Taxol® plus Fu group. Thus, the results suggested the micelles-hydrogel DDDS may have great potential clinical applications.Nanoscale 04/2012; 4(10):3095-104. · 6.23 Impact Factor