Liandong Deng

Tianjin University, T’ien-ching-shih, Tianjin Shi, China

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Publications (81)273.38 Total impact

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    ABSTRACT: Due to their biodegradable character, polyesters such as polycaprolactone (PCL), poly(d,l-lactide) (PDLLA), and polylactic-co-glycolic acid (PLGA) were widely used as the hydrophobic cores of amphiphilic cationic nanoparticles (NPs) for siRNA delivery. However, fewer researches focused on facilitating siRNA delivery by adjusting the polyester composition of these nanoparticles. Herein, we investigated the contribution of polyester segments in siRNA delivery in vitro by introducing different ratio of DLLA moieties in PCL segments of mPEG-block-PCL-graft-poly(dimethylamino ethyl methacrylate)(PEG-b-PCL-g-PDMAEMA). It was noticed that compared with the other ratios of DLLA moieties, a certain molar ratio (about 70%) of the NPs, named mPEG45-P(CL21-co-DLLA48)-g-(PDMAEMA29)2 (PECLD-70), showed the highest gene knockdown efficiency but poorest cellular uptake ability in vitro. Further research revealed that NPs with various compositions of the polyester cores showed different physicochemical properties including particle size, zeta potential and stiffness, leading to different endocytosis mechanisms thus influencing the cellular uptake efficiency. Subsequently, we observed that the cells treated by PECLD-70 NPs/Cy5 siRNA complexes exhibited more diffuse Cy5 signal distribution than other NPs by confocal laser scanning microscope, which suggested that siRNA delivered by PECLD-70 NPs/Cy5 siRNA complexes possessed of stronger capabilities in escaping from endosome/lysosome, entering the RNA-induced silencing complex (RISC) and cutting the target mRNA efficiently. The different siRNA release profile was dominated by the degradation rate of polyester segments. Therefore, it could be concluded that the adjustment of hydrophobic core of cationic nanoparticles could significantly affect their transfection behavior and appropriate polyester composition should be concerned in designing of analogous siRNA vectors. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 04/2015; 48. DOI:10.1016/j.biomaterials.2015.01.026 · 8.31 Impact Factor
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    ABSTRACT: Combining functions of multidrug co-delivery and multistep release in biocompatible membranes is an oncoming requirement for improving therapeutic process. In this paper, a kind of polymer micelle-embedded core/shell nanofibrous membranes was prepared by a simple and effective technology of coaxial electrospinning. The nanofibers were composed of hydrophobic polycaprolactone (PCL) shell layer and hydrophilic polyvinyl pyrrolidone (PVP) core in which more than 40 % (w/w) amphiphilic block copolymer mPECT micelles (mPECT Ms) were embedded. Two bioactive drugs, lincomycin hydrochloride (LH) as the anti-inflammatory drug and Vitamin E (VE) as the fibrinolysis drug, were effectively loaded in the PVP core of the fibers and mPECT Ms, respectively. The SEM and TEM figures showed the smooth core/shell nanofibers with interiorly even-distributed micelles were fabricated. The XRD patterns illustrated that drugs distributed amorphously in the composite mats without crystallization. The in vitro degradation test also gave evidence to the time consistency between the degradation time of this material and potential occurrence time of adhesion. Furthermore, the in vitro release profiles indicated that both drugs were controlled to release sustainably for more than 15 days, and multistep release pattern of the early fast release of LH companied by the slow VE release was achieved. Therefore, the polymer micelle-embedded core/shell nanofibrous membranes could provide a new strategy for therapeutic application to realize multidrug co-delivery and multistep release.
    RSC Advances 03/2015; DOI:10.1039/C5RA03345D · 3.71 Impact Factor
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    ABSTRACT: Reducing the toxicity while maintaining high transfection efficiency is an important issue for cationic polymers as gene carriers in clinic application. In this paper, a new zwitterionic copolymer, polycaprolactone-g-poly(dimethylaminoethyl methyacrylate-co-sulfadiazine methacrylate) (PC-SDZ) with unique pH-sensitivity, was designed and prepared. The incorporation of sulfadiazine into PDMAEMA chains successfully mediates the surface properties including compacter shell structure, lower density of positive charges, stronger proton butter capability and enhanced hydrophobicity, which lead to reduction in toxicity and enhancements in stability, cellular uptake, endosome escape and transfection efficiency for the PC-SDZ2 NPs/DNA complexes. Excellent transfection efficiency at the optimal N/P ratio of 10 was observed for PC-SDZ2 NPs/DNA complexes, which was higher than that of the commercial reagent-branched PEI. The cytotoxicity was evaluated by CCK8 measurement and the results showed significantly reduction in cytotoxicity even at high concentration of complexes after sulfadiazine modification. Therefore, this work may conduct a new way in structural mediation of cationic polymer carriers for gene delivery with high efficiency and low toxicity.
    ACS Applied Materials & Interfaces 03/2015; 7(14). DOI:10.1021/am508847j · 5.90 Impact Factor
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    ABSTRACT: pH/redox dual-sensitive nanoparticles (NPs) based on poly(ε-caprolactone) (PCL) and polyethylene glycol (PEG) triblock copolymer were developed and investigated aiming at improving the drug release property of PCL in cancer chemotherapy. A redox-sensitive disulfide bond and pH-sensitive benzoic-imine linkers were introduced to the backbone of the amphiphilic block copolymer termed SCHE, which could self-assemble into stable spherical NPs in aqueous with an average size of about 100 nm. Doxorubicin (DOX) as a hydrophobic anticancer drug was loaded in the NPs by dialysis method. The in vitro drug release results showed that the accumulative release amount of DOX at pH 5.0 with 10 mM glutathione (GSH) was accelerated apparently by more than twice as compared to that at pH 7.4 without GSH. After a pre-treatment with GSH, the intracellular fluorescence intensity of Hela cells was enhanced as compared to those without the pretreatment, which indicated faster DOX release in cells with higher GSH concentration. In MTT assay, no obvious toxicity of blank NPs was found. In conclusion, SCHE NPs could serve as a novel colloidal drug delivery system in cancer chemotherapy and the introduced unstable linkers could enhance the drug release rate at tumor sites.
    RSC Advances 03/2015; DOI:10.1039/C5RA01833A · 3.71 Impact Factor
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    ABSTRACT: Considering the journey of the nanocarriers holistically, which begins from the administration site to the target tissue, looking for simple design that may complete that journney, is the key to bringing more of these nanocarriers into clinical applications. Herein, amphiphilic copolymers cRGDfK-poly(ethylene glycol)-b-poly(2,4,6-Trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate) (termed as cRGD-PETM) were synthesized for constructing the multifunctional micelles, which combined enhanced drug loading efficiency, tumor targeting and visual detecting property, controlled intracellular drug release ability, to improve the chemotherapeutic effect in vivo. Doxorubicin (DOX) was encapsulated within the cRGD-PETM micelles as a model drug (termed as cRGD-PETM/DOX Ms). The size and morphology of the micelles were characterized systematically. Due to not only the hydrophobic interaction but also π-π conjugate action between DOX molecules and the PTTMA copolymers, the cRGD-PETM/DOX Ms exhibited excellent drug loading capacity. The results of in vitro drug release studies indicated that the cumulative DOX release from cRGD-PETM/DOX Ms at pH 5.0 was twice that at pH 7.4. The results of fluorescent microscope analysis showed that the cRGD-PETM/DOX Ms could be internalized by 4T1 and HepG2 cells via receptor-mediated endocytosis with rapid drug release intracellularly, which resulted in commendable cytotoxicity in comparation with free DOX. Furthermore, the ex vivo imaging studies represented that the cRGD-PETM/DOX Ms improved the drug accumulation and retention in tumor tissues. The in vivo anticancer effect studies demonstrated that the cRGD-PETM/DOX Ms obtained significantly higher therapeutic efficacy with lowest side effects in comparation with free DOX and PETM/DOX Ms. These results highlighted that the multifunctional cRGD-PETM/DOX Ms showed great potential as vehicles for hydrophobic anticancer drug delivery.
    Nanoscale 01/2015; DOI:10.1039/C4NR07435A · 6.74 Impact Factor
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    ABSTRACT: Efficient delivery of small interfering RNA (siRNA) is crucially required for cancer gene therapy. Herein, a thermo-sensitive copolymer with a simple structure, poly (ethylene glycol) methyl ether acrylate-b-poly (N-isopropylacrylamide) (mPEG-b-PNIPAM) was developed. A novel kind of thermo-sensitive nanoparticles (DENPs) was constructed for the cold-shock triggered release of siRNA by double emulsion-solvent evaporation method using mPEG-b-PNIPAM and a cationic lipid, 3β [N-(N', N'-dimethylaminoethane)-carbamoyl] cholesterol [DC-Chol]. DENPs were observed by transmission electron microscopy and dynamical light scattering before and after 'cold shock' treatment. The encapsulation efficiency (EE) of siRNA in DENPs, which was measured by fluorescence spectrophotometer was 96.8% while it was significantly reduced to be 23.2% when DC-Chol was absent. DENPs/siRNA NPs exhibited a thermo-sensitive siRNA release character that the cumulatively released amount of siRNA from cold shock was approximately 2.2 folds higher after 7 days. In vitro luciferase silencing experiments indicated that DENPs showed potent gene silencing efficacy in HeLa-Luc cells (HeLa cells steadily expressed luciferase), which was further enhanced by a cold shock. Furthermore, MTT assay showed that cell viability with DENPs/siRNA up to 200 nM remained above 80%. We also observed that most of siRNA was accumulated in kidney mediated by DENPs instead of liver and spleen in vivo experiments. Thus, DENPs as a cold shock responsive quick release model for siRNA or hydrophilic macromolecules delivery provide a new way to nanocarrier design and clinic therapy.
    Journal of Biomaterials Science Polymer Edition 01/2015; 26(4):1-13. DOI:10.1080/09205063.2014.997559 · 1.36 Impact Factor
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    ABSTRACT: The application of PEG-b-PCL micelles was dampened by their inherent low drug loading capability and relatively poor cell uptake efficiency. In this study, a series of novel PEG-b-PCL copolymers methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-γ-dimethyl maleamidic acid -ε-caprolactone) (mPEG-b-P(CL-co-DCL)) bearing different amounts of acid-labile β-carboxylic amides on the polyester moiety were synthesized. The chain structure and chemical composition of copolymers were characterized by 1H-NMR, FT-IR and GPC. mPEG-b-P(CL-co-DCL) with critical micellar concentrations (CMC) of 3.2 ~ 6.3 μg/mL could self-assemble into stable micelles in water with diameters 100 to 150 nm. Doxorubicin (DOX), a cationic hydrophobic drug, was successfully encapsulated into the polymer micelles, achieving a very high loading content due to electrostatic interaction. Then the stability, charge-conversional behavior, loading and release profiles, cellular uptake and in vitro cytotoxicity of drug free and drug-loaded micelles were evaluated. The β-carboxylic amides functionalized polymer micelles are negatively charged and stable in neutral solution but quickly become positively charged at pH 6.0, due to the hydrolysis of β-carboxylic amides in acidic conditions. The pH-triggered negative-to-positive charge reversal not only resulted in a very fast drug release in acidic conditions, but also effectively enhanced the cellular uptake by electrostatic absorptive endocytosis. The MTT assay demonstrated that mPEG-b-P(CL-co-DCL) micelles were biocompatible to HepG2 cells while DOX-loaded micelles showed significant cytotoxicity. In sum, the introduction of acid-labile β-carboxylic amides on the polyester block in mPEG-b-P(CL-co-DCL) exhibited great potentials for the modifications in the stability in blood circulation, drug solubilization and release properties, as well as cell internalization and intracellular drug release.
    Biomacromolecules 10/2014; 15(11). DOI:10.1021/bm501290t · 5.79 Impact Factor
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    ABSTRACT: The optimal structure design of nanocarriers to inhibit premature release of anticancer drugs from nanocarriers during blood circulation and improve drug release inside tumor cells is still a significant issue for polymer micelles applied in antitumor drug delivery. Herein, in order to balance the contradiction between polymer micellar stability and drug release, dual-sensitive cleavable cross-linkages of benzoic imine conjugated disulfide bonds were introduced into the core of the amphiphilic copolymer micelles to form core cross-linked micelles. Firstly, biodegradable poly(ethylene glycol)-b-(polycaprolactone-g-poly(methacrylic acid-p-hydroxy benzaldehyde-cystamine)), i.e. mPEG-b-(PCL-g-P(MAA-Hy-Cys)) (PECMHC) copolymers were synthesized and assembled into PECMHC micelles (PECMHC Ms). Then, simply by introducing H2O2 to the PECMHC Ms dispersions to oxidate the thiols groups of cystamine moieties in the core, the core-cross-linked PECMHC micelles (cc-PECMHC Ms) with size of about 100 nm in water were readily obtained. The in vitro studies of doxorubicin (DOX) loaded cc-PECMHC Ms show that the cross-linked core impeded the drug release in the physical conditions due to high stability of the micelles against both extensive dilution and salt concentration, while greatly accelerated DOX release in mildly acidic (pH 5.0 ∼ 6.0) medium with glutathione (GSH) due to the coordination of the pH-sensitive cleaving of benzoic imine bonds and the reduction-sensitive cleaving of disulfide bonds. The in vivo tissue distribution and tumor accumulation of the DOX-loaded cc-PECMHC Ms were monitored via fluorescence images of DOX. DOX-loaded cc-PECMHC Ms exhibited enhanced tumor accumulation because of the high stability in blood circulation and less DOX premature release. Therefore, the cc-PECMHC Ms with dual-sensitive cleavable bonds in cross-linked core were of excellent biocompatibility, high extracellular stability, and intelligent intracellular drug release property, indicating a promising candidate for anticancer drug delivery.
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    ABSTRACT: Poly(vinyl alcohol) electrospun nanofibrous membranes (PVANF membrane) which could sensitively detect and adsorb metal ions, were modified with spirolactam-rhodamineine derivatives (PVANF-SRD membrane) and sulfo-spirolactam-rhodamine derivatives (PVANF-SSRD membrane), respectively. Surface chemistry and morphology during functionalization of PVANF membranes were monitored using Fourier transform-infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). These two membranes could display real-time sensing by naked eyes based on ring-opening reaction of spirolactam-rhodamine derivatives induced by corresponding metals. PVANF-SRD and PVANF-SSRD membranes exhibited high selectivity and sensitivity toward Fe3+/Cr3+ and Hg2+, respectively. In terms of PVANF-SSRD membrane, adsorption capacity for Hg2+ in contaminated water was studied. Freundlich isotherm could better describe the interactions than Langmuir: Kf = 7.0175 mg/g (r2 = 0.9996) for Hg2+. The regenerability of these two membranes was investigated via Na4EDTA solution treatment, and the results demonstrated they had good sustainability in detection and adsorption efficiency.
    RSC Advances 09/2014; 4(93). DOI:10.1039/C4RA07505F · 3.71 Impact Factor
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    ABSTRACT: Enabling nanocarriers to complete the sophisticated journey from the initial injection site to the targeted tumor cells and achieve "spatiotemporally pinpointed" drug release intracellularly is a challenging task in anticancer drug delivery. Herein, versatile shell-crosslinked nanoparticles (SCNPs) were prepared by one-step assembly of triblock zwitterionic copolymers, polycarboxybetaine methacrylate-block-poly (N-(2-(2-pyridyl disulde) ethyl methacrylamide-block-poly (2-(diisopropylamino) ethyl methacrylate) (PCB-b-PDS-b-PDPA, termed as PCSSD), which was well-defined via reversible additive fragment transfer (RAFT) polymerization, followed by functionalization with Arg-Gly-Asp (RGD). Thus, the RGD-PCSSD SCNPs cooperatively combine the ultra pH-sensitive PDPA core for efficient drug loading and pH-responsive drug release, the disulfide-crosslinked PDS shell that prevents premature drug release, the zwitterionic PCB corona to stabilize the SCNPs and prolong its systemic circulation, the RGD ligand for active tumor targeting and receptor-mediated endocytosis. Doxorubicin (DOX) was loaded as a model medicine (termed as RGD-PCSSD/DOX SCNPs). The dual-sensitivity studies showed that the pH-sensitivity of PDPA core could be adjusted by the shell-crosslinking density, accompanied with better control over premature drug release. Furthermore, results obtained by flow cytometry and fluorescence microscopy analysis demonstrated that once the RGD-PCSS10D/DOX SCNPs were internalized into tumor cells via receptor-mediated endocytosis, boost drug release was observed with considerable cytotoxicity in vitro. The results of ex vivo imaging studies further confirmed the successful drug delivery from the injection site to the tumor tissue. In summary, the well-constructed RGD-PCSS10D/DOX SCNPs with cooperative multifunctionality showed great potential as novel nanocarriers for tumor targeted anticancer drug delivery.
    ACS Applied Materials & Interfaces 08/2014; 6(16). DOI:10.1021/am503974y · 5.90 Impact Factor
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    ABSTRACT: In this work, a new hydrogel was constructed using poly(ɛ-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)–poly(ethylene glycol)–poly(ɛ-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) tri-block copolymers (PECT) with hyaluronic acid (HA) in order to expand application scopes of PECT hydrogel. The rheological and sol–gel phase transition behaviors were investigated by rheometer and test tube inversion method, and the interior morphologies of hydrogel systems were observed by scanning electron microscope (SEM). With the introduction of HA, certain properties of PECT hydrogel, such as viscosity and morphology, have present trends with regularity. Furthermore, with the participation of HA, the degradation and release of acetylsalicylic acid was slightly affected, however, the drug release mechanism of hydrogel has not been changed. PECT/HA hydrogel is confirmed to be non-toxic through a test to NIH3T3 cells. In conclusion, blending with HA is a feasible and safe method to tune properties of PECT hydrogel.
    Carbohydrate Polymers 08/2014; 108:26–33. DOI:10.1016/j.carbpol.2014.03.016 · 3.92 Impact Factor
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    ABSTRACT: As drug therapies become increasingly sophisticated, the synergistic benefits of two or more drugs are often required. In this study, we aimed at improving anti-tumor efficiency of paclitaxel(PTX)-incorporated thermo-sensitive injectable hydrogel by the synergy of burst release of doxorubicin hydrochloride(DOX·HCl). Thermosensitive injectable hydrogel composed of nanoparticles assembled from amphiphilic copolymer poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro -9-undecanone)-poly(ethylene glycol)-poly(ε-caprolaone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) was fabricated. Hydrophobic PTX and hydrophilic DOX·HCl were loaded simultaneously in the thermo-sensitive injectable hydrogel by a two-stage entrapment. Thermosensitive gelling behaviors of drug-loading PECT nanoparticle aqueous dispersions were studied. In vitro release profiles of PTX and DOX·HCl and in vivo anti-tumor effect by dual drugs from PECT hydrogel were investigated. The results showed that hydrophilic and hydrophobic drugs could be successfully entrapped in PECT hydrogel simultaneously without affecting its thermo-sensitive behavior. In vitro release profiles demonstrated the burst release of DOX·HCl and the sustained release of PTX. Anti-tumor effect was improved by a fast and tense attack caused by the burst release of hydrophilic DOX·HCl from hydrogel, which was continued by the sequent sustained release of PTX-incorporated nanoparticles and remnant DOX·HCl. Unintentionally, entrapped in PECT hydrogel, hydrophilic DOX·HCl was observed to have a sustained releasing pattern in vitro and in vivo.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 06/2014; DOI:10.1016/j.ejps.2014.06.002 · 3.01 Impact Factor
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    ABSTRACT: Sequentially overcoming the obstacles mainly from the low water solubility of lipophilic anticancer drugs, gastrointestinal microenvironment and systemic circulation is the major concern for designing oral anticancer drug carriers. Herein, we prepared the multifunctional polyelectrolyte complex nanoparticles (CNPs), engineered by hyaluronic acid (HA) grafted polycaprolactone (PCL) nanoparticles (HA-g-PCL NPs) coated with chitosan (CS) electrostatically, as a platform to improve the oral delivery efficiency of lipophilic anticancer drugs. Paclitaxel (PTX) and doxorubicin (DOX) were used as the model medicine and fluorescence probe, respectively. The size, zeta potential, morphology and pH-sensitivity of the NPs were studied systematically. The results indicated that the core–shell structure of CS/HA-g-PCL CNPs was formed at pH 5.0, which remained intact in the pH ranging from 3.0 to 6.8, while the CS layer detached gradually with the increase of pH to 7.4 and the HA-g-PCL NPs were released. In vitro drug release studies showed that accelerated drug release was triggered by hyaluronidase-1 (Hyal-1), which was a major HA degradation enzyme abundant within tumor cells. Cell uptake studies showed that HA-g-PCL NPs were internalized into cancer cells (EC109) via receptor-mediated endocytosis, but were rarely taken up by normal fibroblasts (NIH3T3). Furthermore, intracellular drug release indicated that HA-g-PCL NPs could provide an effective approach for transport of loaded cargoes into the cytoplasm. Therefore, higher cytotoxicity for PTX loaded HA-g-PCL NPs (HA-g-PCL/PTX NPs) against cancer cells EC109 but lower cytotoxicity against normal cells NIH3T3 was observed. In vivo studies showed that CS/HA-g-PCL CNPs via oral administration were able to preferentially deliver drugs into tumor tissue with commendable antitumor efficiency and few side effects. Overall, CS/HA-g-PCL CNPs showed great potential for improving oral delivery efficiency of lipophilic anticancer drugs.
    06/2014; 2(25). DOI:10.1039/C4TB00273C
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    ABSTRACT: The improvement of the solid content of the hydrophobic drugs (such as paclitaxel (PTX), etc.) loaded nanoparticles (NPs) dispersion is important for enhancing drug-loaded efficiency and reducing the cost in production and application. A diblock copolymer methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (mPECT) is synthesized via the ring-opening polymerization of ε-caprolactone and 1,4,8-trioxa[4.6]spiro-9-undecanone (TOSUO) with methoxy poly(ethyleneglycol) (mPEG) as the initiator. The chemical structures and thermal properties of mPECT are characterized by (1)HNMR, Fourier transform infrared (FT-IR), gel permeation chromatography, differential scanning calorimetry, etc. PEG45.45-b-P(C28.33-co-T5.38) (mPECT-2) is able to self-assemble into stable NPs in water via nanoprecipitation method at a high solid content (≤25 wt%) and their freeze-dried powders can well re-disperse in water. The paclitaxel (PTX) is chosen as a hydrophobic drug model and successfully encapsulate into the mPECT-2 NPs via the same method at a high solid content. The encapsulation efficiency, cytotoxicity and in vitro release of PTX-loaded NPs are investigated. The results suggest that the behavior of the drug-loaded mPECT-2 NPs prepared at a solid content of 25 wt% is similar to that of NPs prepared at a solid content of 1 wt%, which indicate that increasing solid content of polymer has no negative effect on the properties of NPs dispersion in application. In summary, the freeze-dried NPs prepared from the high solid content dispersion (≤25 wt%) has a good redispersibility and exhibits great potential in cost control of preparing NPs dispersion used as drug delivery system.
    Journal of Biomaterials Science Polymer Edition 06/2014; DOI:10.1080/09205063.2014.923365 · 1.36 Impact Factor
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    ABSTRACT: Polymeric nanoparticles assembled from the amphiphilic graft copolymer with cyclic benzylidene acetal-functionalized backbone and short poly(2-hydroxyethyl methacrylate) side chains can remain structurally stable at pH 7.4, but undergo stepwise disassembly in mildly acidic conditions due to the acid-triggered cleavage of the acetals, providing a promising nanocarrier for cancer therapy.
    02/2014; 5(6). DOI:10.1039/C3PY01324C
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    ABSTRACT: Injectable thermosensitive hydrogels provide local non‐invasive platforms for sustained drug release,tissue engineering and cellular immunity. As a long‐term implant, the toxicity and in vivo biological effect should be concerned.Previously we developed a novel type of injectable nanoparticular self‐supported hydrogel (PECT NPsGel)of PEG and pendent cycle ethers modified poly(ε‐caprolactone) triblock copolymer (PECT), which could sustainedly release PECT or drug‐loaded PECT nanoparticles with the hydrogel disassembly and provided efficient antitumor activity and significant decrease of side effects. Herein, the aim of this work was to reveal the toxicity and in vivo biological effect of PECT nanoparticles and PECT NPsGel. In vitro cytotoxicity indicated no cell cytotoxicity was observed when the concentration of PECT nanoparticle was up to 500 µg/mL, and also nomutagenic effect and no genotoxicity were observed.In vivo intravenous injection of PECT nanoparticles demonstrated that the LD50 was approximate high to 2.564 g/kg, and compared with the control mice, the mice treated with daily administration of PECT nanoparticles showed no difference in the physical or behavioral alterations, body weight changes, biochemical and hematological parameters as well as organ coefficients. The in vivo chronic effect of PECT NPsGelconfirmed no toxic lesions to animals in a whole period of three months even the dosage was high to 20 g/kg. These findings indicated PECT nanoparticles and PECT NPsGel were of well biocompatibility and did not provoke any side effect to body, which represented a new class of injectable and non‐invasive systemic or site‐specific delivery carrier. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 17–29, 2014.
    Journal of Biomedical Materials Research Part A 01/2014; 102(1). · 2.84 Impact Factor
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    ABSTRACT: Injectable thermosensitive hydrogels provide local non-invasive platforms for sustained drug release,tissue engineering and cellular immunity. As a long-term implant, the toxicity and in vivo biological effect should be concerned.Previously we developed a novel type of injectable nanoparticular self-supported hydrogel (PECT NPsGel )of PEG and pendent cycle ethers modified poly(ε-caprolactone) triblock copolymer (PECT), which could sustainedly release PECT or drug-loaded PECT nanoparticles with the hydrogel disassembly and provided efficient antitumor activity and significant decrease of side effects. Herein, the aim of this work was to reveal the toxicity and in vivo biological effect of PECT nanoparticles and PECT NPsGel . In vitro cytotoxicity indicated no cell cytotoxicity was observed when the concentration of PECT nanoparticle was up to 500 µg/mL, and also nomutagenic effect and no genotoxicity were observed.In vivo intravenous injection of PECT nanoparticles demonstrated that the LD50 was approximate high to 2.564 g/kg, and compared with the control mice, the mice treated with daily administration of PECT nanoparticles showed no difference in the physical or behavioral alterations, body weight changes, biochemical and hematological parameters as well as organ coefficients. The in vivo chronic effect of PECT NPsGel confirmed no toxic lesions to animals in a whole period of three months even the dosage was high to 20 g/kg. These findings indicated PECT nanoparticles and PECT NPsGel were of well biocompatibility and did not provoke any side effect to body, which represented a new class of injectable and non-invasive systemic or site-specific delivery carrier. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
    Journal of Biomedical Materials Research Part A 01/2014; 102(1). DOI:10.1002/jbm.a.34694 · 2.83 Impact Factor
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    ABSTRACT: Nanoparticles (NPs)-assisted drug delivery systems with disassemblable behaviors in response to intracellular microenvironment are urgently demanded in systemic cancer chemotherapy for enhanced intracellular drug release. Curcumin (CUR), an effective and safe anticancer agent, was limited by its water insolubility and poor bioavailability. Herein, pH and reduction dual-induced disassemblable NPs for high loading efficiency and improved intracellular release of CUR were developed based on an acid degradable cyclic benzylidene acetals (CBAs)-functionalized poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-g-SS-poly(ethylene glycol) (PTTMA-g-SS-PEG) graft copolymer, which was readily prepared via RAFT copolymerization and coupling reaction. The NPs self-assembled from PTTMA-g-SS-PEG copolymers were stable at physiological pH, and quickly disassembled in mildly acidic and reductive environment due to the hydrolysis of CBAs in hydrophobic PTTMA core and the cleavage of disulfide-linked detachable PEG shell. PTTMA-g-SS-PEG NPs exhibited excellent CUR loading capacity with drug loading content up to 19.2% and entrapment efficiency of 96.0%. Within 20 h in vitro, less than 15.0% of CUR was released from the CUR-loaded NPs in normal physiological condition, whereas 94.3% was released in the presence of reductive agent and mildly acidic condition analogous to the microenvironment in endosome/lysosome and cytoplasm. Confocal fluorescence microscopies revealed that the CUR-loaded PTTMA-g-SS-PEG NPs exhibited more efficiently intracellular CUR release for EC-109 cells than that of CUR-loaded reduction-unresponsive PTTMA-g-PEG NPs and free CUR. In vitro cytotoxicity studies displayed blank PTTMA-g-SS-PEG NPs showed low toxicity at concentrations up to 1.0 mg/mL, whereas CUR-loaded PTTMA-g-SS-PEG NPs demonstrated more efficient growth inhibition towards EC-109 and HepG-2 cells than reduction-unresponsive controls and free CUR. Therefore, the above results indicated that pH and reduction dual-induced disassemblable PTTMA-g-SS-PEG NPs may have emerged as superior nanocarriers for active loading and promoted intracellular drug delivery in systemic cancer chemotherapy.
    ACS Applied Materials & Interfaces 12/2013; 5(24). DOI:10.1021/am404213w · 5.90 Impact Factor
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    ABSTRACT: A new platform of paclitaxel (PTX) for application as an oral delivery system was developed, by combining the pH sensitivity of polyelectrolyte complex nanoparticles (CNPs) and the active targeting of hyaluronic acid (HA). Chitosan/hyaluronic acid-paclitaxel (CS/HA-PTX) CNPs were prepared by coating the CS onto the HA-PTX nanoparticles (NPs), and characterized by Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (1H NMR), transmission electron microscopy (TEM) and high-performance liquid chromatography (HPLC). HA-PTX conjugates could self-assemble into NPs in aqueous solution with an average size of 100±5 nm, and the PTX content of HA-PTX conjugates was 10.6 wt%. The CS/HA-PTX CNPs had a smaller size and higher PTX content when the ratio of positive charge to negative charge was 2:1. The in vitro release of PTX from CNPs was pH-responsive, suggesting that the CS shell could prevent the breakage of the ester bond in HA-PTX NPs in acidic pH conditions. HA-PTX NPs exhibited higher cellular uptake than free PTX against HepG2 cells via receptor-mediated endocytosis. PTX could accumulate remarkably into tumor sites after oral administration of CNPs. These results indicate that the CNP drug delivery system has great potential for applications in the oral administration of hydrophobic drugs.
    Macromolecular Research 12/2013; 21(12). DOI:10.1007/s13233-013-1171-x · 1.68 Impact Factor
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    ABSTRACT: The pH-responsive micelles have enormous potential as nano-sized drug carriers for cancer therapy due to their physicochemical changes in response to the tumor intracellular acidic microenvironment. Herein, a series of comb-like amphiphilic copolymers bearing acetal-functionalized backbone were developed based on poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate-co-poly(ethylene glycol) methyl ether methacrylate] [P(TTMA-co-mPEGMA)] as effective nanocarriers for intracellular curcumin (CUR) release. P(TTMA-co-mPEGMA) copolymers with different hydrophobic-hydrophilic ratios were prepared by one-step RAFT copolymerization of TTMA and mPEGMA. Their molecular structures and chemical compositions were confirmed by 1H-NMR, FTIR and GPC. P(TTMA-co-mPEGMA) copolymers could self-assemble into nano-sized micelles in aqueous solution and displayed low critical micelle concentration (CMC). All P(TTMA-co-mPEGMA) micelles displayed excellent drug loading capacity, due to the strong π-π conjugate action and hydrophobic interaction between the PTTMA and CUR. Moreover, the hydrophobic PTTMA chain could be selectively hydrolyzed into a hydrophilic backbone in the mildly acidic environment, leading to significant swelling and final disassembly of the micelles. These morphological changes of P(TTMA-co-mPEGMA) micelles with time at pH 5.0 were determined by DLS and TEM. The in vitro CUR release from the micelles exhibited a pH-dependent behavior. The release rate of CUR was significantly accelerated at mildly acidic pH of 4.0 and 5.0 compared with at pH 7.4. Toxicity test revealed that the P(TTMA-co-mPEGMA) copolymers exhibited low cytotoxicity whereas the CUR-loaded micelles remained high cytotoxicity for HepG-2 and EC-109 cells. The results indicated that the novel P(TTMA-co-mPEGMA) micelles with low CMC, small and tunable sizes, high drug loading, pH-responsive drug release behavior and good biocompatibility may have potential as hydrophobic drug delivery nanocarriers for cancer therapy with intelligent delivery.
    Biomacromolecules 10/2013; 14(11). DOI:10.1021/bm401087n · 5.79 Impact Factor