Huile Gao

Targeting mesoporous silica-encapsulated gold nanorods for chemo-photothermal therapy with near-infrared radiation

Mesoporous silica-encapsulated gold nanorods (GNRs@mSiO(2)) have great potential both in photothermal therapy and drug delivery. In this paper, we firstly developed GNRs@mSiO(2) as a synergistic therapy tool for delivery heat and drug to the tumorigenic region. We studied the ablation of tumor both in vitro and in vivo by the combination of photothermal therapy and chemotherapy using doxorubicin (DOX)-loaded GNRs@mSiO(2). Significantly greater cell killing was observed when A549 cells incubated with DOX-loaded GNRs@mSiO(2) were irradiated with near-infrared (NIR) illumination, attributable to both GNRs@mSiO(2)-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. We then performed in vivo therapy studies and observed a promising tumor treatment. Compared with chemotherapy or photothermal treatment alone, the combined treatment showed a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, the lower systematic toxicity of GNRs@mSiO(2) has been validated.

Preparation and brain delivery property of biodegradable polymersomes conjugated with OX26.

A novel drug carrier for brain delivery, poly(ethyleneglycol)-poly(epsilon-caprolactone) (PEG-PCL) polymersomes conjugated with mouse-anti-rat monoclonal antibody OX26 (OX26-PO), was developed and its brain delivery property was evaluated. The diblock copolymers of methoxy-PEG-PCL and Maleimide-PEG-PCL were synthesized and applied to prepare polymersomes (PO) which were verified by direct cryogenic temperature transmission electron micrograph (Cryo-TEM) imaging. The TEM examination and dynamic light scattering results showed that OX26-PO had a round and vesicle-like shape with a mean diameter around 100 nm. Coupling of OX26 with PO was confirmed by immuno-gold labeling of OX26 visualized under the TEM and X-ray photoelectron spectroscopy test. The surface OX26 densities were obtained from enzyme-linked immunosorbant assay. The result of brain delivery in rats proved that the increase of surface OX26 density of OX26-PO decreased blood AUC. The optimized OX26 number conjugated per polymersome was 34, which can acquire the greatest blood-brain barrier (BBB) permeability surface area product and percentage of injected dose per gram brain (%ID/g brain). Furthermore, NC-1900, as a model peptide, was encapsulated into OX26(34)-PO and improved the scopolamine-induced learning and memory impairments in a water maze task via i.v. administration. These results indicated that OX26(34)-PO is a promising carrier for peptide brain delivery.

Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles

Glioma is still hard to be treated due to their complex microenvironment. In this study, a gold nanoparticle-based delivery system was developed. The system, An-PEG-DOX-AuNPs, was loaded with doxorubicin (DOX) through hydrazone, an acid-responsive linker, and was functionalized with angiopep-2, a specific ligand of low density lipoprotein receptor-related protein-1 (LRP1), which could mediate the system to penetrate blood brain barrier and target to glioma cells. The particle size of An-PEG-DOX-AuNPs was 39.9 nm with a zeta potential of -19.3 mV, while the DOX loading capacity was 9.7%. In vitro, the release of DOX from DOX-AuNPs was pH-dependent. At lower pH values, especially 5.0 and 6.0, release of DOX was much quicker than that at pH 6.8 and 7.4. After coating with PEG, the acid-responsive release of DOX from PEG-DOX-AuNPs was almost the same as that from DOX-AuNPs. Cellular uptake study showed obviously higher intensity of intracellular An-PEG-DOX-AuNPs compared with PEG-DOX-AuNPs. In vivo, An-PEG-DOX-AuNPs could distribute into glioma at a higher intensity than that of PEG-DOX-AuNPs and free DOX. Correspondingly, glioma-bearing mice treated with An-PEG-DOX-AuNPs displayed the longest median survival time, which was 2.89-fold longer than that of saline. In conclusion, An-PEG-DOX-AuNPs could specifically deliver and release DOX in glioma and significantly expand the median survival time of glioma-bearing mice.

Angiopep-2 and Activatable Cell-Penetrating Peptide Dual-Functionalized Nanoparticles for Systemic Glioma-Targeting Delivery

Gliomas are hard to treat because of the two barriers involved: the blood-brain barrier and blood-tumor barrier. In this study, a dual-targeting ligand, angiopep-2, and an activatable cell-penetrating peptide (ACP) were functionalized onto nanoparticles for glioma-targeting delivery. The ACP was constructed by conjugating RRRRRRRR (R8) with EEEEEEEE through a matrix metalloproteinase-2 (MMP-2)-sensitive linker. ACP modification effectively enhanced the C6 cellular uptake because of the high expression of MMP-2 on C6 cells. The uptake was inhibited by batimastat, an MMP-2 inhibitor, suggesting that the cell-penetrating property of the ACP was activated by MMP-2. By combining the dual-targeting delivery effect of angiopep-2 and activatable cell-penetrating property of the ACP, the dual-modified nanoparticles (AnACNPs) displayed higher glioma localization than that of single ligand-modified nanoparticles. After loading with docetaxel, a common chemotherapeutic, AnACNPs showed the most favorable antiglioma effect both in vitro and in vivo. In conclusion, a novel drug delivery system was developed for glioma dual targeting and glioma penetrating. The results demonstrated that the system effectively targeted gliomas and provided the most favorable antiglioma effect.

Tumor cells and neovasculature dual targeting delivery for glioblastoma treatment

Glioblastoma multiforme (GBM), one of the most common primary malignant brain tumors, was characterized by angiogenesis and tumor cells proliferation. Antiangiogenesis and antitumor combination treatment gained much attention because of the potency in dual inhibition of both the tumor proliferation and the tumor invasion. In this study, a neovasculature and tumor cell dual targeting delivery system was developed through modification of nanoparticles with interleukin-13 peptide and RGD (IRNPs), in which interleukin-13 peptide was targeting GBM cells and RGD was targeting neovasculature. To evaluate the potency in GBM treatment, docetaxel was loaded into IRNPs. In vitro, interleukin-13 peptide and RGD could enhance the corresponding cells (C6 and human umbilical vein endothelial cells) uptake and cytotoxicity. In combination, IRNPs showed high uptake in both cells and increased the cytotoxicity on both cells. In vivo, IRNPs could effectively deliver cargoes to GBM with higher intensity than mono-modified nanoparticles. Correspondingly, docetaxel-IRNPs displayed best anti-tumor effect with a median survival time of 35 days, which was significantly longer than that of mono-modified and unmodified nanoparticles. Importantly, treatment with docetaxel-IRNPs could avoid the accumulation of HIF1α in GBM site, which was crucial for the tumor invasion. After the treatment, there was no obvious change in normal organs of mice.

Brain delivery and cellular internalization mechanisms for transferrin conjugated biodegradable polymersomes.

Transferrin conjugated biodegradable polymersomes (Tf-PO) were exploited for efficient brain drug delivery, and its cellular internalization mechanisms were investigated. Tf-PO was prepared by a nanoprecipitation method with an average diameter of approximately 100 nm and a surface Tf molecule number per polymersome of approximately 35. It was demonstrated that the uptake of Tf-PO by bEnd.3 was mainly through a clathrin mediated energy-dependent endocytosis. Both the Golgi apparatus and lysosomes are involved in intracellular transport of Tf-PO. Thirty minutes after a 50mg/kg dose of Tf-PO or PO was injected into rats via the tail vein, fluorescent microscopy of brain coronal sections showed a higher accumulation of Tf-PO than PO in the cerebral cortex, the periventricular region of the lateral ventricle and the third ventricle. The brain delivery results proved that the blood-brain barrier (BBB) permeability surface area product (PS) and the percentage of injected dose per gram of brain (%ID/g brain) for Tf-PO were increased to 2.8-fold and 2.3-fold, respectively, as compared with those for PO. These results indicate that Tf-PO is a promising brain delivery carrier.

The interaction of nanoparticles with plasma proteins and the consequent influence on nanoparticles behavior

Introduction: Plasma protein binding with nanoparticles (NPs) occurs immediately upon their introduction into a physiological environment and is affected by the characteristics of NPs, including their composition, size, shape and surface properties. According to their specific functions, adsorbed proteins can be divided into opsonins and dysopsonins. Opsonins often induce the rapid blood clearance of NPs, while dysopsonins benefit prolonged blood circulation. Areas covered: This review discusses the influential factors that are involved in the interaction between NPs and plasma proteins. The influence of this interaction on distribution of NPs was reviewed followed by the function and influence of ligand modification. Expert opinion: Protein adsorption is a key element that influences biological responses, such as endocytosis and biodistribution, and also contributes to the characteristics of NPs and the physiological environment. By contrast, the surface modification of ligands is a common and useful method to functionalize NPs to provide an engineered targeting effect. The protein adsorption of ligand-modified NPs is even more important and requires in-depth discussion. Differences between modified and unmodified NPs lead to varying degrees of opsonization, which greatly affects targeting and may result in opposing effects. Understanding these influences is necessary to improve targeting effects and reduce defects in protein adsorption, which are crucial for drug delivery.

Progress and perspectives on targeting nanoparticles for brain drug delivery.

Due to the ability of the blood–brain barrier (BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood–brain tumor barrier (BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

Glioma-homing peptide with a cell-penetrating effect for targeting delivery with enhanced glioma localization, penetration and suppression of glioma growth.

Tumor-targeted delivery systems are useful in enhancing drug delivery and increasing anti-tumor effects. Cell-penetrating peptides have been widely used for this purpose but have been hampered by the poor selectivity between neoplastic and non-neoplastic cells. As a peptide derived from interleukin-13, interleukin-13 peptide (IL-13p) is specifically targeted to IL13Rα2, a tumor-restricted receptor. More interestingly, IL-13p possesses cell-penetrating properties that can specifically enhance the uptake by tumor cells compared with endothelial cells. Thus, we anchored IL-13p onto nanoparticles (ILNPs) for glioma-targeting delivery. The uptake of ILNPs by U87 cells was higher than that of unmodified nanoparticles (NPs). However, there was no significant difference in the uptake by human umbilical vein endothelial cells. In addition, free IL-13p could also enhance the uptake of both NPs and ILNPs by U87 cells. Anchoring with IL-13p could enhance the penetration of particles into the core of spheroids. In vivo, the fluorescence intensity of ILNPs in tumors was 2.96-fold higher than that of NPs. The modification with IL-13p also significantly improved the speed and rate of penetration from vessels to tumor cells. The enhanced tumor localization of ILNPs was mostly attributable to the elevated tumor cell internalization of ILNPs, whereas most NPs were colocalized with microvessels or macrophages. Correspondingly, docetaxel-loaded NPs effectively suppressed the growth of subcutaneous U87 tumors. The average tumor volume of the ILNP group was only 31.4% that of the control, which was significantly smaller than that of the docetaxel and NP groups. In conclusion, the modification of IL-13p selectively enhanced tumor cell uptake, improved the penetration effect of NPs and improved the glioma localization ability, which led to a better tumor-suppression effect.

A Novel Strategy through Combining iRGD Peptide with Tumor-Microenvironment-Responsive and Multistage Nanoparticles for Deep Tumor Penetration

Despite the great achievements that nanomedicines have obtained so far, deep penetration of nanomedicines into tumors is still a major challenge in tumor treatment. The enhanced permeability and retention (EPR) effect was the main theoretical foundation for using nanomedicines to treat solid tumor. However, the antitumor efficiency is modest because the tumor is heterogeneous, with dense collagen matrix, abnormal tumor vasculature, and lymphatic system. Nanomedicines could only passively accumulate near leaky site of tumor vessels, and they cannot reach the deep region of tumor. To enhance further the tumor penetration efficiency, we developed a novel strategy of coadministering cell-homing penetration peptide iRGD with size-shrinkable and tumor-microenvironment-responsive multistage system (DOX-AuNPs-GNPs) to overcome these barriers. First, iRGD could specifically increase the permeability of tumor vascular and tumor tissue, leading to more DOX-AuNPs-GNPs leaking out from tumor vasculature. Second, the multistage system passively accumulated in tumor tissue and shrank from 131.1 to 46.6 nm to reach the deep region of tumor. In vitro, coadministering iRGD with DOX-AuNPs-GNPs showed higher cellular uptake and apoptosis ratio. In vivo, coadministering iRGD with DOX-AuNPs-GNPs presented higher penetration and accumulation in tumor than giving DOX-AuNPs-GNPs alone, leading to the best antitumor efficiency in 4T1 tumor-bearing mouse model.