Yang Liu

pH-sensitive pullulan-based nanoparticles for intracellular drug delivery

This study reports the design of a novel pH-sensitive nanoparticle carrier based on pullulan for realizing intracellular drug delivery. A series of pullulan derivatives (UCPA) were synthesized by conjugation of both urocanic acid (a pH-sensitive grafted moiety) and cholesterol succinate (a hydrophobically modified moiety) to pullulan. UCPAs exhibited amphiphilic and pH-sensitive properties, and their responding pH value was around 6.5. UCPA nanoparticles prepared by the precipitation method had roughly spherical shapes, and sizes ranging from 150 to 300 nm. Doxorubicin (DOX), as a model antitumor drug, was physically loaded into the UCPA nanoparticles and its in vitro release at different pH values was studied using a dialysis method. UCPA-1 nanoparticles, with the degree of substitution (DS) of urocanyl and cholesterol moieties of 6.8% and 3.5%, respectively, exhibited relatively high drug-loading capability and strong in vitro pH-induced drug release. The results of MTT assays, flow cytometric analyses and confocal microscopy observations confirmed that the UCPA-1 nanoparticles can realize the intracellular delivery of DOX after internalization and enhanced cytotoxicity of DOX against MCF-7 cells.

A hematoporphyrin-based delivery system for drug resistance reversal and tumor ablation

Nanotechnology-based drug delivery systems have been intensively investigated, while only a few of them can be used for clinic application. Hematoporphyrin (HP), a major molecule in erythrocyte, has been widely used in photodynamic therapy (PDT). In the present study, polyethylene glycol (PEG) modified hematoporphyrin (HPP)-based nanoparticle system was designed to load doxorubicin (HPPD), in achieving a synergistic effect of chemotherapy and PDT. Herein we presented that HPPD formed narrowly dispersed nanoparticles at 35xa0±xa02xa0nm, yielding an enhanced drug release at pH5.8 along with laser radiation. This combined treatment with HPPD and radiation facilitated drug penetration to the nucleus thereby reducing 12-fold decrease in IC50 value and promoting apoptosis in drug-resistant breast cancer cells. Notably, little toxicity was detected with HPP at the cellular level and in animal models. Live animal imaging revealed that HPPD performed ultra high tumor uptake in both mice and marmoset models. Strikingly, intravenous administration of HPPD and radiation on the tumor achieved efficient tumor ablation, without inducing myocardial injury. We report here the development of a biomolecule, HP-based nanoparticle system, which can synergistically yield chemotherapy and PDT.

Core–Shell Nanoparticles Based on Pullulan and Poly(β-amino) Ester for Hepatoma-Targeted Codelivery of Gene and Chemotherapy Agent

This study designs a novel nanoparticle system with core-shell structure based on pullulan and poly(β-amino) ester (PBAE) for the hepatoma-targeted codelivery of gene and chemotherapy agent. Plasmid DNA expressing green fluorescent protein (pEGFP), as a model gene, was fully condensed with cationic PBAE to form the inner core of PBAE/pEGFP polycomplex. Methotrexate (MTX), as a model chemotherapy agent, was conjugated to pullulan by ester bond to synthesize polymeric prodrug of MTX-PL. MTX-PL was then adsorbed on the surface of PBAE/pEGFP polycomplex to form MTX-PL/PBAE/pEGFP nanoparticles with a classic core-shell structure. MTX-PL was also used as a hepatoma targeting moiety, because of its specific binding affinity for asialoglycoprotein receptor (ASGPR) overexpressed by human hepatoma HepG2 cells. MTX-PL/PBAE/pEGFP nanoparticles realized the efficient transfection of pEGFP in HepG2 cells and exhibited significant inhibitory effect on the cell proliferation. In HepG2 tumor-bearing nude mice, MTX-PL/PBAE/pEGFP nanoparticles were mainly distributed in the tumor after 24 h postintravenous injection. Altogether, this novel codelivery system with a strong hepatoma-targeting property achieved simultaneous delivery of gene and chemotherapy agent into tumor at both cellular and animal levels.

Molecular Mapping of the Blast Resistance Genes Pi2-1 and Pi51(t) in the Durably Resistant Rice 'Tianjingyeshengdao'

Tianjingyeshengdao (TY) is a rice cultivar with durable resistance to populations of Magnaporthe oryzae (the causal agent of blast) in China. To understand the genetic basis of its resistance to blast, we developed a population of recombinant inbred lines from a cross between TY and the highly susceptible CO39 for gene mapping analysis. In total, 22 quantitative trait loci (QTLs) controlling rice blast resistance were identified on chromosomes 1, 3, 4, 5, 6, 9, 11, and 12 from the evaluation of four disease parameters in both greenhouse and blast nursery conditions. Among these QTLs, 19 were contributed by TY and three by CO39. Two QTL clusters on chromosome 6 and 12 were named Pi2-1 and Pi51(t), respectively. Pi2-1 was detected under both growth chamber and natural blast nursery conditions, and explained 31.24 to 59.73% of the phenotypic variation. Pi51(t) was only detected in the natural blast nursery and explained 3.67 to 10.37% of the phenotypic variation. Our results demonstrate that the durable resistance in TY is controlled by two major and seven minor genes. Identification of the markers linked to both Pi2-1 and Pi51(t) in this study should be useful for marker-aided selection in rice breeding programs as well as for molecular cloning of the identified resistance genes.

A polymeric prodrug of cisplatin based on pullulan for the targeted therapy against hepatocellular carcinoma

A polymeric prodrug of cisplatin (CP) with simple chemical structure was synthesized based on pullulan and its therapeutic effects on human hepatocellular carcinoma (HCC) were studied in vitro and in vivo. Briefly, CP was linked to pullulan monosuccinate (SUPA) via coordination bond to form prodrug of CP-SUPA with the CP weight content of 18.7%. CP-SUPA exhibited in vitro sustained releases and strong interactions with genomic DNA. CP-SUPA could effectively inhibit the proliferation of HCC HepG2 cells by promoting the cell apoptosis and arresting the cell cycle, and showed a significantly higher cytotoxicity on HepG2 cells than that on human lung epithelial A549 cells. Compared to free CP, CP-SUPA obviously prolonged the survival times of Balb/c mice after intravenous injection at CP doses of 15 and 30 μmol/kg, and no signs of toxic effects in main tissues were detected by histologic examination. In MHCC-97H tumor-bearing nude mice, CP-SUPA was mainly distributed in the liver and the tumor after 24h post administration and evidently inhibited the tumor growth at CP doses of 3.5 and 7.0 μmol/kg. In conclusion, CP-SUPA was an ideal candidate of polymeric prodrug for the targeted therapy against HCC.

Recent advances of sonodynamic therapy in cancer treatment

Sonodynamic therapy (SDT) is an emerging approach that involves a combination of low-intensity ultrasound and specialized chemical agents known as sonosensitizers. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer which offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. In this article, we critically reviewed the currently accepted mechanisms of sonodynamic action and summarized the classification of sonosensitizers. At the same time, the breath of evidence from SDT-based studies suggests that SDT is promising for cancer treatment.

A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignancies worldwide. To date, the survival of patients with HCC has not improved because of the insensitivity of HCC to conventional treatments. Sonodynamic therapy (SDT) is a promising new approach that shows remarkable potential in the treatment of HCC. Here, we designed a simple, biocompatible, and multifunctional nanosystem that combines SDT and chemotherapy to treat HCC. This nanosystem, called HPDF nanoparticles, had a core–shell structure in which hematoporphyrin (HP) was complexed with doxorubicin (DOX) to form the hydrophobic core and the surface was coated with Pluronic F68 to form the hydrophilic shell. In HCC cells, HPDF nanoparticles in combination with ultrasonic irradiation (1.0 MHz, 1.5 W/cm2, 30 s) exhibited potent cytotoxicity, resulting from the synergistic effects of a large amount of reactive oxygen species generated from HP and DOX-induced DNA damage. Notably, HPDF nanoparticles in combination with ultrasonic irradiation significantly reversed drug resistance in Nanog-positive cancer stem cells (CSCs) in HCC. In nude mice bearing HCC tumors, HPDF nanoparticles efficiently accumulated in the tumors and reached the maximum levels within 6‒8 h, post intravenous injection. HPDF nanoparticles, in combination with ultrasonic irradiation (1.0 MHz, 3 W/cm2, 5 min), suppressed tumor growth, angiogenesis, and collagen deposition, considerably. In summary, our results show that HPDF nanoparticles can effectively combine SDT and chemotherapy to inhibit HCC growth and progression through multiple mechanisms in both cellular and animal models.

Hematoporphyrin and doxorubicin co-loaded nanomicelles for the reversal of drug resistance in human breast cancer cells by combining sonodynamic therapy and chemotherapy

Drug resistance is a main reason for the failure of chemotherapy in cancer treatments. Sonodynamic therapy (SDT) shows great potential for reversing drug resistance of chemotherapy. Here, a sonosensitizer hematoporphyrin (HP) and a chemotherapeutic drug doxorubicin (DOX) were co-loaded into Pluronic F68 nanomicelles for combining SDT and chemotherapy to reverse cancer drug resistance. This multi-functional nanosystem, called HPDF nanomicelle, had a classic “core–shell” structure and a size smaller than 100 nm. In drug-resistant human breast cancer MCF-7/ADR cells that over-express P-glycoprotein (P-gp), HPDF nanomicelles combined with a low-intensity ultrasound could effectively inhibit cell proliferation, promote cell apoptosis and arrest cell cycle at S-phase. Compared free DOX, HPDF nanomicelles significantly reversed drug resistance in MCF-7/ADR cells and the reversal index reached up to 19.0. Apparently, the synergistic effects of combination treatment of SDT and chemotherapy induced by HPDF nanomicelles played important roles in the reversal process against drug resistance. In summary, our study provides a novel strategy for overcoming drug resistance in breast cancer by combining SDT and chemotherapy.