Liu-Jie Zhang

Folic acid-conjugated iron oxide porous nanorods loaded with doxorubicin for targeted drug delivery.

Iron oxide porous nanorods (IOPNR) with lengths ranging from 40nm to 60nm and pore diameters ranging from 5nm to 10nm were prepared, and further modified with NH2-PEG-FA (FA-PEG-IOPNR) for ligand targeting and modified with NH2-PEG-OCH3 (PEG-IOPNR) as a control. Instead of chemical bonding, doxorubicin (DOX), a low water solubility anticancer drug, was loaded in the pores of the modified IOPNR because of their porous structure and high porosity. The release of DOX in acidic PBS solution (pH 5.3) was faster than that in neutral (pH 7.4) solution. The analysis results from TEM, inductively coupled plasma emission spectroscopy, confocal laser scanning microscopy, and flow cytometry analyses indicated that the presence of FA on the surface of the nanorods increase the cellular uptake of nanorods in the case of HeLa cells, a folate receptor (FR)-positive cell line. In contrast, for COS 7 cells, a FR-negative cell line, FA ligand on the surface of the nanorods showed no effect on the cellular uptake. MTT assay indicated that the cytotoxicity of DOX loaded in FA-PEG-IOPNR to HeLa cells was higher than that of DOX in PEG-IOPNR. In the case of COS 7 cells, no significant difference between the cytotoxicity of DOX loaded in FA-PEG-IOPNR and PEG-IOPNR was found. These results suggested that FA-PEG-IOPNR had the potential for target delivery of chemotherapeutic into cancer cells.

Codelivery of doxorubicin and triptolide with reduction-sensitive lipid–polymer hybrid nanoparticles for in vitro and in vivo synergistic cancer treatment

Codelivery is a promising strategy to overcome the limitations of single chemotherapeutic agents in cancer treatment. Despite progress, codelivery of two or more different functional drugs to increase anticancer efficiency still remains a challenge. Here, reduction-sensitive lipid–polymer hybrid nanoparticles (LPNPs) drug delivery system composed of monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16), soybean lecithin, and poly(D,L-lactide-co-glycolide) (PLGA) was used for codelivery of doxorubicin (DOX) and a Chinese herb extract triptolide (TPL). Hydrophobic DOX and TPL could be successfully loaded in LPNPs by self-assembly. More importantly, drug release and cellular uptake experiments demonstrated that the two drugs were reduction sensitive, released simultaneously from LPNPs, and taken up effectively by the tumor cells. DOX/TPL-coloaded LPNPs (DOX/TPL-LPNPs) exhibited a high level of synergistic activation with low combination index (CI) in vitro and in vivo. Moreover, the highest synergistic therapeutic effect was achieved at the ratio of 1:0.2 DOX/TPL. Further experiments showed that TPL enhanced the uptake of DOX by human oral cavity squamous cell carcinoma cells (KB cells). Overall, DOX/TPL-coencapsulated reduction-sensitive nanoparticles will be a promising strategy for cancer treatment.

Synergetic enhancement of antitumor efficacy with charge-reversal and reduction-sensitive polymer micelles

The important characteristics of a nanoparticle-based anticancer drug delivery system at least include high stability in blood, highly efficient tumor cellular uptake and stimuli-responsive release of the anticancer drug inside the tumor cells. We here report a nanomicellar drug delivery system via self-assembly of PLA-SS-PAEMA/DMMA, an amphiphilic block copolymer composed of a poly(lactide) block and a poly(PAEMA/DMMA) block with disulfide linkage. Doxorubicin (DOX) was loaded into the micelles with a high drug-loading efficiency (10.6%, LE) and entrapment efficiency (59.5%, EE). In a neutral environment, PLA-SS-PAEMA/DMMA micelles are negatively charged, which ensures low adsorption of protein in the blood and excellent hemocompatibility. The surface charges of the micelles convert to positive under slightly acidic conditions at the tumor site, which improves the uptake of the micelles by the tumor cells. Once the drug-loaded micelles enter into the tumor cells, rapid release of DOX is triggered by reductive agents inside the tumor cells, such as GSH. In comparison to single responsive DOX-loaded PLA-CC-PAEMA/DMMA micelles and DOX-loaded PLA-SS-PAEMA/SA micelles, DOX-loaded PLA-SS-PAEMA/DMMA micelles showed higher cytotoxicity against HeLa cells due to the combinational effect of charge-reversal on cellular uptake and reduction-sensitivity on intracellular DOX release. The synergetic enhancement of antitumor efficacy by charge-reversal and reduction-sensitivity in DOX-loaded PLA-SS-PAEMA/DMMA micelles was further revealed by CLSM and flow cytometry analysis.

Lipid-polymer hybrid nanoparticles for the delivery of gemcitabine.

for paclitaxel (20–30 wt.%) and drug was released slowly form the micelles (50% in about 10 days), demonstrating a good retention of the drug in the micelles. Long blood circulation time (t1/2 of around 8 h) for PTX loaded in the polymeric micelles and the NIR-labeled polymeric micelles (t1/2 of around 10 h) was shown. The PTX-loaded micelles showed full inhibition of the tumor growth whereas Taxol at an equal dose was hardly effective. In conclusion, polymeric micelles stabilized by π–π stacking are attractive systems for solubilization and targeted delivery of PTX and probably also for other hydrophobic chemotherapeutic drugs.

Long circulating anionic liposomes for hepatic targeted delivery of cisplatin

In this paper, a receptor-mediated liposomal drug delivery system (DDS) was developed aiming to deliver cisplatin (cis-diaminedichloroplatinum(II); CDDP) targeting the liver. Acetyl glycyrrhetinic acid (AGA) was chosen as the hepatic targeting ligand and acetyl glycyrrhetinic acid-poly(ethylene glycol)-stearate (AGA-PEG-ST) was synthesized. Anionic 5-cholestene-3-beta-ol-3-hemisuccinate (CHO-HS) was also synthesized. The liposomal CDDPs were prepared by employing these functional moieties with phosphatidylcholine (PC) at various ratios. Meanwhile, methoxypolyethylene glycol-stearate (MPEG-ST) with an analogous structure but without AGA was also prepared as a control. The particle sizes of AGA modified liposomes ranged from 120 nm to 180 nm and the zeta potentials were located between −39.7 mV and −3.18 mV. The liposomes had encapsulation percentages of 51.5–61.7% and a loading capacity of 23.2–26.7% for CDDP. The transmission electron microscopy (TEM) observations showed that the liposomes had spherical morphologies with homogeneous distribution. In vitro cytotoxicity of CDDP-loaded liposomes against HepG2 human liver cancer cells and A549 human lung epithelial carcinoma cells were evaluated by MTT assays. The results demonstrated that the introduction of AGA could enhance the cytotoxicity of liposomal CDDP against HepG2 cells but showed less significant impact on A549 cells. CLSM observation and FCM measurement further confirmed that AGA modified liposomes had a stronger affinity to HepG2 cells than that of liposomes without AGA. The tissue distribution of calcein in mice indicated that AGA modified liposomes resulted in higher accumulation in the liver than that of liposomes without the AGA ligand. These results demonstrated the promise of AGA decorated anionic liposomes for hepatic targeted delivery of cisplatin.