Targeted Paclitaxel by conjugation to iron oxide and gold nanoparticles.

The Fe(3)O(4) nanoparticles, tailored with maleimidyl 3-succinimidopropionate ligands, were conjugated with paclitaxel molecules that were attached with a poly(ethylene glycol) (PEG) spacer through a phosphodiester moiety at the (C-2')-OH position. The average number of paclitaxel molecules/nanoparticles was determined as 83. These nanoparticles liberated paclitaxel molecules upon exposure to phosphodiesterase.

Dental cement's biological and mechanical properties improved by ZnO nanospheres.

Metal oxide nanoparticles are a new class of important materials used in a wide variety of biomedical applications. Bulk zinc oxide (ZnO) particles have been used for temporal or permanent luting cement because of their excellent mechanical strength and biocompatibility. ZnO nanoparticles have distinct optical and antibacterial properties and a high surface-to-volume ratio. We investigated the mechanical and antibacterial properties of luting cement with different ratios of ZnO nanospheres. We showed that luting cement with 5% and 10% ZnO nanospheres was less soluble in low-pH (pH 3) artificial saliva. Antibacterial activity was 40% higher for Streptococcus mutans and 90% higher for Porphyromonas gingivalis when >10% (w/v) of the bulk particles were replaced with ZnO nanospheres in ZnO polycarboxylate cement. ZnO nanospheres were also biocompatible with mammalian cells. Additionally, the compressive strength was 1.2 times greater and the diametral tensile strength was 1.5 times greater for cements with 10% ZnO nanospheres than for conventional ZnO polycarboxylate cement. We propose a new method for improving dental luting cement by integrating it with ZnO nanospheres. This method simultaneously adds their greater antibacterial, mechanical, and acid resistance properties and retains an outstanding degree of biocompatibility.

The Clinical Implication of Vitamin D Nanomedicine for Peritoneal Dialysis-Related Peritoneal Damage.

PURPOSE: Vitamin D is a novel potential therapeutic agent for peritoneal dialysis (PD)-related peritoneal fibrosis, but it can induce hypercalcemia and vascular calcification, which limits its applicability. In this study, we create nanotechnology-based drug delivery systems to investigate its therapeutics and side effects. MATERIALS AND METHODS: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino-(polyethylene glycol)2000] (DSPE-PEG) and L-α-phosphatidylcholine (PC), which packages with 1α,25(OH)2D3, were used to construct vitamin D nanoliposomes. To confirm the function and safety of vitamin D nanoliposomes, peritoneal mesothelial cells were treated with TGF-ß1 and the reverse was attempted using vitamin D nanoliposomes. Antibodies (Ab) against the peritoneum-glycoprotein M6A (GPM6A) Ab were conjugated with vitamin D nanoliposomes. These particles were implanted into mice by intraperitoneal injection and the animals were monitored for the distribution and side effects induced by vitamin D. RESULTS: Vitamin D nanoliposomes were taken up by the mesothelial cells over time without cell toxicity and it also provided the same therapeutic effect in vitro. In vivo study, fluorescent imaging showed vitamin D nanoliposomes allow specific peritoneum target effect and also ameliorate vitamin D side effect. CONCLUSION: Nanoliposomes vitamin D delivery systems for the prevention of PD-related peritoneal damage may be a potential clinical strategy in the future.

Stabilizer-free poly(lactide-co-glycolide) nanoparticles for multimodal biomedical probes.

Apart from the reported PLGA submicro- and microspheres with broad size distribution, we have successfully developed a methodology using nanoprecipitation to prepare different sizes of PLGA nanoparticles with narrow size distributions. The newly developed PLGA nanoparticles could be readily modified with hydrophilic biomaterials on their surface and entrap hydrophobic drugs into their interiors. The encapsulation of FITC inside PLGA nanoparticles displayed a controlled release of drug system. The surfaces of the FITC entrapped PLGA nanoparticles were conjugated with quantum dots to serve as bimodal imaging probes. For nuclear transport, combination of nuclear localization signal (NLS) and PLGA nanoparticles, PLGA nanoparticles could successfully enter into HeLa cells nuclei. From tissue uptake results, PLGA nanoparticles had more uptaken by brain and liver than other tissues. The iron oxide nanoparticles-conjugated PLGA nanoparticle showed high efficiency of relaxivities r2 and could be used as the powerful magnetic resonance imaging (MRI) agents.

Resveratrol-loaded nanoparticles conjugated with kidney injury molecule-1 as a drug delivery system for potential use in chronic kidney disease.

AIM: We used resveratrol (Res)-loaded nanoparticles (Res NPs) as a novel method for improving the pharmacokinetic properties of Res and analyzed the effect of Res NPs in chronic kidney disease (CKD). MATERIALS & METHODS: We coupled anti-kidney injury molecule-1 antibodies to Res NPs and analyzed safety and efficacy. RESULTS: Res NPs had low toxicity and induced autophagy. Res NPs inhibited the NLRP3 inflammasome and IL-1ß secretion. Higher NLRP3 expression levels were observed in peripheral blood monocytic cells of CKD patients than healthy individuals. Treatment with kidney injury molecule-1-Res NPs significantly reduced creatinine and protected against tubulointerstitial injury in a murine model of CKD. CONCLUSION: Res NPs through NLRP3 inflammasome attenuation and autophagy induction may be as a strategy to prevent CKD.

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.

Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction.

Recent developments in nanotechnology have created considerable potential toward diagnosis and cancer therapy. In contrast, the use of nanotechnology in tissue repair or regeneration remains largely unexplored. We hypothesized that intramyocardial injection of insulin-like growth factor (IGF)-1-complexed poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (PLGA-IGF-1 NPs) increases IGF-1 retention, induces Akt phosphorylation, and provides early cardioprotection after acute myocardial infarction (MI). We synthesized 3 different sizes of PLGA particles (60 nm, 200 nm, and 1 µm) which were complexed with IGF-1 using electrostatic force to preserve the biological function of IGF-1. Afterward, we injected PLGA-IGF-1 NPs in the heart after MI directly. Compared with the other two larger particles, the 60 nm-sized PLGA-IGF-1 NPs carried more IGF-1 and induced more Akt phosphorylation in cultured cardiomyocytes. PLGA-IGF-1 NPs also prolonged Akt activation in cardiomyocytes up to 24h and prevented cardiomyocyte apoptosis induced by doxorubicin in a dose-dependent manner. In vivo, PLGA-IGF-1 NP treatment significantly retained more IGF-1 in the myocardium than the IGF-1 alone treatment at 2, 6, 8, and 24 h. Akt phosphorylation was detected in cardiomyocytes 24h post-MI only in hearts receiving PLGA-IGF-1 NP treatment, but not in hearts receiving injection of PBS, IGF-1 or PLGA NPs. Importantly, a single intramyocardial injection of PLGA-IGF-1 NPs was sufficient to prevent cardiomyocyte apoptosis (P<0.001), reduce infarct size (P<0.05), and improve left ventricle ejection fraction (P<0.01) 21 days after experimental MI in mice. Our results not only demonstrate the potential of nanoparticle-based technology as a new approach to treating MI, but also have significant implications for translation of this technology into clinical therapy for ischemic cardiovascular diseases.

PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells.

BACKGROUND: Effective cancer chemotherapy remains an important issue in cancer treatment, and signal transducer and activator of transcription-3 (Stat3) activation leads to cellular resistance of anticancer agents. Polymers are ideal vectors to carry both chemotherapeutics and small interfering ribonucleic acid (siRNA) to enhance antitumor efficacy. In this paper, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with paclitaxel and Stat3 siRNA were successfully synthesized, and their applications in cancer cells were investigated. METHODS: Firstly, paclitaxel was enclosed by PLGA nanoparticles through solvent evaporation. They were then coated with cationic polyethylenimine polymer (PLGA-PEI-TAX), enabling it to carry Stat3 siRNA on its surface through electrostatic interactions (PLGA-PEI-TAX-S3SI). The size, zeta potential, deliver efficacy, and release profile of the PLGA nanocomplexes were characterized in vitro. The cellular uptake, intracellular nanoparticle trajectory, and subsequent cellular events were evaluated after treatment with various PLGA nanocomplexes in human lung cancer A549 cells and A549-derived paclitaxel-resistant A549/T12 cell lines with α-tubulin mutation. RESULTS: A549 and A549/T12 cells contain constitutively activated Stat3, and silencing Stat3 by siRNA made both cancer cells more sensitive to paclitaxel. Therefore, PLGA-PEI-TAX-S3SI was synthesized to test its therapeutic role in A549 and A549/T12 cells. Transmission electron microscopy showed the size of PLGA-PEI-TAX-S3SI to be around 250 nm. PLGA-PEI nanoparticles were nontoxic. PLGA-PEI-TAX was taken up by A549 and A549/T12 cells more than free paclitaxel, and they induced more condensed microtubule bundles and had higher cytotoxicity in these cancer cells. Moreover, the yellowish fluorescence observed in the cytoplasm of the cancer cells indicates that the PLGA-PEI nanoparticles were still simultaneously delivering Oregon Green paclitaxel and cyanine-5-labeled Stat3 siRNA 3 hours after treatment. Furthermore, after the cancer cells were incubated with the synthesized PLGA nanocomplexes, PLGA-PEI-TAX-S3SI suppressed Stat3 expression and induced more cellular apoptosis in A549 and A549/T12 cells compared with PLGA-PEI-TAX. CONCLUSION: The PLGA-PEI-TAX-S3SI complex provides a new therapeutic strategy to control cancer cell growth.