Human chromosome 7 open reading frame 24 has been identified as a tumor-related protein, and later it was shown to be γ-glutamylcyclotransferase (GGCT). This protein is upregulated in various types of cancer and is proved to be associated with cellular proliferation. RNA interference is an effective method to achieve highly specific gene regulation. In this study, the anti-GGCT siRNA was incorporated into a comprehensively evaluated polyethylene glycol–hyaluronic acid-modified liposomal siRNA delivery system (PEG–HA–NP) for drug-resistant MCF-7 breast cancer therapy by systemic administration. The PEG–HA–NP had a diameter of 216 nm and a zeta potential of −17.4 mV. Transfection of anti-GGCT siRNA-loaded PEG–HA–NP could achieve effective GGCT downregulation and induce the subsequent cell cytotoxicity against MCF-7/ADR cells. Systemic administration of PEG–HA–NP at 0.35 mg/kg siRNA could retard the tumor growth and induce necrosis of tumor tissue while showing no obvious toxicity to normal tissues. Therefore, systemic administration of anti-GGCT-loaded PEG–HA–NP was proved to be a promising strategy for drug-resistant MCF-7 breast cancer therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:476–484, 2015

To combine the advantage of poly(ethylene gylcol) (PEG) for longer circulation and cell-penetrating peptides (CPPs) for efficient cellular uptake, paclitaxel (PTX)-loaded liposomes functionalized with TAT, the most frequently used CPP, and cleavable PEG via a redox-responsive disulfide linker (PTX-C-TAT-LP) were successfully developed here. Under physiological conditions, TAT was shielded by PEG layer and liposomes exhibited a long blood circulation. At tumor site, PEG could be detached in the presence of exogenous reducing agent [glutathione (GSH)] and TAT was exposed to facilitate cell internalization. In the presence of GSH, the liposomal vesicle C-TAT-LP showed increased cellular uptake and improved three-dimensional tumor spheroids penetration in vitro compared with analogous stable shielded liposomes. C-TAT-LP achieved enhanced tumor distribution and demonstrated superior delivery efficiency in vivo. PTX-C-TAT-LP with GSH strongly inhibited the proliferation of murine melanoma B16F1 tumor cells in vitro and in vivo with the tumor inhibition rate being 69.4% on B16F1-bearing mice. In addition, the serum aspartate transaminase level, alanine transaminase level, and creatine kinase level were almost completely within normal range in the PTX-C-TAT-LP with GSH group, revealing PTX-C-TAT-LP with GSH had no obvious drug-related adverse events for liver and heart. Taken together, C-TAT-LP is a promising tumor-targeting drug carrier. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1160–1173, 2015

The development of a drug delivery strategy that can not only cross the blood–brain barrier (BBB) rapidly, but also target the glioma and reach the core of glioma is essential and important for glioma treatment. To achieve this goal, we established a dual-targeting liposomal system modified with TAT (AYGRKKRRQRRR) and T7 (HAIYPRH), in which the specific ligand T7 could target BBB and brain glioma tumor and the nonspecific ligand TAT could enhance the effect of passing through BBB, and elevate the penetration into the tumor. The dual-targeting effects were evaluated by both in vitro and in vivo experiments. To identify the targeting effect, in vitro cellular uptake and BBB model were performed. Tumor spheroid penetration was performed to evaluate the penetration characteristics of the dual-targeting liposomes. In vivo pharmacokinetic studies were utilized to evaluate the influence of T7 and TAT peptides on the behavior of nanoparticle drug delivery system, and tissue distribution was further utilized to evaluate the glioma-targeting efficiency of the dual-targeting liposomes. 103:3891–3901, 2014