Electroactive membrane fusion-liposome for increased electron transfer to enhance radiodynamic therapy.

Dynamic therapies have potential in cancer treatments but have limitations in efficiency and penetration depth. Here a membrane-integrated liposome (MIL) is created to coat titanium dioxide (TiO2) nanoparticles to enhance electron transfer and increase radical production under low-dose X-ray irradiation. The exoelectrogenic Shewanella oneidensis MR-1 microorganism presents an innate capability for extracellular electron transfer (EET). An EET-mimicking photocatalytic system is created by coating the TiO2 nanoparticles with the MIL, which significantly enhances superoxide anions generation under low-dose (1 Gy) X-ray activation. The c-type cytochromes-constructed electron channel in the membrane mimics electron transfer to surrounding oxygen. Moreover, the hole transport in the valence band is also observed for water oxidation to produce hydroxyl radicals. The TiO2@MIL system is demonstrated against orthotopic liver tumours in vivo.

Safe magnetic resonance imaging on biocompatible nanoformulations.

Magnetic resonance imaging (MRI) holds promise for the early clinical diagnosis of various diseases, but most clinical MR techniques require the use of a contrast medium. Several nanomaterial (NM) mediated contrast agents (CAs) are widely used as T1- and T2-based MR contrast agents for clinical and non-clinical applications. Unfortunately, most NM-based CAs are toxic or non-biocompatible, restricting their practical/clinical applications. Therefore, the development of nontoxic and biocompatible CAs for clinical MRI diagnosis is highly desired. To this end, several biocompatible and biomimetic strategies have been developed to offer long blood circulation time, significant biocompatibility, in vivo biodistribution and high contrast ability for efficient imaging. However, detailed review reports on biocompatible NMs, specifically for MR imaging have not yet been summarized. Thus, in the present review we summarize  various surface coating strategies (such as polymers, proteins, cell membranes, etc.) to achieve biocompatible NPs, providing a detailed discussion of advances and future prospects for safe MRI imaging.

Near-Infrared Light-Triggered Drug Release from Ultraviolet- and Redox-Responsive Polymersome Encapsulated with Core-Shell Upconversion Nanoparticles for Cancer Therapy.

Combining upconversion nanoparticles (UCNPs) and UV-sensitive polymers to form a smart drug delivery system (DDS) is a promising strategy to circumvent drawbacks of direct UV excitation in clinical applications. This study tuned up core-shell UCNPs with a shell thickness of 6 nm and emission wavelength falling in the ultraviolet region at 350 nm under near-infrared (NIR) light irradiation at 980 nm. An amphiphilic block copolymer with UV-responsive o-nitrobenzyl ester (ONB) next to a glutathione (GSH)-responsive disulfide linkage was synthesized and formulated into a polymersome. Core-shell UCNPs and doxorubicin (DOX) were simultaneously encapsulated into the polymersome during double emulsion for DDS. The combination of NIR light-inducing photolysis of the ONB linkage and GSH cleaving the disulfide linkage enhanced DOX release for chemotherapy. From in vitro evaluation, the polymersome alone was nontoxic against three lung cancer cell lines, but the one loaded with core-shell UCNPs and DOX showed severe cell-killing effect under the assistance of a 980 nm diode laser. In vivo study in A549 tumor-bearing mice verified significant inhibition of tumor growth in mice treated with the polymersome containing core-shell UCNPs and DOX under 980 nm diode laser irradiation as compared with those without laser irradiation and those treated with free DOX. This intriguing nanomedicine of well-defined structures responsive to NIR light and reducing agents offers potential for smart DDS applications.

Multi-Stimuli-Responsive DOX Released from Magnetosome for Tumor Synergistic Theranostics.

BACKGROUND: To improve responses to tumor microenvironments for achieving a better therapeutic outcome in combination cancer therapy, poly(ε-caprolactone)-SS-poly(methacrylic acid) diblock copolymer (PCL-SS-PMAA) with a disulfide linkage between the hydrophobic and hydrophilic junctions was synthesized. MATERIALS AND METHODS: Repeating units of PCL and PMAA in PCL-SS-PMAA were controlled and formulated into polymersomes (PSPps). Truncated octahedral Fe3O4 nanoparticles (IONPs) were synthesized and encapsulated to produce IONPs-PSPps NPs and doxorubicin (DOX) was further loaded to produce IONPs-PSPps@DOX NPs for theranostic applications. RESULTS: IONPs-PSPps NPs remained a superparamagnetic property with a saturation magnetization value of 85 emu⋅gFe3O4 -1 and a relaxivity value of 180 mM-1⋅s-1. Upon exposure to an alternating magnetic field (AMF), IONPs-PSPps NPs increased temperature from 25°C to 54°C within 15 min. Among test groups, the cell apoptosis was greatest in the group exposed to IONPs-PSPps@DOX NPs with AMF and magnet assistance. In vivo T2-weighted magnetic resonance images of A549 tumor-bearing mice also showed highest contrast and greatest tumor suppression in the tumor with AMF and magnet assistance. CONCLUSION: IONPs-PSPps@DOX NPs are a potential theranostic agent having multifaceted applications involving magnetic targeting, MRI diagnosis, hyperthermia and chemotherapy.

Potential Orphan Drug Therapy of Intravesical Liposomal Onabotulinumtoxin-A for Ketamine-Induced Cystitis by Mucosal Protection and Anti-inflammation in a Rat Model.

Ketamine abusers may develop ulcerative cystitis and severe lower urinary tract symptoms, which is a medical dilemma. Recently, researchers have found the endemic of ketamine-induced cystitis worldwide. The intravesical administration of liposome-encapsulated onabotulinumtoxinA (Lipotoxin) might facilitate the healing of the damaged urothelium from liposomes, and reduce the urinary symptoms by onabotulinumtoxinA-induced chemo-denervation. Using female Sprague-Dawley rats, we investigated the effects of Lipotoxin on ketamine-induced cystitis. Functional magnetic resonance imaging, metabolic cage study, and cystometry were conducted. Paraffin-embedded sections were stained. The bladder mucosa and muscle proteins were assessed through Western blotting. We observed that repeated intravesical Lipotoxin instillation could improve suburothelial hemorrhage, recover the urothelial tight junction and adhesion proteins (zonula occludens-1 and E-cadherin), ensure less substance P in the urothelium, inhibit the overexpression of inflammatory mediators (IL-6, TNF-α, nuclear NF-κB, and COX-2) in the detrusor, suppress the upregulation of the mucosal TRPV1 and detrusor M2-mAChR, and ameliorate bladder overactivity in the ketamine-treated rats. These data reveal the mechanisms underlying the action of Lipotoxin in ketamine-induced cystitis of rats, which provide a basis of Lipotoxin for further treating ketamine-induced cystitis in humans.

Assembly of hybrid oligonucleotide modified gold (Au) and alloy nanoparticles building blocks.

The alloy-based hybrid materials with macroscopic network arrays were developed by AuAg/Au and AuAgPd/Au nanoparticle composites through oligonucleotides hybridization. AuAg/Au and AuAgPd/Au exhibited distinct organization. The morphology of AuAg/Au conjugation assembled mainly as compact aggregates while AuAgPd/Au hybrid conjugated into the loosen network assemblies. The dehybridization temperatures were studied as a function of molar ratio of alloy/Au. It was found that higher alloy/gold molar ratio led to stronger hybridization for alloy/gold composite, accompanied with increased melting temperature. These results could be interpreted in terms of more alloy nanoparticles bound to a Au particle when the molar ratio of alloy/gold increased. The thermal analysis also showed that AuAg/Au exhibited higher dehybridization temperature. A modified model describing the dehybridization probability of an intact Au/alloy aggregate was performed to support the dehybridization temperature increased with increasing alloy/Au molar ratio. As to more oligonucleotides carried by AuAg (4.9 +/- 1.9 nm) than by AuAgPd (4.4 +/- 1.5 nm) due to larger size in AuAg, the efficient hybridization could result in higher dehybridization temperature in AuAg/Au.

Ultrasound-Induced Reactive Oxygen Species Mediated Therapy and Imaging Using a Fenton Reaction Activable Polymersome.

Ultrasound techniques have been extensively employed for diagnostic purposes. Because of its features of low cost, easy access, and noninvasive real-time imaging, toward clinical practice it is highly anticipated to simply use diagnostic ultrasound to concurrently perform imaging and therapy. We report a H2O2-filled polymersome to display echogenic reflectivity and reactive oxygen species-mediated cancer therapy simply triggered by the microultrasound diagnostic system accompanied by MR imaging. Instead of filling common perfluorocarbons, the encapsulation of H2O2 in H2O2/Fe3O4-PLGA polymersome provides O2 as the echogenic source and (•)OH as the therapeutic element. On exposure to ultrasound, the polymersome can be easily disrupted to yield (•)OH through the Fenton reaction by reaction of H2O2 and Fe3O4. We showed that malignant tumors can be completely removed in a nonthermal process.

Characterization of aqueous dispersions of Fe(3)O(4) nanoparticles and their biomedical applications.

A newly developed non-polymer coated Fe(3)O(4) nanoparticles showing well-dispersion were synthesized using Fe(II) and Fe(III) salt chemical coprecipitation with tetramethylammonium hydroxide (N(CH(3))(4)OH) in an aqueous solution. Transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectrometer (FT-IR), X-ray photoelectron spectrometer (XPS) and superconducting quantum interference measurement device (SQUID) measurements were employed to investigate the iron oxide properties. The resulting iron oxide particles were manipulated to be as small as 9 nm diameter in size. Based on FT-IR and X-ray photoelectron spectrometer results, it is suggested that the surfaces of the magnetite (Fe(3)O(4)) particles are covered with hydroxide (-OH) groups incorporated with (CH(3))(4)N(+) through electrostatic interaction. The in vitro cytotoxicity test revealed that the magnetite particles exhibited excellent biocompatibility, suggesting that they may be further explored for biomedical applications. NMR measurements revealed significantly reduced water proton relaxation times T1 and T2. The MR images of the nanoparticles in water, serum, and whole blood were investigated using a 1.5 T clinical MR imager. Significant reduction of the background medium signal was achieved in the T2-weighted and the T2*-weighted sequence especially in the serum and whole blood. Combining the advantage of MRI signal contrast, the non-polymer-coated surface chemistry for distinct bioconjugation and the homogenous nanometer size for better controlled biodistribution, these preliminary experiments demonstrated the potential of the as-synthesized magnetite material in functional molecular imaging for biomedical research and clinical diagnosis.

Aqueous dispersions of magnetite nanoparticles with NH3+ surfaces for magnetic manipulations of biomolecules and MRI contrast agents.

In the current study, amine surface modified iron-oxide nanoparticles of 6 nm diameter without polymer coating were fabricated in an aqueous solution by organic acid modification as an adherent following chemical coprecipitation. Structure and the superparamagnetic property of magnetite nanoparticles were characterized by selected area electron diffraction (SAED) and superconducting quantum interference measurement device (SQUID). X-ray photoelectron spectrometer (XPS) and zeta potential measurements revealed cationic surface mostly decorated with terminal -NH(3)(+). This feature enables them to function as a magnetic carrier for nucleotides via electrostatic interaction. In addition, Fe(3)O(4)/trypsin conjugates with well-preserved functional activity was demonstrated. The nanoparticles displayed excellent in vitro biocompatibility. The NMR and the in vitro MRI measurements showed significantly reduced water proton relaxation times of both T(1) and T(2). Significantly reduced T(2) and T(2)*-weighted signal intensity were observed in a 1.5 T clinical MR imager. In vivo imaging contrast effect showed a fast and prolonged inverse contrast effect in the liver that lasted for more than 1 week. In addition, it was found that the spherical Fe(3)O(4) assembled as rod-like configuration through an aging process in aqueous solution at room temperature. Interestingly, TEM observation of the liver tissue revealed the rod-like shape but not the spherical-type nanoparticles being taken up by the Kupffer cells 120 h after tail vein infusion. Combining these results, we have demonstrated the potential applications of the newly synthesized magnetite nanoparticles in a broad spectrum of biomedical applications.

Au nanorod design as light-absorber in the first and second biological near-infrared windows for in vivo photothermal therapy.

Photothermal cancer therapy using near-infrared (NIR) laser radiation is an emerging treatment. In the NIR region, two biological transparency windows are located in 650-950 nm (first NIR window) and 1000-1350 nm (second NIR window) with optimal tissue transmission obtained from low scattering and energy absorption, thus providing maximum radiation penetration through tissue and minimizing autofluorescence. To date, intensive effort has resulted in the generation of various methods that can be used to shift the absorbance of nanomaterials to the 650-950 nm NIR regions for studying photoinduced therapy. However, NIR light absorbers smaller than 100 nm in the second NIR region have been scant. We report that a Au nanorod (NR) can be designed with a rod-in-shell (rattle-like) structure smaller than 100 nm that is tailored to be responsive to the first and second NIR windows, in which we can perform hyperthermia-based therapy. In vitro performance clearly displays high efficacy in the NIR photothermal destruction of cancer cells, showing large cell-damaged area beyond the laser-irradiated area. This marked phenomenon has made the rod-in-shell structure a promising hyperthermia agent for the in vivo photothermal ablation of solid tumors when activated using a continuous-wave 808 m (first NIR window) or a 1064 nm (second NIR window) diode laser. We tailored the UV-vis-NIR spectrum of the rod-in-shell structure by changing the gap distance between the Au NR core and the AuAg nanoshell, to evaluate the therapeutic effect of using a 1064 nm diode laser. Regarding the first NIR window with the use of an 808 nm diode laser, rod-in-shell particles exhibit a more effective anticancer efficacy in the laser ablation of solid tumors compared to Au NRs.

Synthesis of apolipoprotein B lipoparticles to deliver hydrophobic/amphiphilic materials.

To develop a drug delivery system (DDS), it is critical to address challenging tasks such as the delivery of hydrophobic and amphiphilic compounds, cell uptake, and the metabolic fate of the drug delivery carrier. Low-density lipoprotein (LDL) has been acknowledged as the human serum transporter of natively abundant lipoparticles such as cholesterol, triacylglycerides, and lipids. Apolipoprotein B (apo B) is the only protein contained in LDL, and possesses a binding moiety for the LDL receptor that can be internalized and degraded naturally by the cell. Therefore, synthetic/reconstituting apoB lipoparticle (rABL) could be an excellent delivery carrier for hydrophobic or amphiphilic materials. Here, we synthesized rABL in vitro, using full-length apoB through a five-step solvent exchange method, and addressed its potential as a DDS. Our rABL exhibited good biocompatibility when evaluated with cytotoxicity and cell metabolic response assays, and was stable during storage in phosphate-buffered saline at 4 °C for several months. Furthermore, hydrophobic superparamagnetic iron oxide nanoparticles (SPIONPs) and the anticancer drug M4N (tetra-O-methyl nordihydroguaiaretic acid), used as an imaging enhancer and lipophilic drug model, respectively, were incorporated into the rABL, leading to the formation of SPIONPs- and M4N- containing rABL (SPIO@rABL and M4N@rABL, respectively). Fourier transform infrared spectroscopy suggested that rABL has a similar composition to that of LDL, and successfully incorporated SPIONPs or M4N. SPIO@rABL presented significant hepatic contrast enhancement in T2-weighted magnetic resonance imaging in BALB/c mice, suggesting its potential application as a medical imaging contrast agent. M4N@rABL could reduce the viability of the cancer cell line A549. Interestingly, we developed solution-phase high-resolution transmission electron microscopy to observe both LDL and SPIO@rABL in the liquid state. In summary, our LDL-based DDS, rABL, has significant potential as a novel DDS for hydrophobic and amphiphilic materials, with good cell internalization properties and metabolicity.