Liandong Deng

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

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Publications (72)218.73 Total impact

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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; · 5.01 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; · 2.61 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.
    J. Mater. Chem. B. 06/2014; 2(25).
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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; · 1.70 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.
    Polym. Chem. 02/2014; 5(6).
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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 01/2014; 108:26–33. · 3.48 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 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). · 2.83 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; · 5.01 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; · 1.64 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; · 5.37 Impact Factor
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    ABSTRACT: Nanoparticles (NPs) assembled from amphiphilic polycations has been certificated as potential carriers for gene delivery. Structural modification on polycation moieties may be an efficient route to further enhance gene delivery efficiency. In this study, two electroneutral monomers with different hydrophobicity, 2-hydroxyethyl methacrylate (HEMA) and 2-hydroxyethyl acrylate (HEA), are respectively incorporated into the cationic PDMAEMA side chains of amphiphilic poly(ε-caprolactone)-graft-poly(dimethylamino ethylmethacrylate) (PCD) by random copolymerization, to obtain poly(ε-caprolactone)-graft-poly(dimethylamino ethyl methacrylate-co-2-hydroxyethyl methacrylate) (PCD-HEMA) and poly(ε-caprolactone)-graft-poly(dimethylamino ethyl methacrylate-co-2-hydroxyethyl acrylate) (PCD-HEA). Minimal HEA or HEMA moieties in PDMAEMA do not lead to statistically significant changes in particle size, zeta potential, DNA condensation properties and buffering capacity of the naked NPs. But the incorporation of HEMA and HEA respectively leads to reduction and increase in the surface hydrophilicity of the naked NPs and NPs/DNA complexes which is confirmed by water contact angles assay. These simple modifications on PDMAEMA by HEA and HEMA moieties significantly affect the gene transfection efficiency on HeLa cells in vitro: PCD-HEMA NPs/DNA complexes show much higher transfection efficiency than PCD NPs/DNA complexes, while PCD-HEA NPs/DNA complexes show lower transfection efficiency than PCD NPs/DNA complexes. Fluorescence activated cell sorter and confocal laser scanning microscope results indicate that the incorporation of hydrophobic HEMA moieties facilitates the enhancement in both cellular uptake and endosomal/lysosomal escape, leading to the higher transfection efficiency. Moreover, the process of endosomal/lysosomal escape is confirmed in our research that the PCD and its derivatives do not just rely on the proton sponge mechanism, but the membranous damage owing to polycation chains, especially the hydrophobic modified ones. Hence, it is proved that hydrophobic modification of cationic side chains is a crucial route to improve gene transfection mediated by polycation NPs.
    Acta biomaterialia 10/2013; · 5.09 Impact Factor
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    ABSTRACT: A novel strategy was purposed to sustainedly deliver drug-loaded nanoparticles (NPs) to tumor sites and further enhance intracellular drug release. NPs with the ability of sequential self-gelation and self-release in response to a tumor-specific microenvironment were developed, which involved the conjugation of doxorubicin (DOX) on a thermosensitive amphiphilic copolymer (poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone), PCEC) via acid-cleavable hydrazone linkages. The conjugate (PCEC-co-DOX) can self-assemble into micelle-like NPs in water. Moreover, the freeze-dried PCEC-co-DOX NP powder with good dispersibility in water can easily be constructed into an injectable NP aqueous dispersion at ambient temperature, making it convenient for storage and clinical applications. After injection, the dispersion can in situ thermosensitively self-gelate, anchoring large amounts of NPs at the tumor site. Subsequently, the formed NP self-supported gel can sustainedly release NPs themselves in an acidic tumor microenvironment. The released DOX-co-PCEC NPs were taken up by tumor cells and finally realized in intracellular drug release by the acid-triggered cleavage of the hydrazone bond. Compared with the repeated injection of free DOX, a single peritumoral injection of DOX-co-PCEC NP aqueous dispersion achieved a similar tumor inhibition effect but exhibited lower systemic toxicity. In vivo biodistribution studies indicated that DOX delivered by the DOX-co-PCEC NP hydrogel accumulated mainly in tumor tissue rather than in healthy tissue in mice treated with a single peritumoral injection. These results suggest that the design presented here provides a promising nanomedicine platform for cancer therapy.
    J. Mater. Chem. B. 08/2013; 1(36).
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    ABSTRACT: Novel biodegradable core-crosslinked nanoparticles (CNPs) consisting of methoxy poly(ethylene glycol)-block-poly(ϵ-caprolactone-co-γ-cinnamoyloxy-ϵ-caprolactone) (mPEG-b-P(CL-co-CCL)) were prepared and evaluated for paclitaxel (PTX) delivery. mPEG113-b-P(CL65.2-co-CCL10.1) had a higher drug loading efficiency (95%) compared to mPEG113-b-PCL93.1 (43%). The stability of NPs has been largely improved and PTX release was significantly inhibited by crosslinking via UV irradiation at λ = 254 nm. MTT assays demonstrated that both blank non-crosslinked and crosslinked NPs showed low cytotoxicity to NCL-H460 cells while PTX-loaded non-crosslinked and crosslinked NPs exhibited obvious cytotoxicity against NCL-H460 cells, and the cytotoxicity was both dose-dependent and time-dependent. Furthermore, after 48 h incubation the cell viability of PTX-loaded crosslinked NPs was lower compared to that of PTX-loaded non-crosslinked NPs or free PTX. These properties indicated that CNPs prepared from mPEG-b-P(CL-co-CCL) have great potentials as carriers for drug delivery.
    Journal of Biomaterials Science Polymer Edition 06/2013; · 1.70 Impact Factor
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    ABSTRACT: Coating the polycation/DNA binary complexes with PEGylated polyanions can improve long-circulation and biocompatibility in vivo. However, it has been certificated PEG dilemma can reduces gene transfection efficiency because of inhibition in cellular uptake and endosomal escape. Herein, two PEGylated anionic polymers, PEGylated hyaluronic acid (HgP) and PEGylated polyglutamic acid (PGgP) were synthesized to coat the binary complexes of core-shell cationic polycaprolactone-graft-poly (N, N-dimethylaminoethyl methacrylate) nanoparticles/DNA (NP-D). The effects of polyanion structure were evaluated in terms of particle size, zeta potential, cytotoxicity, cellular uptake and transfect efficiency in vitro and in vivo. In vitro study illustrated that HgP coated complexes showed better efficiencies in both cell uptake and transfection than PGgP coated complexes. The coating of HgP on NP-D improved the biocompatibility without reduction in cell uptake and transfection efficacy, and resulted in higher accumulation and gene expression in tumor after IV injection. The success of HgP coating in overcoming PEG dilemma is attributed to the hyaluronic acid (HA)-receptor-mediated endocytosis and outer shell-detachment through the hyaluronidases catalyzed degradation of HA. These results demonstrated that HgP was a promising anionic polymer for coating the polycation/DNA complexes and ternary complexes (HgP coated NP-D) hold promising potential for cancer therapy.
    Biomaterials 05/2013; · 8.31 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 03/2013; · 2.83 Impact Factor
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    ABSTRACT: A novel pH-sensitive, amphiphilic and biodegradable copolymer brush, methoxy poly(ethylene glycol)-block-(polycaprolactone-graft-poly(methacrylic acid)) (mPEG-b-(PCL-g-PMAA)), was developed for NPs for the oral delivery of hydrophobic drugs. The copolymer brush was synthesized by combining ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP), followed by selective hydrolysis. The structure and composition of the copolymer and its precursors were characterized by 1H-NMR, FT-IR and GPC. The critical micelle concentrations (CMC) of mPEG-b-(PCL-g-PMAA) in aqueous medium were determined to be 6.8 × 10−4 and 9.6 × 10−4 mg mL−1. The copolymer could self-assemble into NPs in aqueous solution with an average size of 104–129 nm, determined by DLS. The morphology of the NPs was spherical, as observed by TEM. The zeta potentials of the NPs were about −25 mV, measured by zeta potential measurements. Ibuprofen (IBU), a poorly water-soluble drug, was chosen as the model drug and encapsulated into the core of the NPs via a nano-precipitation method. The drug loading content (DLC) of the NPs prepared from mPEG-b-(PCL-g-PMAA) reached about 13%, with a drug loading efficiency (DLE) of above 75%. The in vitro release behavior of IBU from the NPs was pH-dependent. Typically, at pH 3.0 (0.01 M), the cumulative release percentage of IBU was about 40% over 12 h, whereas at pH 7.4 (0.01 M), more than 95% was released within 12 h for NPs prepared from mPEG113-b-(PCL91-g-PMAA155). The MTT assay indicated that blank NPs prepared from mPEG-b-(PCL-g-PMAA) did not show significant toxicity against NCL-H460 cells. These results indicated that this new type of pH-dependent polymeric NPs prepared from mPEG-b-(PCL-g-PMAA) has great potential to be used as a drug carrier for the oral administration of hydrophobic drugs.
    Polym. Chem. 02/2013; 4(5):1430-1438.
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    ABSTRACT: Glycol modified poly(sebacic anhydride) (PSA), a biodegradable poly(ester anhydride) copolymer, was prepared by melt bulk reaction of PSA and glycol. The structure of PSAG was characterized by FTIR, 1H NMR, and GPC. The results indicate the formation of ester bonds along the polyanhydride backbone. The thermal properties and crystallinity changes of the polyanhydrides were investigated using DSC and XRD. In vitro degradation experiments show that the degradation rate of PSAG is slower than that of PSA because of the introduction of the glycol. Using dexamethasone as a model drug, the in vitro release rate of a drug from PSAG discs was shown to be slower than that from PSA discs, and no initial burst releases were observed for 13 days. PSAG is therefore a promising candidate, which control the release of an incorporated drug over a sustained period of time. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
    Journal of Applied Polymer Science 01/2013; 127(5). · 1.40 Impact Factor
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    ABSTRACT: Combination delivery systems composed of injectable hydrogels and drug-incorporated micelles or nanoparticles with tunable and convenient properties for clinical operation and storage are urgently demanded in regional cancer chemotherapy to prolong and control drug release, enhance antitumor efficiency and decrease side effects. Previously, we developed a novel thermosensitive amphiphilic triblock copolymer, poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)–poly(ethylene glycol)–poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT), and fabricated a reconstituted “two into one” combination system of thermosensitive injectable hydrogel PTX/PECTGel, assembled from paclitaxel (PTX)-loaded PECT nanoparticles (NPs). PTX/PECTGel could be stored as freeze-dried powders of paclitaxel-loaded PECT NPs, which could be reconstituted into aqueous fluid dispersions at ambient temperature just by mixing with water after gentle stirring for several minutes, and form a hydrogel at the injected site in vivo. Herein, the drug release, in vivo morphology, antitumor efficiency and pharmacokinetic properties of PTX/PECTGel were evaluated. The PTX/PECTGel combination system could continuously release PTX in a near linear manner over 42 days in vitro, and simultaneously, PTX/PECT NPs containing 75% of the total released PTX could dissociate from the PTX/PECTGel. PTX/PECTGel exhibited remarkable in vitro anti-proliferative activities against Ehrlich ascites carcinoma (EAC) cancer cells. The peritumorally or intratumorally injected PECT gel could cover the entire surface or fill up the interior space of the tumor, respectively. A single peritumoral injection of the PTX/PECTGel formulation at a low dosage of 10 mg kg−1 could completely inhibit the growth of an EAC tumor inoculated in Balb/c mice after the first week, and the inhibition could be sustained for more than 21 days. The plasma pharmacokinetic study demonstrated that PTX/PECTGel could greatly decrease the systemic exposure of PTX, as confirmed by the rather low plasma concentration. On the other hand, the PTX concentration in normal tissues with the intratumoral injection of PTX/PECTGel was approximately 2 μg g−1, which was 3–10 times lower than that with the intraperitoneal or intratumoral injection of Taxol®, implying fewer off-target side effects. These data confirmed that the PTX/PECTGel combination local delivery system could vastly prolong the in vitro and in vivo paclitaxel release, enhance the local tumor inhibition effect and lower the systemic exposure and tissue distribution of paclitaxel. Hence, the “two into one” PTX/PECTGel system holds underlying value for regional cancer chemotherapy.
    J. Mater. Chem. B. 12/2012; 1(4):552-563.
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    ABSTRACT: To improve the biocompatibility and application properties of injectable chitosan hydrogel, an injectable triple crosslinking network hydrogel (CTGP) is prepared by physical interaction, Michael addition and disulfide bond formation based on thiolated chitosan (CS-TGA), β-glycerophosphate (β-GP) and poly(ethylene glycol) diacrylate (PEGDA) without the addition of cytotoxic crosslinkers and catalysts. Compared with the short gelation time of 2 min of CTG hydrogel (without PEGDA) at 37°C, CTGP hydrogel containing different molecular weight of PEGDA exhibits controllable gelation times from 1 to 22 min, which could meet the different demands in clinical application. Further, the compressive modulus is improved differently by introducing PEGDA into the system. The presence of PEGDA in CTGP hydrogel imparts better swelling property, and there is a sustained protein release from the hydrogel without any initial burst. In vitro cytotoxicity and hemolysis reveal that the gel is biocompatible. In vivo subdermal injection into mice models further confirms the non-cytotoxicity of the hydrogel and the hydrogel is highly resistant to degradation. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2012.
    Journal of Biomedical Materials Research Part A 08/2012; · 2.83 Impact Factor
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    ABSTRACT: A novel biodegradable amphiphilic diblock copolymer methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-γ-hydroxyl-ε-caprolactone) (mPEG-b-P(CL-co-HCL)) bearing pendant hydroxyl groups on the PCL block was prepared. The hydroxyl groups were formed through the reduction of ketones by sodium borohydride without protection and deprotection. The obtained polymers were well characterized by (1)H NMR, Fourier transform infrared (FT-IR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and contact angle measurement. mPEG-b-P(CL-co-HCL) could self-assemble into stable nanoparticles (NPs) with critical micellar concentrations (CMC) of 6.3 × 10(-4) ∼ 8.1 × 10(-4) mg/mL. The NPs prepared from mPEG-b-P(CL-co-HCL) were spherical in shape with diameters about 100 to 140 nm. The hydrophobic doxorubicin (DOX) was chosen as a drug model and successfully encapsulated into the NPs. The encapsulation efficiency and release kinetics of DOX were investigated. The results indicated that the introduction of hydroxyl groups onto the core-forming block could decrease the hydrophobicity of copolymers, thus improving the storage stability of NPs in aqueous solution. Moreover, higher loading capacity and slower in vitro release of DOX were observed, which was due to the hydrogen-bonding formation between DOX and hydroxyl groups. Meanwhile, the MTT assay demonstrated that the blank NPs were biocompatible to HepG2 cell,s while free DOX and DOX-loaded NPs showed significant cytotoxicity against the cells. Moreover, Compared to the free DOX, the DOX-loaded NPs were more efficiently internalized by HepG2 cells. In sum, the introduction of hydroxyl groups on the polyester block in mPEG-b-P(CL-co-HCL) exhibited great potentials for modifications in the stability, drug solubilization, and release properties of NPs.
    Biomacromolecules 08/2012; 13(10):3301-10. · 5.37 Impact Factor

Publication Stats

248 Citations
218.73 Total Impact Points


  • 2005–2014
    • Tianjin University
      • • School of Chemical Engineering and Technology
      • • School of Materials Science and Engineering
      T’ien-ching-shih, Tianjin Shi, China
  • 2010
    • National Center for Nanoscience and Technology
      Peping, Beijing, China