Kuo-Chen Wei

Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain

The superparamagnetic properties of magnetic nanoparticles (MNPs) allow them to be guided by an externally positioned magnet and also provide contrast for MRI. However, their therapeutic use in treating CNS pathologies in vivo is limited by insufficient local accumulation and retention resulting from their inability to traverse biological barriers. The combined use of focused ultrasound and magnetic targeting synergistically delivers therapeutic MNPs across the blood–brain barrier to enter the brain both passively and actively. Therapeutic MNPs were characterized and evaluated both in vitro and in vivo, and MRI was used to monitor and quantify their distribution in vivo. The technique could be used in normal brains or in those with tumors, and significantly increased the deposition of therapeutic MNPs in brains with intact or compromised blood–brain barriers. Synergistic targeting and image monitoring are powerful techniques for the delivery of macromolecular chemotherapeutic agents into the CNS under the guidance of MRI.

Blood-Brain Barrier Disruption with Focused Ultrasound Enhances Delivery of Chemotherapeutic Drugs for Glioblastoma Treatment

PURPOSE To demonstrate the feasibility of using focused ultrasound to enhance delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to glioblastomas in rats with induced tumors and determine if such an approach increases treatment efficacy. MATERIALS AND METHODS All animal experiments were approved by the animal committee and adhered to the experimental animal care guidelines. A 400-kHz focused ultrasound generator was used to transcranially disrupt the blood-brain barrier (BBB) in rat brains by delivering burst-tone ultrasound energy in the presence of microbubbles. The process was monitored in vivo by using magnetic resonance (MR) imaging. Cultured C6 glioma cells implanted in Sprague-Dawley rats were used as the tumor model. BCNU (13.5 mg/kg) was administered intravenously and its concentration in brains was quantified by using high-performance liquid chromatography. MR imaging was used to evaluate the effect of treatments longitudinally, including analysis of tumor progression and animal survival, and brain tissues were histologically examined. Methods including the two-tailed unpaired t test and the Mantel-Cox test were used for statistical analyses, with a significance level of .05. RESULTS Focused ultrasound significantly enhanced the penetration of BCNU through the BBB in normal (by 340%) and tumor-implanted (by 202%) brains without causing hemorrhaging. Treatment of tumor-implanted rats with focused ultrasound alone had no beneficial effect on tumor progression or on animal survival up to 60 days. Administration of BCNU only transiently controlled tumor progression; nevertheless, relative to untreated controls, animal survival was improved by treatment with BCNU alone (increase in median survival time [IST(median)], 15.7%, P = .023). Treatment with focused ultrasound before BCNU administration controlled tumor progression (day 31: 0.05 cm(3) + or - 0.1 [standard deviation] vs 0.28 cm(3) + or - 0.1) and improved animal survival relative to untreated controls (IST(median), 85.9%, P = .0015). CONCLUSION This study demonstrates a means of increasing localized chemotherapeutic drug delivery for brain tumor treatment and strongly supports the feasibility of this treatment in a clinical setting.

Dual targeted delivery of doxorubicin to cancer cells using folate-conjugated magnetic multi-walled carbon nanotubes.

By combining the advantage of multi-walled carbon nanotubes (MWCNTs) and iron oxide magnetic nanoparticles (MNs), we develop a magnetic dual-targeted nanocarrier for drug delivery. MWCNTs were functionalized with poly(acrylic acid) through free radical polymerization, decorated with MNs, conjugated with a targeting ligand folic acid (FA), for loading of an anti-cancer drug doxorubicin (DOX). The proposed methodology provides dual targeted delivery of the anti-cancer drug to cancer cells under the guidance of a magnetic field and through ligand-receptor interactions. The chemico-physical properties of the nanocarrier were characterized, in addition to its drug loading efficiency and drug releasing characteristics. Doxorubicin could be loaded to MWCNTs with high efficiency via π-π stacking and hydrogen bonding and showed enhanced cytotoxicity toward U87 human glioblastoma cells compared with free DOX. From transmission electron microscopy and confocal laser scanning microscopy, we confirmed that DOX-FA-MN-MWCNT could be efficiently taken up by U87 cells with subsequent intracellular release of DOX, followed by transport of DOX into the nucleus with the nanocarrier left in the cytoplasm. These properties make the magnetic nanocarrier a potential candidate for targeted delivery of DOX for cancer treatment.

Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor. The blood-brain barrier (BBB) provides a major obstacle to chemotherapy since therapeutic doses cannot be achieved by traditional drug delivery without severe systemic cytotoxic effects. Recently, microbubble (MB)-enhanced focused ultrasound (FUS) was shown to temporally and locally disrupt the BBB thereby enhancing drug delivery into brain tumors. Here we propose the concept of smart, multifunctional MBs capable of facilitating FUS-induced BBB disruption while serving as drug-carrying vehicles and protecting drugs from rapid degradation. The designed MBs had a high loading capacity (efficiency of 68.01 ± 4.35%) for 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU). When combined with FUS (1-MHz), these BCNU-MBs facilitated local BBB disruption and simultaneously released BCNU at the target site, thus increasing local BCNU deposition. Encapsulation of BCNU in MBs prolonged its circulatory half-life by 5-fold, and accumulation of BCNU in the liver was reduced 5-fold due to the slow reticuloendothelial system uptake of BCNU-MBs. In tumor-bearing animals, BCNU-MBs with FUS controlled tumor progression (915.3%-39.6%) and improved median survival (29 days-32.5 days). This study provides a new approach for designing multifunctional MBs to facilitate FUS-mediated chemotherapy for brain tumor treatment.

Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

The effectiveness of a magnetic nanoparticle-based delivery system for BCNU in the treatment of gliomas

This study describes the creation and characterization of drug carriers prepared using the polymer poly[aniline-co-N-(1-one-butyric acid) aniline] (SPAnH) coated on Fe(3)O(4) cores to form three types of magnetic nanoparticles (MNPs); these particles were used to enhance the therapeutic capacity and improve the thermal stability of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a compound used to treat brain tumors. The average hydrodynamic diameter of the MNPs was 89.2 ± 8.5 nm and all the MNPs displayed superparamagnetic properties. A maximum effective dose of 379.34 μg BCNU could be immobilized on 1 mg of MNP-3 (bound-BCNU-3). Bound-BCNU-3 was more stable than free-BCNU when stored at 4 °C, 25 °C or 37 °C. Bound-BCNU-3 could be concentrated at targeted sites in vitro and in vivo using an externally applied magnet. When applied to brain tumors, magnetic targeting increased the concentration and retention of bound-BCNU-3. This drug delivery system promises to provide more effective tumor treatment using lower therapeutic doses and potentially reducing the side effects of chemotherapy.

Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment

Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood-brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood-brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.

Magnetic gold-nanorod/ PNIPAAmMA nanoparticles for dual magnetic resonance and photoacoustic imaging and targeted photothermal therapy

Nanomedicine can provide a multi-functional platform for image-guided diagnosis and treatment of cancer. Although gold nanorods (GNRs) have been developed for photoacoustic (PA) imaging and near infra-red (NIR) photothermal applications, their efficiency has remained limited by low thermal stability. Here we present the synthesis, characterization, and functional evaluation of non-cytotoxic magnetic polymer-modified gold nanorods (MPGNRs), designed to act as dual magnetic resonance imaging (MRI) and PA imaging contrast agents. In addition, their high magnetization allowed MPGNRs to be actively localized and concentrated by targeting with an external magnet. Finally, MPGNRs significantly enhanced the NIR-laser-induced photothermal effect due to their increased thermal stability. MPGNRs thus provide a promising new theranostic platform for cancer diagnosis and treatment by combining dual MR/PA imaging with highly effective targeted photothermal therapy.

Gadolinium-functionalized nanographene oxide for combined drug and microRNA delivery and magnetic resonance imaging.

The delivery of anti-cancer therapeutics to tumors at clinically effective concentrations, while avoiding nonspecific toxicity, remains a major challenge for cancer treatment. Here we present nanoparticles of poly(amidoamine) dendrimer-grafted gadolinium-functionalized nanographene oxide (Gd-NGO) as effective carriers to deliver both chemotherapeutic drugs and highly specific gene-targeting agents such as microRNAs (miRNAs) to cancer cells. The positively charged surface of Gd-NGO was capable of simultaneous adsorption of the anti-cancer drug epirubicin (EPI) and interaction with negatively charged Let-7g miRNA. Using human glioblastoma (U87) cells as a model, we found that this conjugate of Let-7g and EPI (Gd-NGO/Let-7g/EPI) not only exhibited considerably higher transfection efficiency, but also induced better inhibition of cancer cell growth than Gd-NGO/Let-7g or Gd-NGO/EPI. The concentration of Gd-NGO/Let-7g/EPI required for 50% inhibition of cellular growth (IC50) was significantly reduced (to the equivalent of 1.3 μg/mL EPI) compared to Gd-NGO/EPI (3.4 μg/mL EPI). In addition, Gd-NGO/Let-7g/EPI could be used as a contrast agent for magnetic resonance imaging to identify the location and extent of blood-brain barrier opening and quantitate drug delivery to tumor tissues. These results suggest that Gd-NGO/Let-7g/EPI may be a promising non-viral vector for chemogene therapy and molecular imaging diagnosis in future clinical applications.

EGRF conjugated PEGylated nanographene oxide for targeted chemotherapy and photothermal therapy.

Low accumulation of chemotherapeutic agent in tumor tissue and multidrug resistance (MDR) present a major obstacle to curing cancer treatment. Therefore, how to combine several therapeutics in one system is a key issue to overcome the problem. Here, we demonstrate epidermal growth factor receptor (EGFR) antibody-conjugated PEGylated nanographene oxide (PEG-NGO) to carry epirubicin (EPI) for tumor targeting and triple-therapeutics (growth signal blocking, chemotherapy, photothermal therapy) in tumor treatment. This synergistic targeted treatment simultaneously enhances the local drug concentration (6.3-fold) and performs the ultra-efficient tumor suppression to significantly prolong the mice survival (over the course of 50 days).