Plasmon-Enhanced Controlled Drug Release from Ag-PMA Capsules.

Silver (Ag)-grafted PMA (poly-methacrylic acid, sodium salt) nanocomposite loaded with sorafenib tosylate (SFT), an anticancer drug, showed good capability as a drug carrier allowing on-demand control of the dose, timing and duration of the drug release by laser irradiation stimuli. In this study, the preparation of Ag-PMA capsules loaded with SFT by using sacrificial silica microparticles as templates was reported. A high drug loading (DL%) of ∼13% and encapsulation efficiency (EE%) of about 76% were obtained. The photo-release profiles were regulated via the adjustment of light wavelength and power intensity. A significant improvement of SFT release (14% vs. 21%) by comparing SFT-Ag-PMA capsules with Ag-PMA colloids under the same experimental conditions was observed. Moreover, an increase of drug release by up to 35% was reached by tuning the laser irradiation wavelength near to Ag nanoparticles' surface plasmon resonance (SPR). These experimental results together with more economical use of the active component suggest the potentiality of SFT-Ag-PMA capsules as a smart drug delivery system.

Noninvasive, targeted gene therapy for acute spinal cord injury using LIFU-mediated BDNF-loaded cationic nanobubble destruction.

Various gene delivery systems have been widely studied for the acute spinal cord injury (SCI) treatment. In the present study, a novel type of brain-derived neurotrophic factor (BDNF)-loaded cationic nanobubbles (CNBs) conjugated with MAP-2 antibody (mAbMAP-2/BDNF/CNBs) was prepared to provide low-intensity focused ultrasound (LIFU)-targeted gene therapy. In vitro experiments, the ultrasound-targeted tranfection to BDNF overexpressioin in neurons and efficiently inhibition neuronal apoptosis have been demonstrated, and the elaborately designed mAbMAP-2/BDNF/CNBs can specifically target to the neurons. Furthermore, in a acute SCI rat model, LIFU-mediated mAbMAP-2/BDNF/CNBs transfection significantly increased BDNF expression, attenuated histological injury, decreased neurons loss, inhibited neuronal apoptosis in injured spinal cords, and increased BBB scores in SCI rats. LIFU-mediated mAbMAP-2/BDNF/CNBs destruction significantly increase transfection efficiency of BDNF gene both in vitro and in vivo, and has a significant neuroprotective effect on the injured spinal cord. Therefore, the combination of LIFU irradiation and gene therapy through mAbMAP-2/BDNF/CNBs can be considered as a novel non-invasive and targeted treatment for gene therapy of SCI.

Treatment of Parkinson's disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles.

Parkinson's disease (PD) is a very common neurological disorder. However, effective therapy is lacking. Although the blood-brain-barrier (BBB) protects the brain, it prevents the delivery of about 90% of drugs and nucleotides into the brain, thereby hindering the development of gene therapy for PD. Magnetic resonance imaging (MRI)-guided focused ultrasound delivery of microbubbles enhances the delivery of gene therapy vectors across the BBB and improves transfection efficiency. In the present study, we delivered nuclear factor E2-related factor 2 (Nrf2, NFE2L2) contained in nanomicrobubbles into the substantia nigra of PD rats by MRI-guided focused ultrasound, and we examined the effect of Nrf2 over-expression in this animal model of PD. The rat model of PD was established by injecting 6-OHDA in the right substantia nigra stereotactically. Plasmids (pDC315 or pDC315/Nrf2) were loaded onto nanomicrobubbles, and then injected through the tail vein with the assistance of MRI-guided focused ultrasound. MRI-guided focused ultrasound delivery of nanomicrobubbles increased gene transfection efficiency. Furthermore, Nrf2 gene transfection reduced reactive oxygen species levels, thereby protecting neurons in the target region.

Development of a novel resin-based dental material with dual biocidal modes and sustained release of Ag+ ions based on photocurable core-shell AgBr/cationic polymer nanocomposites.

Research on the incorporation of cutting-edge nano-antibacterial agent for designing dental materials with potent and long-lasting antibacterial property is demanding and provoking work. In this study, a novel resin-based dental material containing photocurable core-shell AgBr/cationic polymer nanocomposite (AgBr/BHPVP) was designed and developed. The shell of polymerizable cationic polymer not only provided non-releasing antibacterial capability for dental resins, but also had the potential to polymerize with other methacrylate monomers and prevented nanoparticles from aggregating in the resin matrix. As a result, incorporation of AgBr/BHPVP nanocomposites did not adversely affect the flexural strength and modulus but greatly increased the Vicker's hardness of resin disks. By continuing to release Ag+ ions without the impact of anaerobic environment, resins containing AgBr/BHPVP nanoparticles are particularly suitable to combat anaerobic cariogenic bacteria. By reason of the combined bactericidal effect of the contact-killing cationic polymers and the releasing-killing Ag+ ions, AgBr/BHPVP-containing resin disks had potent bactericidal activity against S. mutans. The long-lasting antibacterial activity was also achieved through the sustained release of Ag+ ions due to the core-shell structure of the nanocomposites. The results of macrophage cytotoxicity showed that the cell viability of dental resins loading less than 1.0 wt% AgBr/BHPVP was close to that of neat resins. The AgBr/BHPVP-containing dental resin with dual bactericidal capability and long term antimicrobial effect is a promising material aimed at preventing second caries and prolonging the longevity of resin composite restorations.

Magnetic Field-Induced Accentuation of Drug Release from Core/Shell Magnetic Mesoporous Silica Nanoparticles for Anticancer Treatment.

Drug (9-aminoacridine) loaded core/shell magnetic iron oxide-containing mesoporous silica nanoparticles (MMSN) were treated with HeLa cells and the drug carriers were agitated by expo- sure to magnetic field. Viability studies show the applicability of drug loaded magnetic material for anticancer treatment, which is enhanced upon stimulation with magnetic field. Confocal micrographs of fluorescein grafted MMSN-treated HeLa cells confirmed the ability of magnetic field to concentrate the synthesized material in the exposed area of the cells. The synthesized material and the applied drug delivery method may find application in magnetic field-responsive targeted treatment of cancer.

Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer.

A lack of intracellular delivery systems has limited the use of biologics such as monoclonal antibodies (mAb) that abrogate molecular signaling pathways activated to promote escape from cancer treatment. We hypothesized that intracellular co-delivery of the photocytotoxic chromophore benzoporphyrin derivative monoacid A (BPD) and the anti-VEGF mAb bevacizumab in a nanophotoactivatable liposome (nanoPAL) might enhance the efficacy of photodynamic therapy (PDT) combined with suppression of VEGF-mediated signaling pathways. As a proof-of-concept we found that nanoPAL-PDT induced enhanced extra- and intracellular bevacizumab delivery and enhanced acute cytotoxicity in vitro. In an in vivo subcutaneous mouse model of pancreatic ductal adenocarcinoma, nanoPAL-PDT achieved significantly enhanced tumor reduction. We attribute this to the optimal incorporation of insoluble BPD into the lipid bilayer, enhancing photocytotoxicity, and the simultaneous spatiotemporal delivery of bevacizumab, ensuring efficient neutralization of the rapid but transient burst of VEGF following PDT. From the Clinical Editor: Most patients with pancreatic ductal adenocarcinoma (PDAC) by the time present the disease it is very advanced, which unavoidably translates to poor survival. For these patients, use of traditional chemotherapy often becomes ineffective due to tumor resistance to drugs. Photodynamic therapy (PDT) can be an effective modality against chemo-resistant cancers. In this article, the authors investigated the co-delivery of a photocytotoxic agent and anti-VEGF mAb using liposomes. This combination was shown to results in enhanced tumor killing. This method should be applicable to other combination of treatments.

Nanoscintillator-mediated X-ray inducible photodynamic therapy for in vivo cancer treatment.

Photodynamic therapy is a promising treatment method, but its applications are limited by the shallow penetration of visible light. Here, we report a novel X-ray inducible photodynamic therapy (X-PDT) approach that allows PDT to be regulated by X-rays. Upon X-ray irradiation, the integrated nanosystem, comprised of a core of a nanoscintillator and a mesoporous silica coating loaded with photosensitizers, converts X-ray photons to visible photons to activate the photosensitizers and cause efficient tumor shrinkage.

Magnetic iron oxide nanoparticles: Recent trends in design and synthesis of magnetoresponsive nanosystems.

Recent developments in nanotechnology and application of magnetic nanoparticles, in particular in magnetic iron oxide nanosystems, offer exciting possibilities for nanomedicine. Facile and precise synthesis procedures, high magnetic response, tunable morphologies and multiple bio-functionalities of single- and multi-core magnetic particles designed for nanomedicine applications are thoroughly appraised. This review focuses on the structural and magnetic characterization of the cores, the synthesis of single- and multicore iron oxide NPs, especially the design of the latter, as well as their protection, stabilization and functionalization by desired coating in order to protect against the corrosion of core, to prevent non-specific protein adsorption and particle aggregation in biological media, and to provide binding sites for targeting and therapeutic agents.

Magnetic nanoparticle-based drug delivery for cancer therapy.

Nanoparticles have belonged to various fields of biomedical research for quite some time. A promising site-directed application in the field of nanomedicine is drug targeting using magnetic nanoparticles which are directed at the target tissue by means of an external magnetic field. Materials most commonly used for magnetic drug delivery contain metal or metal oxide nanoparticles, such as superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs consist of an iron oxide core, often coated with organic materials such as fatty acids, polysaccharides or polymers to improve colloidal stability and to prevent separation into particles and carrier medium [1]. In general, magnetite and maghemite particles are those most commonly used in medicine and are, as a rule, well-tolerated. The magnetic properties of SPIONs allow the remote control of their accumulation by means of an external magnetic field. Conjugation of SPIONs with drugs, in combination with an external magnetic field to target the nanoparticles (so-called "magnetic drug targeting", MDT), has additionally emerged as a promising strategy of drug delivery. Magnetic nanoparticle-based drug delivery is a sophisticated overall concept and a multitude of magnetic delivery vehicles have been developed. Targeting mechanism-exploiting, tumor-specific attributes are becoming more and more sophisticated. The same is true for controlled-release strategies for the diseased site. As it is nearly impossible to record every magnetic nanoparticle system developed so far, this review summarizes interesting approaches which have recently emerged in the field of targeted drug delivery for cancer therapy based on magnetic nanoparticles.

Nano "Chocolate Waffle" for near-IR Responsive Drug Releasing System.

A majority of the photo-responsive drug-delivery systems that are currently being studied require a complicated synthesis method. Here, we prepare a near-infrared responsive, photothermally controllable, drug-delivery carrier by a simple mixing and extraction process without the incorporation of toxic chemicals. A blend of doxorubicin (DOX), an anticancer drug, and a phase-change material (PCM) are loaded onto the mesoporous structure of silica-coated graphene oxide (GO@MS) to form a waffle-like structure, which is confirmed by various physicochemical analyses. The cytotoxicity of DOX/PCM-loaded GO@MS (DOX/PCM-GO@MS) against HeLa cells is 50 times higher than that of free DOX, and this improved activity can be attributed to the photothermal effectiveness of GO@MS. Additionally, the cytotoxicity and uptake mechanism of the PCM-based material are analyzed by flow cytometry. Taken together, our results suggest an enormous potential for spatio-temporal control in photothermally responsive drug-delivery systems.

Ultrasound-Propelled Nanocups for Drug Delivery.

Ultrasound-induced bubble activity (cavitation) has been recently shown to actively transport and improve the distribution of therapeutic agents in tumors. However, existing cavitation-promoting agents are micron-sized and cannot sustain cavitation activity over prolonged time periods because they are rapidly destroyed upon ultrasound exposure. A novel ultrasound-responsive single-cavity polymeric nanoparticle (nanocup) capable of trapping and stabilizing gas against dissolution in the bloodstream is reported. Upon ultrasound exposure at frequencies and intensities achievable with existing diagnostic and therapeutic systems, nanocups initiate and sustain readily detectable cavitation activity for at least four times longer than existing microbubble constructs in an in vivo tumor model. As a proof-of-concept of their ability to enhance the delivery of unmodified therapeutics, intravenously injected nanocups are also found to improve the distribution of a freely circulating IgG mouse antibody when the tumor is exposed to ultrasound. Quantification of the delivery distance and concentration of both the nanocups and coadministered model therapeutic in an in vitro flow phantom shows that the ultrasound-propelled nanocups travel further than the model therapeutic, which is itself delivered to hundreds of microns from the vessel wall. Thus nanocups offer considerable potential for enhanced drug delivery and treatment monitoring in oncological and other biomedical applications.

Characterization and Insights Into the Nano Liposomal Magnetic Gene Vector Used for Cell Co-Transfection.

The development of magnetofection technology has brought a promising method for gene delivery. Here, we develop a novel liposomal magnetofection system, consisted of magnetic nanoparticle and liposome through molecular assembly, was applied to introduce double genes into porcin somatic cells with high co-transfection efficiency. The performace of liposomal magnetic gene nanovectors has been evaluated by involving the micro morphology, diameters distribution, zeta potentials and the capacity of loading DNA molecules. The assembly way among magnetic gene nanovectors and DNA molecules was investigated by atomic force microscopy. Liposomal nano magnetic gene vectors complexes displayed nanoscale assembly and formed compact "fishing-net structure" after combining with plasmid DNA, which is favorable to enhance the loading capacity of DNA molecules.

Design of Albumin-Coated Microbubbles Loaded With Polylactide Nanoparticles.

OBJECTIVES: A protocol was designed to produce albumin-coated microbubbles (MBs) loaded with functionalized polylactide (PLA) nanoparticles (NPs) for future drug delivery studies. METHODS: Microbubbles resulted from the sonication of 5% bovine serum albumin and 15% dextrose solution. Functionalized NPs were produced by mixing fluorescent PLA and PLA-polyethylene glycol-carboxylate conjugates. Nanoparticle-loaded MBs resulted from the covalent conjugation of functionalized NPs and MBs. Three NP/MB volume ratios (1/1, 1/10, and 1/100) and unloaded MBs were produced and compared. Statistical evaluations were based on quantitative analysis of 3 parameters at 4 time points (1, 4, 5, and 6 days post MB fabrication): MB diameter using a circle detection routine based on the Hough transform, MB number density using a hemocytometer, and NP-loading yield based on MB counts from fluorescence and light microscopic images. Loading capacity of the albumin-coated MBs was evaluated by fluorescence. RESULTS: Loaded MB sizes were stable over 6 days after production and were not significantly different from that of time-matched unloaded MBs. Number density evaluation showed that only 1/1 NP/MB volume ratio and unloaded MB number densities were stable over time, and that the 1/1 MB number density evaluated at each time point was not significantly different from that of unloaded MBs. The 1/10 and 1/100 NP/MB volume ratios had unstable number densities that were significantly different from that of unloaded MBs (P < .05). Fluorescence evaluation suggested that 1/1 MBs had a higher NP-loading yield than 1/10 and 1/100 MBs. Quantitative loading evaluation suggested that the 1/1 MBs had a loading capacity of 3700 NPs/MB. CONCLUSIONS: A protocol was developed to load albumin MBs with functionalized PLA NPs for further drug delivery studies. The 1/1 NP/MB volume ratio appeared to be the most efficient to produce stable loaded MBs with a loading capacity of 3700 NPs/MB.

Photo-controllable molecular hydrogels for drug delivery.

A photocleavable nitrobenzyl ester group was introduced in the backbone of self-assembling peptides using standard Fmoc-peptide systhesis. The nitrobenzyl ester group could be used as a cleavable linker to connect a gelator and a hydrophilic group. Photo-irradiation would lead to the generation of the molecular gelator and the formation of a molecular hydrogel. The nitrobenzyl ester group could also be used as one part of hydrophobic capping group for short peptides to produce molecular hydrogelators. In this case, photo-irradiation would lead to the release of hydrophobic anti-imflammatory drug of Naproxen and the gel-sol phase transition. The application of photocleavable group in molecular self-assembly would lead to photo-controllable self-assembly materials for controlled drug release, tissue engineering, and regenerative medicine.

Multifunctional polymeric nanocurcumin for cancer therapy.

Nanotechnology-based drug delivery systems have the potential to enhance the efficacy of poorly soluble systemic drugs. Curcumin, a yellow pigment isolated from turmeric, possesses a wide range of pharmacological activities, including anticancer effects. The anticancer potential of curcumin is mediated through the inhibition and modulation of several intracellular signaling pathways, as confirmed in various in vitro and in vivo cancer studies. However, clinical application of dietary curcumin for the treatment of cancer and other chronic diseases have been hindered by poor bioavailability, due to low systemic solubility as well as rapid metabolism and elimination from the body. Different techniques for sustained and efficient curcumin delivery, including nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles are the focus of this study. Previous studies have shown that nanocurcumin has improved anticancer effects as compared to normal curcumin formulations. Among nanoformulations, few composite nanosystems have the simultaneous properties of therapeutic activity and multifunctional nanoparticles as enhanced image contrast agents. We also address the challenges to the development of nanocurcumin delivery platforms by enhancing a steady aqueous dispersion state. Further studies are needed using preclinical and clinical cancer models to recommend nanocurcumin as a drug of choice for cancer therapy.

Fabrication and characterization of photoluminescent silicon nanoparticles for drug delivery applications.

Photoluminescent silicon nanoparticles containing camptothecin (CPT) were fabricated by using a CPT-derivatized porous silicon (PSi). PSi samples displaying red photoluminescence (PL) were prepared by an electrochemical etch of n-type silicon under the illumination with a 300 W tungsten filament bulb for the duration of etch. For the drug-derivatized PSi, luminescent PSi was oxidized and derivatized with CPT. Silicon nanoparticles containing CPT were obtained by fracturing of luminescent PSi with ultrasono-method. Optical characteristic of drug-derivatized silicon particles were investigated in aqueous buffer solution. The release of CPT was measured by UV-vis spectrometer. The intensity of fluorescence of the silicon nanoparticles was measured with a drug release. The concentration of released drug exhibited non-linear relationship with a release time.

Photocontrolled nanoparticles for on-demand release of proteins.

We describe here light-regulated swelling and degradation features of polymeric nanoparticles that are produced using an inverse microemulsion polymerization method. We demonstrate the phototriggered release characteristics of the nanoparticles by sequestering protein molecules and releasing them using light as a trigger. Furthermore, the intracellular translocation of the nanoparticles, along with its fluorescent protein payload, was achieved using a cell-penetrating peptide-based surface modification. We expect that the noncovalent encapsulation of proteins using nanoparticles and their photo triggered release using an external light would provide opportunities for achieving intracellular release of molecular therapeutics for on-demand requirements.

Ionizing radiation increases systemic nanoparticle tumor accumulation.

Nanoparticle-based therapies are currently being explored for both the imaging and treatment of primary and metastatic cancers. Effective nanoparticle cancer therapy requires significant accumulations of nanoparticles within the tumor environment. Various techniques have been used to improve tumor nanoparticle uptake and biodistribution. Most notable of these techniques is the use of tumor-specific peptide-conjugated nanoparticles and chemical modification of the nanoparticles with immune-evading polymers. Another strategy for improving the tumor uptake of the nanoparticles is modification of the tumor microenvironment with a goal of intensifying the enhanced permeability and retention effect inherent to solid tumors. We demonstrate a twofold increase in the tumor accumulation of systemically delivered iron oxide nanoparticles following a single 15-Gy radiation dose in a syngeneic mouse breast tumor model. This increase in nanoparticle tumor accumulation correlates with a radiation-induced decrease in tumor interstitial pressure and a subsequent increase in vascular permeability.

Photothermal release of small molecules from gold nanoparticles in live cells.

The ability of gold (Au) nanoparticles (NPs) to generate heat efficiently by absorbing visible and near-infrared (NIR) light holds great promise as a means to trigger chemical and biochemical events near the NPs. Previous demonstrations show that pulsed laser irradiation can selectively elicit the release of a fluorescent dye covalently anchored to the NP surface through a heat-labile linker without measurably changing the temperature of the surroundings. This article reports that the authors demonstrate the biological efficacy of this approach to photodelivery by showing that the decorated Au NPs are rapidly internalized by cells, are stable under physiological conditions, are nontoxic, and exhibit nonlethal photorelease following exposure to pulsed laser radiation. These observations, further supported by the versatility of our delivery motif, reaffirm the potential for further development of nonlethal photothermal therapeutics and their future relevance to such fields as gene therapy and stem-cell differentiation.

Enhancement of focused ultrasound with microbubbles on the treatments of anticancer nanodrug in mouse tumors.

Ultrasound sonication with microbubbles (MBs) has the potential to enhance the delivery of nanoparticles into the sonicated tumors. In this study, we investigated the feasibility of focused ultrasound (FUS) sonication with MBs to improve nanodrug delivery and tumor treatment. Tumor-bearing mice were first injected with MBs (SonoVue) intravenously, were then sonicated at the tumors with FUS sonication, and were finally injected with the PEGylated liposomal doxorubicin (DOX). The accumulation of DOX in tumors with time, the tumor growth responses for initial treated tumor size and DOX dosage, and the response for an additional sonication after DOX injection were studied. The results demonstrate that FUS sonication with MBs can significantly enhance DOX accumulation in the sonicated tumor at 24 hours after treatment. A significant hindrance to tumor growth is achieved for a small tumor with a low dose, whereas large tumors require a higher dose.