Yongwei Hao

The tumor-targeting core-shell structured DTX-loaded PLGA@Au nanoparticles for chemo-photothermal therapy and X-ray imaging.

In this study, an organic-inorganic hybrid nanocomposite was synthesized by deposition of Au onto the surface of docetaxel (DTX)-loaded poly (lactide-co-glycolide) (PLGA) nanoparticle cores to form the core-shell structured DTX-loaded PLGA@Au nanoparticles. The tumor targeting peptide, angiopep-2, was then introduced onto the gold nanoshell through Au-S bond, achieving drug delivery with active targeting capability. This novel system allowed combined chemotherapy and thermal therapy for cancer, resulting from DTX and gold nanoshell. The formation of tumor-targeting gold nanoshell surrounding PLGA nanocore, designated as ANG/GS/PLGA/DTX NPs, was confirmed by its surface plasmon resonance (SPR) band in the UV-Vis spectrum and by a transmission electron microscope (TEM). The release profiles of DTX from this system showed strong dependence on near-infrared (NIR) laser. Compared with DTX alone, the ANG/GS/PLGA/DTX NPs afforded much higher anti-tumor efficiency without obvious toxic effects. Besides, it also showed potential X-ray imaging ability. These results demonstrated that the tumor-targeting core-shell structured DTX-loaded PLGA@Au nanoparticles could be used as a multifunctional nanomaterial system with NIR-triggered drug-releasing properties for tumor-targeted chemo-photothermal therapy and theranostics.

Targeted Imaging and Chemo‐Phototherapy of Brain Cancer by a Multifunctional Drug Delivery System

The aim of this study was to develop multifunctional poly lactide-co-glycolide (PLGA) nanoparticles with the ability to simultaneously deliver indocyanine green (ICG) and docetaxel (DTX) to the brain by surface decoration with the brain-targeting peptide angiopep-2 to achieve combined chemo-phototherapy for glioma under near-infrared (NIR) imaging. ICG was selected as a near-infrared imaging and phototherapy agent and DTX was employed as a chemotherapeutic agent. ICG and DTX were simultaneously incorporated into PLGA nanoparticles with higher stability. These nanoparticles were further decorated with angiopep-2 via the outer maleimide group of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]-maleinimide incorporated in the nanoparticles. The NIR image-guided chemo-phototherapy of the angiopep-2 modified PLGA/DTX/ICG nanoparticles (ANG/PLGA/DTX/ICG NPs) not only highly induced U87MG cell death in vitro, but also efficiently prolonged the life span of the brain orthotopic U87MG glioma xenograft-bearing mice in vivo. Thus, this study suggests that ANG/PLGA/DTX/ICG NPs have the potential for combinatorial chemotherapy and phototherapy for glioma.

Co-delivery of doxorubicin and siRNA for glioma therapy by a brain targeting system: angiopep-2-modified poly(lactic-co-glycolic acid) nanoparticles

Abstract It is very challenging to treat brain cancer because of the blood–brain barrier (BBB) restricting therapeutic drug or gene to access the brain. In this research project, angiopep-2 (ANG) was used as a brain-targeted peptide for preparing multifunctional ANG-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which encapsulated both doxorubicin (DOX) and epidermal growth factor receptor (EGFR) siRNA, designated as ANG/PLGA/DOX/siRNA. This system could efficiently deliver DOX and siRNA into U87MG cells leading to significant cell inhibition, apoptosis and EGFR silencing in vitro. It demonstrated that this drug system was capable of penetrating the BBB in vivo, resulting in more drugs accumulation in the brain. The animal study using the brain orthotopic U87MG glioma xenograft model indicated that the ANG-targeted co-delivery of DOX and EGFR siRNA resulted in not only the prolongation of the life span of the glioma-bearing mice but also an obvious cell apoptosis in glioma tissue.

Inhalable microspheres embedding chitosan-coated PLGA nanoparticles for 2-methoxyestradiol

Abstract Developing a highly effective and lung-targeted local drug delivery carrier with low irritancy may be critical for improving treatment of lung cancer. Using soluble excipients as microspheres (MS) matrix, respirable MS embedding chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (CNP-MS) for 2-methoxyestradiol (2-ME) were designed, which could avoid macrophage phagocytosis to achieve the targeted delivery of these drugs. 2-ME CNP-MS were prepared by spray-drying and characterized by morphology, redispersability, fine particle fraction (FPF) and drug release. Cytotoxicity, and lung deposition and histological examination were investigated. Results showed that 2-ME CNP-MS were spherical with a rough surfaces, exhibiting good redispersability, a high respirable fraction and sustained release characteristics. CNP-MS markedly enhanced the cytotoxicity of 2-ME by approximately 8.8-fold and 3.65-fold on SPC-A1 cells compared to solution and NP, respectively. After pulmonary administration, 2-ME CNP were distributed in rat lungs and for 10 mg of 2-ME CNP-MS, haematoxylin and eosin staining showed no obvious difference compared to the untreated control group. Therefore, CNP-MS revealed suitable features for local lung delivery and significantly enhanced cytotoxicity of 2-ME without obvious inflammation in lungs of rats, suggesting that 2-ME CNP-MS have great potential as an inhalation agent for targeted, highly effective and safe treatment of lung cancer.

Radiofrequency-triggered tumor-targeting delivery system for theranostics application.

In this study, a new type of magnetic tumor-targeting PEGylated gold nanoshell drug delivery system (DOX-TSMLs-AuNSs-PEG) based on doxorubicin-loaded thermosensitive magnetoliposomes was successfully obtained. The reverse-phase evaporation method was used to construct the magnetoliposomes, and then gold nanoshells were coated on the surface of it. The DOX-TSMLs-AuNSs-PEG delivery system was synthesized after SH-PEG2000 modification. This multifunction system was combined with a variety of functions, such as radiofrequency-triggered release, chemo-hyperthermia therapy, and dual-mode magnetic resonance/X-ray imaging. Importantly, the DOX-TSMLs-AuNSs-PEG complex was found to escape from endosomes after cellular uptake by radiofrequency-induced endosome disruption before lysosomal degradation. All results in vitro and in vivo indicated that DOX-TSMLs-AuNSs-PEG is a promising effective drug delivery system for diagnosis and treatment of tumors.

Manganese dioxide nanosheets-based redox/pH-responsive drug delivery system for cancer theranostic application

The aim of this study was to construct redox- and pH-responsive degradable manganese dioxide (MnO2) nanosheets for cancer theranostic application. The small MnO2 nanosheets were synthesized, and then functionalized by hyaluronic acid (HA), demonstrating excellent stability and tumor-targeting ability. Cisplatin (cis-diamminedichloroplatinum [CDDP]) was absorbed by the nanosheets through a physical action, which was designed as MnO2/HA/CDDP. The prepared MnO2/HA/CDDP formulation was able to efficiently deliver CDDP to tumor cells in vitro and in vivo, resulting in improved therapeutic efficiency. Subsequently, they were triggered by lower pH and higher level of reduced glutathione to generate Mn2+, enabling magnetic resonance imaging. The smart multifunctional system combining efficient magnetic resonance imaging and chemotherapy has the potential to be used as a tumor-targeting theranostic nanomedicine.

A gold nanostar based multi-functional tumor-targeting nanoplatform for tumor theranostic applications

Recently, gold nanomaterials have attracted extensive attention due to their unique physical, chemical and biological properties. In this study, gold nanostars (GNSTs) were synthesized first and functionalized with polyethylene glycol (PEG) and polyethylenimine (PEI). We found that GNSTs and their derivatives can be used as radiofrequency (RF) sensitizers for hyperthermia due to their special star shaped structure. Secondly, a multi-functional tumor-targeting drug delivery system DOX/GNSTs-PEG/PEI-FA was constructed. Doxorubicin (DOX) was covalently conjugated onto GNSTs-PEG/PEI by the pH-sensitive hydrazone linkage, and folic acid (FA) was directly conjugated to excess amino groups by amidation reaction. The release profiles of DOX from GNSTs-PEG/PEI-FA showed a strong dependence on the environmental pH value. These in vitro and in vivo results revealed that this drug delivery system has FA tumor-targeting, pH-sensitive controlled release, RF induced hyperthermia and X-ray contrast imaging effects, demonstrating that DOX/GNSTs-PEG/PEI-FA can be used as a potential nano-platform for tumor theranostic applications.

Gold nanostars mediated combined photothermal and photodynamic therapy and X-ray imaging for cancer theranostic applications

Gold nanomaterials possess unique physical and chemical properties, which attracted much attention in recent years. As a new type of gold nanomaterials, gold nanostars (GNSTs) have been prepared and characterized in this study. GNSTs under near-infrared (NIR) light irradiation can exert not only cancer photothermal therapy via heat production but also photodynamic therapy via generation of reactive oxygen species. GNSTs were able to enter the cytoplasm as well as nuclei of human breast michigan cancer foundation-7 (MCF-7) cells. Under NIR light irradiation, GNSTs caused more severe DNA damage, arrest the cell cycle in G0/G1 phase, and reduce more cellular glutathione level, causing more severe apoptosis and cell death in vitro. Intratumoral injection of GNSTs with NIR light irradiation significantly inhibited tumor growth in vivo. In addition, GNSTs were demonstrated to be a contrast agent for X-ray imaging. All the in vitro and in vivo results showed that GNSTs can be used for the potential diagnosis and medical treatment of cancer.

Multifunctional nanoplatform for enhanced photodynamic cancer therapy and magnetic resonance imaging

Co-delivery of photosensitizers and synergistic agents by one single nanoplatform is interesting for enhancing photodynamic therapy (PDT) of cancer. Here, a multifunctional nanoplatform for enhanced photodynamic therapy and magnetic resonance imaging of cancer was constructed. The poly (lactide-co-glycolide) (PLGA) nanoparticles (NPs) loaded with hematoporphyrin monomethyl ether (HMME) were coated with multifunctional manganese dioxide (MnO2) shells, which were designed as PLGA/HMME@MnO2 NPs. Once the NPs were effectively taken up by tumor cells, the intracellular H2O2 was catalysed by the MnO2 shells to generate O2. Meanwhile, the higher glutathione (GSH) promoted the degradation of MnO2 into Mn2+ ions with the ability of magnetic resonance (MR) imaging. After the degradation of outer layer, the release of photosensitizer was promoted. Under irradiation, the released HMME produced cytotoxic reactive oxygen species (ROS) to damage the tumor cells when the O2 was generated in the hypoxic tumor site. Furthermore, the decreased GSH level further inhibited the consumption of the produced ROS, which greatly enhanced the PDT efficacy. Therefore, this study suggested that this multifunctional system has the potential for enhanced photodynamic therapy and magnetic resonance imaging.

Multifunctional nanosheets based on folic acid modified manganese oxide for tumor-targeting theranostic application.

It is highly desirable to develop smart nanocarriers with stimuli-responsive drug-releasing and diagnostic-imaging functions for cancer theranostics. Herein, we develop a reduction and pH dual-responsive tumor theranostic platform based on degradable manganese dioxide (MnO2) nanosheets. The MnO2 nanosheets with a size of 20-60 nm were first synthesized and modified with (3-Aminopropyl) trimethoxysilane (APTMS) to get amine-functionalized MnO2, and then functionalized by NH2-PEG2000-COOH (PEG). The tumor-targeting group, folic acid (FA), was finally conjugated with the PEGylated MnO2 nanosheets. Then, doxorubicin (DOX), a chemotherapeutic agent, was loaded onto the modified nanosheets through a physical adsorption, which was designated as MnO2-PEG-FA/DOX. The prepared MnO2-PEG-FA/DOX nanosheets with good biocompatibility can not only efficiently deliver DOX to tumor cells in vitro and in vivo, leading to enhanced anti-tumor efficiency, but can also respond to a slightly acidic environment and high concentration of reduced glutathione (GSH), which caused degradation of MnO2 into manganese ions enabling magnetic resonance imaging (MRI). The longitudinal relaxation rate r1 was 2.26 mM(-1) s(-1) at pH 5.0 containing 2 mM GSH. These reduction and pH dual-responsive biodegradable nanosheets combining efficient MRI and chemotherapy provide a novel and promising platform for tumor-targeting theranostic application.