Jieying Liu

Recent progress in studying curcumin and its nano-preparations for cancer therapy.

A hydrophobic polyphenol compound extracted from turmeric, curcumin has been widely utilized as traditional medicines for centuries in China and India. Over the last decades, because of its low toxicity, extensive studies have been focused on its physicochemical properties and pharmacological activities on various diseases, such as cancer, cardio-vascular disease, inflammatory bowel, wound healing, Alzheimers disease, rheumatoid arthritis, and diabetes. In particular, bioactivities of curcumin as an effective chemopreventive agent, chemo-/radio-sensitizer for tumor cells, and chemo-/radio-protector for normal organs, are of extraordinary research interests in the literature. Despite these advantages, applications of curcumin are limited in clinical trials because of its poor water solubility and low oral bioavailability. Nano-preparations as an emerging platform for the efficient delivery of anti-cancer drugs should overcome these problems. In this review, we at first briefly revisit important properties of curcumin as well as its uses in cancer treatments, and then overview various nano-preparations of curcumin for cancer therapy, including nanoparticles, liposomes, micelles, nanoemulsions, cyclodextrin complexes, nanodisks, nanofibres, solid lipid nanoparticles, and curcumin conjugates.

Selective tissue distribution and long circulation endowed by paclitaxel loaded PEGylated poly(ɛ-caprolactone-co-l-lactide) micelles leading to improved anti-tumor effects and low systematic toxicity

High tumor targeting and sustained drug concentration are key points for successful anti-tumor therapy, however, it is a challenging task. In this work, a novel micelle formulation of paclitaxel (PTX) has been prepared for the purpose of prolonging the blood circulation time as well as improving the accumulation of the drug within the tumor tissue. PEGylated P(CL-co-LLA) (poly(ε-caprolactone-co-L-lactide)) micelles containing PTX were prepared by solid dispersion-sonication method with a higher drug-loading efficiency and encapsulation ratio (28.4% and 94.7%, respectively). Pharmacokinetic study revealed that the drug-loading micelles exhibited a higher AUC values and a prolonged residence time of drug in the blood circulation than those of PTX injection. As demonstrated by tissue distribution and anti-tumor study in S180 tumor-bearing mice, the PEG-P(CL-co-LLA)/PTX micelles displayed modified tissue distribution of PTX and increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Furthermore, the preliminary safety tests were performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters, and the results showed no subacute toxicity to hematological system, major organs or tissues in mice. Taken together, our valuation shows that PEG-P(CL-co-LLA) micelles is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for i.v. administration of PTX.

Intracellularly Degradable, Self‐Assembled Amphiphilic Block Copolycurcumin Nanoparticles for Efficient In Vivo Cancer Chemotherapy

Intracellularly degradable, self-assembled amphiphilic biotin-poly(ethylene glycol)-b-poly(curcumin-dithiodipropionic acid) nanoparticles are developed. They display excellent in vivo anticancer efficacy, benefitted from their high tumor-targeted accumulation and stimuli-triggered intracellular drug release. They can be loaded with other anticancer drugs (e.g., doxorubicin) to exploit the synergy of combinational dual-drug therapy to further enhance in vivo anticancer efficacy.

Synthesis, in vitro and in vivo evaluation of new norcantharidin-conjugated hydroxypropyltrimethyl ammonium chloride chitosan derivatives as polymer therapeutics.

New norcantharidin-conjugated hydroxypropyltrimethyl ammonium chloride chitosan derivatives (NCTD-HACCs) were synthesized and characterized by (1)H NMR, Fourier-transform infrared spectroscopy (FT-IR), and wide-angle X-ray diffraction (WAXD). Two NCTD-HACCs with different degrees of substitution (DS) (12.2% and 24.8%) were obtained, which had good water solubility. NCTD was released from the NCTD-HACCs via hydrolysis, faster in pH 5.0 than pH 7.4 and presenting one biphasic drug release pattern with rapid release at the initial stage and slow release later. Fluorescence microscope and flow cytometry analysis demonstrated that the NCTD-HACC was endocytosized into MGC80-3 cells and the uptaken amount increased as incubation time. Compared with free NCTD, the NCTD-HACCs showed lower in vitro anti-tumor activity against human gastric cancer MGC80-3 cells, but higher in vivo tumor growth inhibition in S180 tumor-bearing mice. The in vivo near-infrared (NIR) fluorescence real-time imaging result showed the fluorescence intensity in tumor was much higher than that in heart, liver, spleen and lung (except kidney) after i.v. injection of the FITC-labeled NCTD-HACC2, indicating specific accumulation of the NCTD-HACC in tumor.

Investigation on formulation and preparation of adenovirus encoding human endostatin lyophilized powders

A recombinant adenovirus encoding human endostatin gene, E10A, has finished phase II trials for head and neck cancer. However, the rigid storage temperature (-80°C) and the toxicity of glycerol in the E10A liquid preparation limited its clinical application. In this study, lyophilization was applied to develop a stable E10A lyophilized powder without glycerol that is able to maintain biological activity at 4°C and suitable for intravenous administration. The E10A lyophilized formulations composed of nontoxic and already clinically used excipients were characterized in terms of the pH change during freezing, the eutectic melting temperature (T(eu)) and the collapse temperature (T(c)). Freeze thawing tests were carried out to examine the protective effect of various excipients during freezing. Mannitol and its combinations with sucrose or inulin showed effective protection of E10A. The E10A lyophilized powders were analyzed by particle size measurement, residual humidity quantification, infectivity assay and gene expression level. An optimized formulation (formulation I1) yielded a good recovery of 76% of the starting infectivity after lyophilization and 89% of the original infectivity after storage at 4°C for 180 days. Also the gene expression capability of E10A in formulation I1 was maintained after lyophilization. In addition, it was found that the matrix of amorphous excipients, mannitol combinations with sucrose or inulin, was indispensible in protecting E10A against the stress of freezing and dehydration. Hereby, the E10A lyophilized powder with eliminated glycerol toxicity and improved stability could enhance the applicability of E10A for cancer gene therapy through intravenous administration.

A stent film of paclitaxel presenting extreme accumulation of paclitaxel in tumor tissue and excellent antitumor efficacy after implantation beneath the subcutaneous tumor xenograft in mice

&NA; Anti‐tumor drug/stent combinations play a dual role of stent and local chemotherapy to cancer. Herein, a series of paclitaxel (PTX) loaded polylactic acid (PLA) stent films were studied on drug release characteristics and in vivo antitumor effects. The film was implanted beneath and released drug towards the subcutaneous PC‐3 tumor xenograft in mice, which consisted of a PTX‐loaded layer and a drug‐free backing layer. The concentrations of PTX were 103–104 times higher than those in normal 20 tissue or organs in 26 days after implantation of the 50% PTX/20% PEG‐loaded film, indicating an extreme accumulation of PTX in tumor tissue. The tumor volumes kept unchanged for the initial 10 days after implantation of the PTX‐loaded films and then increased slightly, implying tumor growth was remarkably inhibited. Moreover, the results showed that the drug release can be effectively modulated by addition of PEG in the drug‐loaded layer, present an unidirectional way by adding a backing layer, and the drug films could arrest PC‐3 prostate cancer cells in G2/M phase and induce apoptosis after 300 days of drug release. With the advantages of prolonged drug release and long‐term effectiveness, the films have great potential for anti‐tumor treatment by local administration.

Epitope mapping reveals the binding mechanism of a functional antibody cross-reactive to both human and murine programmed death 1

ABSTRACT Of the inhibitory checkpoints in the immune system, programmed death 1 (PD-1) is one of the most promising targets for cancer immunotherapy. The anti-PD-1 antibodies currently approved for clinical use or under development bind to human PD-1 (hPD-1), but not murine PD-1. To facilitate studies in murine models, we developed a functional antibody against both human and murine PD-1, and compared the epitopes of such antibody to a counterpart that only bound to hPD-1. To quickly identify the epitopes of the 2 antibodies, we used alanine scanning and mammalian cell expression cassette. The epitope identification was based on PD-1-binding ELISA and supported by affinity ranking of surface plasmon resonance results. The hPD-1 epitopes of the 2 functional antibodies were also compared with the binding region on hPD-1 that is responsible for PD-L1 interaction. In silico modeling were conducted to explain the different binding modes of the 2 antibodies, suggesting a potential mechanism of the antibody cross-species binding.