Soft Matter
·
2015
·Vol. 11
·期 21
·4197-4207
·
IF 4.029
Xinyuan Wan,Yi Zhang,Ya Deng,Qin Zhang,Jiehua Li,Kunjie Wang,Jianshu Li,Hong Tan,Qiang Fu
In this paper, to investigate the effects of interactions between poly(quaternary ammonium) salts (PQAs) and poly(ethylene glycol) on their mixed micellar surface structures and properties under spontaneous conditions, a series of PQAs were first designed and synthesized by atom transfer radical polymerization (ATRP) using 2-(dimethylamino) ethyl methacrylate (DMAEMA) quaternized by bromobutane, bromooctane, and bromododecane, respectively. Poly(poly(ethylene glycol) methyl ether methacrylate) (PPEG) with a similar degree of polymerization was also prepared using poly(ethylene glycol) methyl ether methacrylate by ATRP. Next, these PQAs were mixed with an equal weight of PPEG in water to cross-assemble into mixed micelles. The structures and features of these mixed micelles were characterized by fluorescence measurements, transmission electron microscopy (TEM), dynamic light scattering (DLS), phase analysis light scattering (PALS), proton nuclear magnetic resonance (1H NMR), and hydrogen–hydrogen correlation spectroscopy nuclear magnetic resonance (H–H COSY NMR). These results suggest that PQAs and PPEG mixtures can cross-assemble into mixed micelles with low CMC. The surface structures, particle sizes, size distributions, and zeta potentials of PQAs and PPEG mixtures can be tailored by varying the alkyl chain length in quaternary ammonium salts, and the alkyl chain length also influences the distribution and the alkyl chain orientation of quaternary ammonium salts on mixed micelle surfaces. In addition, cytotoxicity of these mixed micelles can be markedly reduced by PPEG compared with their corresponding PQAs, but their good antibacterial activities are still maintained to a certain degree, as evaluated by methyl tetrazolium assay (MTT) and minimum inhibitory concentration (MIC). Our present work provides a new avenue for the preparation of biocompatible and antibacterial materials for biomedical applications.
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Polymer Chemistry
·
2013
·Vol. 4
·期 10
·3012-3019
·
IF 5.231
Haibo Wang,Fangming Xu,Yin Wang,Xiangsheng Liu,Qiao Jin,Jian Ji
The pH-triggered biodegradable micelles based on poly(β-amino ester)-graft-12-acryloyloxy dodecyl phosphorylcholine (PAE-graft-ADPC) were explored as an efficient acid-triggered anticancer drug delivery system. A pH-responsive biodegradable polymer was synthesized by using hydrophilic 12-acryloyloxy dodecyl phosphorylcholine (ADPC) and poly(β-amino ester) (PAE) via Michael addition reaction. Micelles with phosphorylcholine shells were prepared in aqueous solution and doxorubicin (DOX) was loaded into the core of the micelles with high efficiency (73%). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) demonstrated that the size of the drug-loaded micelles was about 230 nm. DOX-loaded micelles were stable in the physiological environment, whereas they disassembled at pH 6.5 which is similar to the extracellular pH of most tumors. In vitro drug release showed that DOX release from micelles was faster at pH 6.5 than at 7.4. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles at pH 6.5. Moreover, an in vitro cytotoxicity study indicated that the growth of HepG2 cells was inhibited remarkably when the cells were preincubated with DOX-loaded micelles at pH 6.5. The results indicated that the pH-triggered biodegradable micelles could serve as promising drug carriers for cancer therapy.
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RSC Advances
·
2014
·Vol. 4
·期 98
·55139-55149
·
IF 3.708
Jinlong Yang,Chunmei Gao,Shaoyu Lü,Xinggang Wang,Mingjia Chen,Mingzhu Liu
A novel amphiphilic polymer (mPEGylated starch-deoxycholic acid, mPEG-St-DCA) was successfully prepared by grafting hydrophobic deoxycholic acid (DCA) into mPEGylated starch. According to the characterization of 1H NMR and FTIR, mPEG-St-DCA polymers could self-assemble into micelles with spherical core–shell structures. With the degree of substitution (DS) of DCA increasing, the average size of micelles (pH 7.4) decreased to below 200 nm. Correspondingly, the critical micelle concentration (CMC) decreased from 0.048 to 0.022 mg mL−1. And zeta potential values were near −2 mV. But under the condition of pH 6.5, the size and CMC showed an increasing trend. Doxorubicin (DOX), a model anticancer drug, was efficiently loaded into mPEG-St-DCA micelles, and in vitro release exhibited that DOX-loaded micelles had a good in vitro pH-induced drug release. MTT assays confirmed that mPEG-St-DCA micelles were biocompatible with HeLa cells, and DOX-loaded micelles had a relatively better cytotoxicity against HeLa cells with a remarkably high IC50 of 5.74 μg mL−1. Confocal laser scanning microscopy (CLSM) analyses demonstrated that mPEG-St-DCA micelles could be internalized efficiently by HeLa cells to realize intracellular DOX release, which further enhanced the inhibition of cell proliferation. On the basis of the above results, it was indicated that novel amphiphilic mPEG-St-DCA micelles with pH-response could be used as drug delivery carriers for cancer therapy.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2014
·
IF 4.287
Chunhua Gu,Vanminh Le,Meidong Lang,Jianwen Liu
Biodegradable graft copolymer, chitosan- graft -poly( ɛ -caprolactone) (CS- g -PCL) was synthesized via ring opening polymerization and characterized by 1 H NMR and FTIR spectroscopy. Then graft copolymers were self-assembled into micelles as drug delivery system. To evaluate drug-polymer compatibility, the Flory–Huggins interaction parameter between 5-fluorouraci (5-Fu) and hydrophobic segment was calculated. The result was in agreement with experimental data from drug loading content and drug loading efficiency. Meanwhile, DLS and TEM were utilized to evaluate the trend of particle size and morphology in aqueous solution with different repeating units of ɛ -CL. The in vitro drug release data was fitted with three kinetic models, usually applied in the drug delivery system. Results indicated that the release of 5-Fu was controllable and the release half-time could reach as long as 54.46 h, much slower than that of free 5-Fu. Cytotoxicity evaluation and cellular apoptosis study suggested good biocompatibility of CS- g -PCL micelles. Moreover, 5-Fu loaded micelles could delay the release of drug and exert comparable cytotoxicity against A549 cells.
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RSC Advances
·
2014
·Vol. 4
·期 77
·40882-40891
·
IF 3.708
Hui Han,De-E Liu,Hongguang Lu,Wen-Xing Gu,Hui Gao
A novel pseudo-graft copolymer was developed for protein delivery, based on the self-assembly of (6-(2-aminoethyl)-amino-6-deoxy)-cyclodextrin (β-CDen)-modified poly(aspartic acid) (PASP-CD) with cholesterol-modified poly(D,L-lactide) (PLA-Chol) by host–guest inclusion complexation. The chemical structures of polymers were confirmed by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. These components were then investigated for their ability to form nanoparticles and encapsulate protein. The diameter of micelles in water ranged from 70 to 200 nm as determined by dynamic light scattering, and the micelles were spherical in shape as observed by transmission electron microscopy. A model protein, bovine serum albumin (BSA), was encapsulated into the pseudo-graft copolymer micelles. The encapsulation efficiency (EE) and loading capacity (LC) of BSA in the micelles could be well tuned by adjusting the composition of the pseudo-graft copolymers. The micelles with a lower molar ratio of CD and cholesterol (hydrophilic/hydrophobic) exhibited a higher EE and LC. While in vitro release studies showed that a shorter chain of hydrophobic segment and higher hydrophilic/hydrophobic molar ratio could enhance the release rate. Cell viability studies showed that these materials possessed good cell viability (>95%). These results suggest that the degradable copolymers with appropriate hydrophilic and hydrophobic composition are able to self-assemble into micelles that are an effective and biocompatible vehicle for delivering protein, paving a new way for the application of pseudo-graft copolymers in protein or peptide delivery.
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Biomaterials Science
·
2014
·Vol. 2
·期 5
·775-783
·
IF 0
Yuanlin Li,Ting Su,Sai Li,Yusi Lai,Bin He,Zhongwei Gu
Polymeric micelles are important nanovehicles for anticancer drug delivery. The lipophilic segment in polymeric micelles is an important factor to affect the drug loading properties. In our previous work, we found that small molecules with π–π conjugated structures could be used to replace hydrophobic polymeric chains as lipophilic segments for anticancer drug delivery. Herein, we report a novel polymeric micelle with π–π conjugated cinnamate moiety on glycerol dendrimer as lipophilic segment, the modified dendritic segment was connected to poly(ethylene glycol) (PEG) via click chemistry. The received amphiphiles self-assembled into micelles in aqueous medium. The properties of the polymeric micelles such as critical micelle concentration (CMC), mean size and morphology were investigated. Anticancer drug doxorubicin (DOX) was loaded in the polymeric micelles. The π–π interaction, drug release profile and in vitro anticancer efficiency of the DOX loaded micelles were studied. The results showed that the micelles with more cinnamate moieties exhibited a lower CMC. The drug loading content and release rate of the micelles increased with increasing generation of glycerol dendrimer. Strong π–π stacking interaction was detected between DOX and carriers. The DOX loaded polymeric micelles exhibited efficient anticancer activity in vitro.
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EUROPEAN POLYMER JOURNAL
·
2015
·
IF 3.005
Yan Zhang,Chenhong Wang,Yunxiao Huang,Husheng Yan,Keliang Liu
Polymeric micelles containing a poly(ethylene glycol) shell and a disulfide-crosslinked core with a hydrophobic moiety and carboxylic acid groups were prepared. The loading of doxorubicin into the core was achieved with a combination of ionic bonding and hydrophobic effects. The cooperativity of these effects enabled doxorubicin to bind tightly to the core, thereby endowing the system with a high loading capacity and a low rate of premature release in the bloodstream. Disulfide crosslinkages prevented the dissociation of the micelles into unimers upon extensive dilution. Under intracellular-like conditions (e.g., pH 5 with the presence of glutathione), the payload was released at a high rate from the micelles. The release was attributed to cleavage of the disulfide crosslinkages by glutathione and disruption of the ionic bonds at a lower pH due to protonation of the carboxylate anions in the core. Intracellular doxorubicin release was found to positively correlate with intracellular glutathione levels.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2015
·
IF 4.152
Wei Xu,Xiaohui Fan,Yanli Zhao,Lingbing Li
The aim of the present study is to construct a cysteine modified polyion complex micelles made of Pluronic F127-chitosan (PF127-CS), Pluronic F127-cysteine (PF127-cysteine) and sodium cholate (NaC) and to evaluate the potential of the micelles as an oral drug delivery system for paclitaxel. Systematic studies on physicochemical properties including size distribution, zeta-potential and morphology were conducted to validate the formation of micelle structure. Compared with Pluronic micelles, drug-loading capacity of PF127-CS/PF127-cysteine/NaC micelles was increased from 3.35% to 12.77%. Both the critical micelle concentration and the stability test confirmed that the PF127-CS/PF127-cysteine/NaC micelles were more stable in aqueous solution than sodium cholate micelles. Pharmacokinetic study demonstrated that when oral administration the area under the plasma concentration–time curve (AUC 0–∞ ) and the absolute bioavailability of paclitaxel-loaded micelles were five times greater than that of the paclitaxel solution. In general, PF127-CS/PF127-cysteine/NaC micelles were proven to be a potential oral drug delivery system for paclitaxel.
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JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2013
·
IF 1.7
Wanyun Liu,Junchao Wei,Ping Huo,Yunhua Lu,Yiwang Chen,Yen Wei
A diblock copolymer of monomethoxy-poly(ethylene glycol)-b-poly(L-lactide) (MePEG-PLLA)/brefeldin A (BFA) conjugate was synthesized by the reaction of carboxyl-terminated copolymer MePEG-PLLA with BFA in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The conjugation efficiency was found to be 95%. Its structure was confirmed by 1H nuclear magnetic resonance and gel permeation chromatography. The MePEG-PLLA/BFA conjugate could self-assemble into micelles in aqueous solutions with a low critical micelle concentration of 1.8 × 10−3 g/L. Dynamic light scattering and transmission electron microscopy analyses of the MePEG-PLLA/BFA micelles revealed their spherical structure with an average diameter of 120 nm. The release profiles of BFA in PBS were measured by high performance liquid chromatography (HPLC), demonstrating that the controlled release of BFA can be gained for long time. The in vitro antitumor activity of the conjugate micelles against human liver carcinoma HepG2 cells was evaluated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl tetrazolium bromide method, and the results showed that BFA can be released from the conjugate micelles without losing cytotoxicity.
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International Journal of Nanomedicine
·
2014
·
IF 4.195
Ziming Zhao,Yu Wang,Jin Han,Keli Wang,Dan Yang,Yihua Yang,Qian Du,Yuanjian Song,Xiaoxing Yin
The aim of this work was to design, synthesize, and characterize self-assembled micelles based on polypeptides as a potential antitumor drug carrier. Amphiphilic poly( l -phenylalanine)- b -poly( l -serine) (PFS) polypeptides were obtained through the polymerization of N -carboxyanhydride. As a novel hydrophilic segment, poly( l -serine) was utilized to enhance tumor targeting due to a large demand of tumors for serine. PFS could self-assemble into micelles with an average diameter of 110–240 nm and a slightly negative charge. PFS polypeptides adopted random coil in pH 7.4 phosphate-buffered saline and could partly transform to α-helix induced by trifluoroethanol. PFS micelles with a low critical micelle concentration of 4.0 μg mL −1 were stable in pH 5–9 buffers and serum albumin solution. PFS micelles had a loading capacity of 3.8% for coumarin-6 and exhibited a sustained drug release. Coumarin-6 loaded rhodamine B isothiocyanate-labeled PFS micelles were incubated with Huh-7 tumor cells to study the correlation between drugs and carriers during endocytosis. The uptake of drugs was consistent with the micelles, illustrating that the intracellular transport of drugs highly depended on the micelles. PFS micelles diffused in whole cytoplasm while coumarin-6 assumed localized distribution, suggesting that the micelles could release the loaded drugs in particular areas. The internalization mechanism of PFS micelles was involved with clathrin-mediated endocytosis and macropinocytosis. Excess serine inhibited the uptake of PFS micelles, which demonstrated that serine receptors played a positive role in the internalization of PFS. The more interesting thing was that the uptake inhibition impacted on normal cells but not on tumor cells at the physiological concentration of serine. The difference in the uptake of PFS micelles was fourfold as high between the tumor cells and the normal cells, which indicated that PFS micelles had good tumor targeting in vitro. In conclusion, PFS micelles reported in this work were a promising drug delivery system for tumor targeting therapy.
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JOURNAL OF PHARMACEUTICAL SCIENCES
·
2016
·
IF 2.641
Hongyan Zhu,Jie Cao,Sisi Cui,Zhiyu Qian,Yueqing Gu
ABSTRACT 10-Hydroxycamptothecin (HCPT) is an effective anticancer drug against various types of solid tumors . But the antitumor efficacy of HCPT is far from satisfactory because of its poor physicochemical properties, short circulating half-life, low stability, and nonspecific toxicity to normal tissues. Therefore, a targeted delivery strategy for HCPT to pathological sites is eagerly needed to overcome these limitations. The folate-modified N-succinyl-N′-octyl chitosan (folate-SOC) micelle was chosen in this study and served as the targeted delivery system for HCPT to improve the antitumor efficacy. The water-insoluble anticancer drug HCPT was encapsulated into the folate-SOC micelles by the dialysis method. The near- spherical HCPT-loaded folate-SOC (HCPT/folate-SOC) micelles were formed in aqueous media with diameter of about 100-200 nm. The HCPT/folate-SOC micelles displayed a good stability, reasonable drug-loading content (about 10%), and sustained release behavior for the water- insoluble HCPT. Compared with free HCPT, HCPT/folate-SOC micelles exhibited a significant enhancement of cellular uptake, higher cytotoxicity against folate receptor positive tumor cell (Bel-7402), excellent tumor-targeting capability and substantially better antitumor efficacy on the nude mice bearing Bel-7402 xenografts. These results demonstrate the potential of folate- SOC micelles as long-term stable and effective drug delivery systems in cancer therapy.
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Journal of Materials Chemistry B
·
2015
·Vol. 4
·期 4
·760-767
·
IF 4.726
Liping wu,Liyan Qiu
Combretastatin A4 phosphate (CA4P), the water-soluble phosphate pro-drug of combretastatin A4 (CA4), acts as a novel vascular disrupting agent (VDA). It strongly inhibits tubulin polymerization and selectively exerts action against tumor blood vessels. However, its quite short half-life (∼30 min) results in a short action time and consequently limits its application. Therefore, it is beneficial to develop a sustained-release preparation of CA4P for relatively long action duration. On the other hand, conventional PLGA microspheres display poor encapsulation capability for water-soluble small molecules due to rapid diffusion outside. Hence, we developed CA4P-loaded microspheres (CA4P-MS) composed of methoxy poly(ethylene glycol)-b-polylactide (PELA) reverse micelles and PLGA with a nano-in-micro sea-island structure. The CA4P encapsulation efficiency of CA4P-MS reached 92.88%. More interestingly, sustained drug release was achieved, which contributed to the prolonged inhibition effect on S180 tumor during a 30-day period with one-time subcutaneous administration. In conclusion, our study established a biodegradable polymer based platform to construct microspheres for water-soluble small molecular compounds with sustained release and a long-lasting action.
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