Zhenyu Liao

PLGA/polymeric liposome for targeted drug and gene co-delivery.

Chemotherapy is one of the most effective approaches to treat cancers in the clinic, but the problems, such as multidrug resistance (MDR), low bioavailability and toxicity, severely constrain the further application of chemotherapy. Our group recently reported that cationic PLGA/folate coated PEGlated polymeric liposome core-shell nanoparticles (PLGA/FPL NPs). It was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell for targeting co-delivery of drug and gene. Hydrophobic drugs can be incorporated into the core and the cationic shell of the drug-loaded nanoparticles can be used to bind DNA. The drug-loaded PLGA/FPL NPs/DNA complexes offer advantages to overcome these problems mentioned above, such as co-delivery of drugs and DNA to improving the chemosensitivity of cancer cells at a gene level, and targeting delivery of drug to the cancer tissue that enhance the bioavailability and reduce the toxicity. The experiment showed that nanoparticles have core-shell structure with nanosize, sustained drug release profile and good DNA-binding ability. Importantly, the core-shell nanoparticles achieve the possibility of co-delivering drugs and genes to the same cells with high gene transfection and drug delivery efficiency. Our data suggest that the PLGA/FPL NPs may be a useful drug and gene co-delivery system.

Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core: In vitro and in vivo evaluation

A functional drug carrier comprised of folic acid modified lipid-shell and polymer-core nanoparticles (FLPNPs) including poly(D,L-lactide-co-glycolide) (PLGA) core, PEGylated octadecyl-quaternized lysine modified chitosan (PEG-OQLCS) as lipid-shell, folic acid as targeting ligand and cholesterol was prepared and evaluated for targeted delivery of paclitaxel (PTX). Confocal microscopy analysis confirmed the coating of the lipid-shell on the polymer-core. Physicochemical characterizations of FLPNPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. The internalization efficiency and targeting ability of FLPNPs were demonstrated by flow cytometry and confocal microscopy. PTX loaded FLPNPs showed a significantly higher cytotoxicity than the commercial PTX formulation (Taxol®). The intravenous administration of PTX encapsulated FLPNPs led to tumor regression and improvement of animal survival in a murine model, compared with that observed with Taxol® and biodistribution study showed that PTX concentration in tumor for PTX encapsulated FLPNPs was higher than other PTX formulations. Our data indicate that PTX loaded FLPNPs are a promising nano-sized drug formulation for cancer therapy.

PEGlated magnetic polymeric liposome anchored with TAT for delivery of drugs across the blood-spinal cord barrier

Due to the existence of the blood-spinal cord barrier (BSCB), many therapeutic macromolecular agents, such as drugs, protein and gene, cannot pass through this barrier to reach the site of injury, all of which restricts the treatment of spinal cord injuries (SCI). In this study, TAT-conjugated PEGlated Magnetic polymeric liposomes (TAT-PEG-MPLs) formed from PEGlated amphiphilic octadecyl quaternized carboxymethyl chitosan (PEG-OQCMC), cholesterol (Chol), superparamagnetic nanoparticles, and transactivating-transduction protein (TAT), were prepared successfully and evaluated the properties in vitro and in vivo. The result indicated that TAT-PEG-MPLs were spherical in solution, with significantly small mean diameter (83.2 nm) and excellent magnetism (magnetization saturation values of 43.5 emu/g). In vitro experiment, the uptake of PEG-MPLs with TAT by MCF-7 cells was greater than that of the PEG-MPLs without TAT. Most importantly, in vivo experiment, a low MRI signal was observed in the T(2)-weighted images; Histological analysis, Cryo-TEM and flame atomic absorption spectrophotometry revealed that TAT-PEG-MPLs nanoparticles significantly accumulated around the site of the SCI even inside the nerve cells. These nanoparticles may provide a promising carrier to locate to the lesion site, deliver therapeutic macromolecular agents across the BSCB and penetrate into the nerve cells for the treatment of SCI.

Polymeric Liposomes-Coated Superparamagnetic Iron Oxide Nanoparticles as Contrast Agent for Targeted Magnetic Resonance Imaging of Cancer Cells

The purpose of this study was to use polymeric liposomes (PLs) with a targeting ligand (folate) to coat superparamagnetic iron oxide nanoparticles (SPIONs) and transfer the magnetic nanoparticles from organic phases to aqueous solutions, and further evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The formed nanoparticles exhibited a narrow range of size dispersity (core size of the particles is about 8-10 nm) and relatively high T2 relaxivities (r2 = 164.14 s(-1) mM(-1) for folate-PLs-coated SPIONs). The in vitro tumor cell targeting efficacy of the folate functionalized and PLs-coated SPIONs was evaluated upon observing cellular uptake of magnetite liposomes by HeLa cells, which overexpresses surface receptors for folic acid. In the Prussian blue staining experiments, cells incubated with folate-PLs-coated SPIONs showed much higher intracellular iron density than did the cells incubated with the folate-free PLs-coated SPIONs. Meanwhile, the MTT assay explains the negligible cell cytotoxicity of SPIONs and folate-PLs-coated SPIONs. In HeLa cells, the in vitro MRI study also indicates the better T2-weighted images in folate-PLs-coated SPIONs than in folate-free PLs-coated SPIONs.

PEG/RGD-modified magnetic polymeric liposomes for controlled drug release and tumor cell targeting

Polymeric liposomes (PEG/RGD-MPLs), composed of amphiphilic polymer octadecyl-quaternized modified poly (γ-glutamic acid) (OQPGA), PEGylated OQPGA, RGD peptide grafted OQPGA and magnetic nanoparticles, was prepared successfully. These PEG/RGD-MPLs could be used as a multifunctional platform for targeted drug delivery. The results showed that PEG/RGD-MPLs were multilamellar spheres with nano-size (50-70 nm) and positive surface charge (28-42 mV). Compared with magnetic conventional liposomes (MCLs), PEG/RGD-MPLs exhibited sufficient size and zeta potential stability, low initial burst release and less magnetic nanoparticles leakage. The cell uptake results suggested that the PEG/RGD-MPLs (with RGD and magnetic particles) exhibited more drug cellular uptake than non RGD and non magnetism carriers in MCF-7 cells. MTT assay revealed that PEG/RGD-MPLs showed lower in vitro cytotoxicity to GES-1cells at ≤ 100 μg/mL. These data indicated that the multifunctional PEG/RGD-MPLs may be an alternative formulation for drug delivery system.

Folate-targeting magnetic core–shell nanocarriers for selective drug release and imaging

One of the most urgent medical requirements for cancer diagnosis and treatment is how to construct a multifunctional vesicle for simultaneous diagnostic imaging and therapeutic applications. In our study, superparamagnetic iron oxide nanocrystals (SPIONs) and doxorubicin hydrochloride (DOX) are co-encapsulated into PLGA/polymeric liposome core-shell nanocarriers for achieving simultaneous magnetic resonance imaging and targeting drug delivery. The core-shell nanocarrier was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell. The experiment showed that folate-targeting magnetic core-shell nanocarriers show clear core-shell structure, excellent magnetism and controlled drug release behavior. Importantly, the core-shell nanoparticles achieve the possibility of co-delivering drugs and SPIONs to the same cells for enhancing magnetic resonance imaging (MRI) effect and improving drug delivery efficiency simultaneously. Our data suggests that the folate-targeting magnetic core-shell nanocarriers (FMNs) could provide effective cancer-targeting and MRI as well as drug delivery. The FMNs may become a useful nanomedical carrier system for cancer diagnosis and treatment.

Smart multifunctional core–shell nanospheres with drug and gene co-loaded for enhancing the therapeutic effect in a rat intracranial tumor model

Glioblastoma with high mortality has been one of the most serious cancers threatening human health. Because of the present treatment limitations, there is an urgent need to construct a multifunctional vesicle for enhancing the treatment of in situ malignant glioblastoma. In our study, drug and gene co-loaded magnetic PLGA/multifunctional polymeric liposome (magnetic PLGA/MPLs) core-shell nanospheres were constructed. They were mainly self-assembled from two parts: hydrophobic PLGA cores that can load drugs and magnetic nanocrystals; and polymeric lipid shells anchored with functional molecules such as PEG chains, TAT peptides and RGD peptides that can help the vectors to condense the gene, prolong the circulation time, cross the blood brain barrier and target delivery to the cancer tissue. The results showed that the magnetic PLGA/MPLs nanosphere has a nanosized core-shell structure, can achieve sustained drug release and has good DNA binding abilities. Importantly, compared with the control group and other groups with single functionality, it can co-deliver the drug and gene into the same cell in vitro and show the strongest inhibiting effect on the growth of the in situ malignant glioblastoma in vivo. All of these results indicated that the different functional components of magnetic PLGA/MPLs, can form an organic whole and none of them can be dispensed with. The magnetic PLGA/MPLs nanosphere may be another option for treatment of glioblastoma.

A UCN@mSiO2@cross-linked lipid with high steric stability as a NIR remote controlled-release nanocarrier for photodynamic therapy

In clinics, the application of photodynamic therapy (PDT) in deep tissue is severely constrained by the limited penetration depth of visible light that was used for activating the photosensitizer (PS). In this work, a protocol of a UCN@SiO2@crosslinked lipid triple layer nanoparticle was developed successfully. The triple layer nanoparticle was assembled from the hydrophobic upconverting nanoparticle (UCN) core, the mesoporous silica middle shell and the cross-linked lipid out shell. The photosensitizer zinc phthalocyanine (ZnPc) loaded triple layer nanoparticle offers possibilities to solve the problem mentioned above. The UCN core works as a transducer to convert deeply penetrating near infrared light to visible light for activating ZnPc for photo dynamic therapy. The middle shell is used for loading ZnPc and the out shell can prevent the drug leaking effectively. The experiment results showed that with the help of the cross-linked lipid shell, the triple layer nanoparticle could prevent the drug leaking and particle aggregation. The ROS production test and PDT test suggested that the fluorescence emitted from the UCNs excited by NIR can effectively activate the photosensitizer ZnPc to generate cytotoxic ROS. The UCN@SiO2@crosslinked lipid triple layer nanoparticle modified with RGD has a much better treatment effect in cancer cells. Our data suggest that the UCN@SiO2@crosslinked lipid triple layer nanoparticle may be a useful nanoplatform for future PDT treatment in deep cancer therapy based on the upconverting mechanism.

A visual guide to gene/optothermal synergy therapy nanosystem using tungsten oxide

Combination of gene therapy and photothermal therapy (PTT) has drawn much attention in cancer therapy in recent years. However, this joint treatment process lacks fluorescence imaging visualization guidance that limits its clinical applications in oncotherapy. Herein, we report the use of gene therapy and tungsten oxide (W18O49, WO) synthetized with template method for combined PTT of cancer. In this system, a novel nanoplatform, with Bax gene, WO and indocyanine green (ICG) loaded in mesoporous silica nanoparticle had been successfully constructed, which was used as the near-infrared imaging-guided gene/optothermal multi-modal oncotherapy. These nanoparticles could achieve a synergistic therapy effect of gene therapy and PTT for tumor under 808nm near-infrared (NIR) laser excitation. In vivo animal experiments showed that they could cause solid tumor regression under 808nm NIR light irradiation, revealing the potential of these nanocomposites as a fluorescence imaging-guided multi-modal therapeutic nanosystem for tumor visual synergistic treatment.