Single-sized N-functionality graphene quantum dot in tunable dual-modality near infrared-I/II illumination detection and photodynamic therapy under multiphoton nonlinear excitation.

Doping sorted graphene quantum dots (GQDs) with heteroatoms and functionalizing them with amino acid could improve their radiative recombination and two-photon properties-including their excitation-wavelength-independent photoluminescence from the ultraviolet to the near-infrared-I (NIR-I) region, absorption, quantum yield, absolute cross section, lifetime, and radiative-to-nonradiative decay ratio-under two-photon excitation (TPE) at a low excitation energy and short photoexcitation duration, as determined using a self-made optical microscopy system with a femtosecond Ti-sapphire laser. Four types of sorted GQDs were investigated: undoped GQDs, nitrogen-doped GQDs (N-GQDs), amino-functionalized GQDs (amino-GQDs), and N-doped and amino-functionalized GQDs (amino-N-GQDs). Among them, the sorted amino-N-GQDs are effective as a two-photon photosensitizer and generate the highest quantity of reactive oxygen species for the elimination of multidrug-resistant cancer cells through two-photon photodynamic therapy (PDT). Larger amino-N-GQDs result in a greater number of C-N and N-functionalities, leading to a superior photochemical effect and more favorable intrinsic luminescence properties, making the dots effective contrast agents for tracking and localizing cancer cells during in-depth bioimaging in a three-dimensional biological environment under TPE in the NIR-II region. Overall, this study highlights the potential of large amino-N-GQDs as a material for future application to dual-modality two-photon PDT and biomedical imaging.

High-frequency ultrasound imaging for monitoring the function of meningeal lymphatic system in mice.

The meningeal lymphatic system drains the cerebrospinal fluid from the subarachnoid space to the cervical lymphatic system, primarily to the deep cervical lymph nodes. Perturbations of the meningeal lymphatic system have been linked to various neurologic disorders. A method to specifically monitor the flow of meningeal lymphatic system in real time is unavailable. In the present study, we adopted the high-frequency ultrasound (HFUS) with 1,1'diocatadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-loaded microbubble and FePt@PLGA nanoparticle contrast agents to evaluate the flow of the meningeal lymphatic system in 2-month-old mice. Statistical analysis was performed to identify changes of HFUS signals among the microbubbles, FePt@PLGA nanoparticles, and saline control groups. Approximately 15 min from the start of intracerebroventricular injection of contrast agents, their signals were evident at the deep cervical lymph nodes and lasted for at least 60 min. These signals were validated on the basis of the presence of DiI and Fe signals in the deep cervical lymph nodes. Ligation of afferent lymphatic vessels to the deep cervical lymph nodes eliminated the HFUS signals. Moreover, ablation of lymphatic vessels near the confluence of sinuses decreased the HFUS signals in the deep cervical lymph nodes. Glioma-bearing mice that exhibited reduced lymphatic vessel immunostaining signals near the confluence of sinuses had lowered HFUS signals in the deep cervical lymph nodes within 60 min. The proposed method provides a minimally invasive approach to monitor the qualities of the meningeal lymphatic system in real time as well as the progression of the meningeal lymphatic system in various brain disease animal models.

Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib's angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

The Surface Amine Group of Ultrasmall Magnetic Iron Oxide Nanoparticles Produce Analgesia in the Spinal Cord and Decrease Long-Term Potentiation.

Our previous studies have revealed the ultrasmall superparamagnetic iron oxide in the amine group USPIO-101 has an analgesic effect on inflammatory pain. Here, we further investigated its effect on the spinal cord and brain via electrophysiological and molecular methods. We used a mouse inflammatory pain model, induced by complete Freund's adjuvant (CFA), and measured pain thresholds via von Frey methods. We also investigated the effects of USPIO-101 via an extracellular electrophysiological recording at the spinal dorsal horn synapses and hippocampal Schaffer collateral-CA1 synapses, respectively. The mRNA expression of pro-inflammatory cytokines was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Our results showed intrathecal USPIO-101 produces similar analgesic behavior in mice with chronic inflammatory pain via intrathecal or intraplantar administration. The potentiated low-frequency stimulation-induced spinal cord long-term potentiation (LTP) at the spinal cord superficial dorsal horn synapses could decrease via USPIO-101 in mice with chronic inflammatory pain. However, the mRNA expression of cyclooxygenase-2 was enhanced with lipopolysaccharide (LPS) stimulation in microglial cells, and we also found USPIO-101 at 30 µg/mL could decrease the magnitude of hippocampal LTP. These findings revealed that intrathecal USPIO-101 presented an analgesia effect at the spinal cord level, but had neurotoxicity risk at higher doses.

Endogenous Conjugation of Biomimetic Dinitrosyl Iron Complex with Protein Vehicles for Oral Delivery of Nitric Oxide to Brain and Activation of Hippocampal Neurogenesis.

Nitric oxide (NO), a pro-neurogenic and antineuroinflammatory gasotransmitter, features the potential to develop a translational medicine against neuropathological conditions. Despite the extensive efforts made on the controlled delivery of therapeutic NO, however, an orally active NO prodrug for a treatment of chronic neuropathy was not reported yet. Inspired by the natural dinitrosyl iron unit (DNIU) [Fe(NO)2], in this study, a reversible and dynamic interaction between the biomimetic [(NO)2Fe(µ-SCH2CH2OH)2Fe(NO)2] (DNIC-1) and serum albumin (or gastrointestinal mucin) was explored to discover endogenous proteins as a vehicle for an oral delivery of NO to the brain after an oral administration of DNIC-1. On the basis of the in vitro and in vivo study, a rapid binding of DNIC-1 toward gastrointestinal mucin yielding the mucin-bound dinitrosyl iron complex (DNIC) discovers the mucoadhesive nature of DNIC-1. A reversible interconversion between mucin-bound DNIC and DNIC-1 facilitates the mucus-penetrating migration of DNIC-1 shielded in the gastrointestinal tract of the stomach and small intestine. Moreover, the NO-release reactivity of DNIC-1 induces the transient opening of the cellular tight junction and enhances its paracellular permeability across the intestinal epithelial barrier. During circulation in the bloodstream, a stoichiometric binding of DNIC-1 to the serum albumin, as another endogenous protein vehicle, stabilizes the DNIU [Fe(NO)2] for a subsequent transfer into the brain. With aging mice under a Western diet as a disease model for metabolic syndrome and cognitive impairment, an oral administration of DNIC-1 in a daily manner for 16 weeks activates the hippocampal neurogenesis and ameliorates the impaired cognitive ability. Taken together, these findings disclose the synergy between biomimetic DNIC-1 and endogenous protein vehicles for an oral delivery of therapeutic NO to the brain against chronic neuropathy.

Transferrin Modified GSH Sensitive Hyaluronic Acid Derivative Micelle to Deliver HSP90 Inhibitors to Enhance the Therapeutic Efficacy of Brain Cancers.

Herein, GSH-sensitive hyaluronic acid-poly(lactic-co-glycolic acid) (HA-SS-PLGA) was synthesized. Surface modification of PLGA with hyaluronic acid produced a highly stable micelle at physiological pH while a micelle was destabilized at a higher GSH level. Fluorescence microscopy results showed that rhodamine-encapsulated micelle was taken up by brain cancer cells, while competitive inhibition was observed in the presence of free HA and free transferrin. In vitro cytotoxicity results revealed that transferrin-targeted nanoformulated AUY922 (TF-NP-AUY922) shows higher cytotoxicity than either free AUY922 or non-targeted AUY922-loaded micelles (NP-AUY922). In comparison to the control groups, free AUY922, TF-NP-AUY922 or NP-AUY922 treatment revealed the upregulation of HSP70, while the expression of HSP90 client proteins was simultaneously depleted. In addition, the treatment group induced caspase-dependent PARP cleavage and the upregulation of p53 expression, which plays a key role in apoptosis of brain cancer cells. In vivo and ex vivo biodistribution studies showed that cypate-loaded micelle was taken up and accumulated in the tumor regions. Furthermore, in vivo therapeutic efficacy studies revealed that the AUY922-loaded micelle significantly suppressed tumor growth in comparison to the free AUY922, or control groups using tumor-bearing NOD-SCID mice. Moreover, biochemical index and histological analysis revealed synthesized micelle does not show any significant cytotoxicity to the selected major organs. Overall, a synthesized micelle is the best carrier for AUY922 to enhance the therapeutic efficiency of brain cancer.

Amino-Functionalized Nitrogen-Doped Graphene Quantum Dots for Efficient Enhancement of Two-Photon-Excitation Photodynamic Therapy: Functionalized Nitrogen as a Bactericidal and Contrast Agent.

BACKGROUND: Although graphene quantum dots (GQDs) have received considerable research attention for their applications in various fields, the use of GQDs, such as nitrogen-doped GQDs (N-GQDs) and amino-functionalized N-GQDs (amino-N-GQDs), as photosensitizers to facilitate photodynamic therapy (PDT) has received limited research intention. To address this research gap, this study prepared novel amino-N-GQDs and investigated their properties. METHODS: The amino-N-GQDs subjected to two-photon excitation (TPE) exhibited remarkable bactericidal capability in PDT. The bonding compositions of nitrogen and the amino-functionalized group played a critical role in their antimicrobial effects. RESULTS: Compared with amino-group-free N-GQDs and amino-N-free GQDs, the amino-N-GQDs generated a higher amount of reactive oxygen species, demonstrating their superior efficacy for two-photon PDT. Additionally, the intrinsic luminescence properties and high photostability of the amino-N-GQDs demonstrate their suitability as an effective two-photon contrast agent for tracking bacteria during two-photon biomedical imaging. CONCLUSION: The amino-N-GQD and their remarkable properties may provide an efficient alternative approach for observing and easily eliminating malignant microbes in the future.

Multiplexed Graphene Quantum Dots with Excitation-Wavelength-Independent Photoluminescence, as Two-Photon Probes, and in Ultraviolet-Near Infrared Bioimaging.

In this study, sorted nitrogen-doped graphene quantum dots were prepared and subsequently conjugated with polymers. The synthesized materials exhibited excitation-wavelength-independent photoluminescence emissions ranging from ultraviolet to near-infrared and were 0.9-8.4 nm in size. The materials also exhibited high-photoluminescence quantum yields and excellent two-photon properties. Therefore, in two-photon bioimaging the materials with different emission spectra can be effective two-photon contrast agents. Specific antibodies were used to label organelles in cancer cells and identify nuclear antigens, thereby enabling the simultaneous detection of four targets in cells at a single two-photon excitation wavelength. The sorted nitrogen-doped graphene quantum dot materials were determined to be considerably more advantageous than organic dyes in identifying multiplexed targets, and they can be effective probes in cellular imaging.

Amino-Functionalized Nitrogen-Doped Graphene-Quantum-Dot-Based Nanomaterials with Nitrogen and Amino-Functionalized Group Content Dependence for Highly Efficient Two-Photon Bioimaging.

We fabricated nanomaterials comprising amino-functionalized and nitrogen-doped graphene quantum dots (amino-N-GQDs) and investigated their photostability and intrinsic luminescence in the near-infrared spectrum to determine their suitability as contrast agents in two-photon imaging (TPI). We observed that amino-N-GQDs with a higher amount of bonded nitrogen and amino-functionalized groups (6.2%) exhibited superior two-photon properties to those with a lower amount of such nitrogen and groups (4.9%). These materials were conjugated with polymers containing sulfur (polystyrene sulfonate, PSS) and nitrogen atoms (polyethylenimine, PEI), forming amino-N-GQD-PSS-PEI specimens (amino-N-GQD-polymers). The polymers exhibited a high quantum yield, remarkable stability, and notable two-photon properties and generated no reactive oxygen species, rendering them excellent two-photon contrast agents for bioimaging. An antiepidermal growth factor receptor (AbEGFR) was used for labeling to increase specificity. Two-photon imaging (TPI) of amino-N-GQD (6.2%)-polymer-AbEGFR-treated A431 cancer cells revealed remarkable brightness, intensity, and signal-to-noise ratios for each observation at a two-photon excitation power of 16.9 nJ pixel-1 under 30 scans and a three-dimensional (3D) depth of 105 µm, indicating that amino-N-GQD (6.2%)-polymer-AbEGFR-treated cells can achieve two-photon luminescence with 71 times less power required for two-photon autofluorescence (1322.8 nJ pixel-1 with 500 scans) of similar intensity. This economy can minimize photodamage to cells, rendering amino-N-GQD-polymers suitable for noninvasive 3D bioimaging.

Targeted Delivery of Curcumin Rescues Endoplasmic Reticulum-Retained Mutant NOX2 Protein and Avoids Leukocyte Apoptosis.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by defects in the leukocyte NADP oxidase. We previously reported that sarcoplasmic/endoplasmic reticulum calcium pump (SERCA) inhibitors could be used to rescue mutant H338Y-gp91phox protein of a particular type of CGD with a CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T mutation on a Cybb knockout background and investigated the therapeutic effects of ER-targeted delivery of the SERCA inhibitor, curcumin, with poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs). We found that PLGA encapsulation improved the efficacy of curcumin as a SERCA inhibitor to induce ER calcium release. ER-targeting curcumin-loaded PLGA NPs reduced and delayed extracellular calcium entry and protected the cells from mitochondrial damage and apoptosis. In vivo studies showed that ER-targeting curcumin-loaded PLGA NPs treatment enhanced neutrophil gp91phox expression, ROS production and peritoneal bacterial clearance ability of the CybbC1024T transgenic Cybb -/- mice. Our findings indicate that ER-targeted delivery of curcumin not only rescues ER-retained H338Y-gp91phox protein, and hence leukocyte function, but also enhances the bioavailability and reduces cytotoxicity. Modulation of ER function by using organelle-targeted NPs may be a promising strategy to improve the therapeutic potential of curcumin as a treatment for CGD.

Morphine Induces Fibroblast Activation through Up-regulation of Connexin 43 Expression: Implication of Fibrosis in Wound Healing.

Morphine is the most effective drugs for attenuating various types of severe pain, but morphine abuse carries a high risk of systemic fibrosis. Our previous have indicated that systemic administration of morphine hinders angiogenesis and delays wound healing. Here we have explained the pathological mechanism underlying the effect of morphine on wound healing. To determine how morphine affects wound healing, we first created a wound in mice treated them with a combination of a low doses (5 mg/kg/day) and high doses (20 or 30 mg/kg/day) of morphine. An In vivo study revealed that high-dose morphine-induced abnormal myofibroblasts persist after the end of wound healing because of connexin 43 (Cx43) upregulation. High-dose morphine-induced Cx43 increased the expression levels of focal adhesion molecules, namely fibronectin and alpha-smooth muscle actin (α-SMA) through the activation of transforming growth factor (TGF)-ß1 signaling. In addition, we found that Cx43 contributed to TGF-ßRII/ Smad2/3 signaling for regulating the differentiation of fibroblasts into myofibroblasts during high-dose morphine exposure. In conclusion, the abnormal regulation of Cx43 by morphine may induce systemic fibrosis because of abnormal myofibroblast function.

Magnetic field distribution modulation of intrathecal delivered ketorolac iron-oxide nanoparticle conjugates produce excellent analgesia for chronic inflammatory pain.

BACKGROUND: Nanoparticles have become one of the most promising among the potential materials used for biomedical applications. However, few researchers have focused on their effects on analgesia. Despite the fact that various nanoparticles have been evaluated for drug delivery and MRI imaging contrast enhancement in clinical settings, no reports have investigated the in vivo synergy of ketorolac iron-oxide nanoparticle conjugates to improve the analgesic effect. METHODS: Ketorolac conjugated magnetic iron oxide nanoparticles (Keto-SPIO) were synthesized via two-stage additions of protective agents and chemical co-precipitation. ICR mice were used to develop inflammatory pain models induced by Complete Freund's adjuvant (CFA) injection in the hind paw. Different magnet field strengths and polarities were applied to the spinal cord after injecting Keto-SPIO into the theca space. Analgesia behavior was evaluated with the up-down method via von Frey microfilament measurement. Spinal cord tissues were harvested at the end analgesia time point upon induction of the inflammatory pain. The presence of the two cyclooxygenases (COX) in the spinal cord was examined via Western blotting to quantify the changes after intra-thecal Keto-SPIO administration. RESULTS: Intrathecal Keto-SPIO administration demonstrated a magnetic field-dependent analgesia effect in CFA pain model with a significant reduction in COX expression. CONCLUSIONS: Our results indicated that intrathecal administration of the Keto-SPIO combined magnet field modulated delivery significantly promoted an analgesia effect with suppression of COX in the mice inflammatory pain model.

Chemo-photothermal effects of doxorubicin/silica-carbon hollow spheres on liver cancer.

Chemo-photothermal therapy, which exhibits synergistic effects, is more effective than either of the treatments administered alone because of its superior ability to target and destroy cancer cells. An anti-cancer compound (doxorubicin, DOX) was embedded in silica-carbon hollow spheres (SCHSs) using heat and vacuum to integrate multi-therapeutic effects onto one platform and subsequently improve the anti-cancer efficacy. SCHSs were synthesized via a surface activation method and its highly porous surface enhanced the loading content of the desired drug. SCHSs are an infrared photothermal material that can destroy targeted cells by heating under near-infrared (NIR) laser illumination at 808 nm. NIR laser illumination also enhances DOX release from SCHSs to increase the anti-cancer efficiency of DOX-loaded SCHSs (DOX-SCHSs) in both two-dimensional and three-dimensional multicellular tumor spheroid cultures. SCHSs exhibited high heat-generating ability and pH-responsive drug delivery. In conclusion, this study demonstrated that DOX-SCHSs represent a potential tool for chemo-photothermal therapy due to its photothermal effects. Thus, our findings imply that the high cancer cell killing efficiency of DOX-SCHSs induced by NIR illumination can be used for the treatment of tumors.

Efficient two-photon luminescence for cellular imaging using biocompatible nitrogen-doped graphene quantum dots conjugated with polymers.

Nitrogen-doped graphene quantum dot (N-GQD) nanomaterials conjugated with polyethylenimine (PEI)-polystyrene sulfonate (PSS)-anti-epidermal growth factor receptor (AbEGFR) antibody (N-GQD-PEI-PSS-AbEGFR) demonstrated impressive two-photon properties and stability, signifying that they can serve as an effective two-photon contrast agent in two-photon bioimaging. Furthermore, they provided high intensity, brightness, and signal-to-noise ratios at an ultra-low two-photon excitation (TPE) power level in an observation extending to a deep, three-dimensional depth.

The analgesia efficiency of ultrasmall magnetic iron oxide nanoparticles in mice chronic inflammatory pain model.

Few studies have investigated the effects of iron oxide nanoparticles (NPs) on analgesia. We developed inflammatory pain models via complete Freund's adjuvant injection over the hind paw in CD1 mice. Various doses of magnetite (Fe3O4) NPs were injected into the paw. Analgesia behavior was checked with von Frey microfilament and thermal irradiation measurements. Paw skin tissues were harvested at the maximal analgesia time point. The presence of activated white cells (CD68, myeloperoxidase) and free radical (reactive oxygen species, ROS) production was also checked. Western blotting was used to identify the changes of ROS production enzymes. Fe3O4 NPs demonstrated a dose-related analgesia effect with significant reduction in inflammatory cells, pro-inflammatory markers, and ROS production in the lesion paw. ROS production enzyme expression also declined. The results indicate that local Fe3O4 NP administration induced significant analgesia via attenuation of inflammatory cell infiltration and pro-inflammatory signaling as well as scavenging of microenvironment free radicals in a mouse inflammatory pain model.

Synergistic Inhibition of Delayed Rectifier K+ and Voltage-Gated Na+ Currents by Artemisinin in Pituitary Tumor (GH3) Cells.

BACKGROUND: Artemisinin (ART) is an anti-malarial agent reported to influence endocrine function. METHODS: Effects of ART on ionic currents and action potentials (APs) in pituitary tumor (GH3) cells were evaluated by patch clamp techniques. RESULTS: ART inhibited the amplitude of delayed-rectifier K+ current (IK(DR)) in response to membrane depolarization and accelerated the process of current inactivation. It exerted an inhibitory effect on IK(DR) with an IC50 value of 11.2 µM and enhanced IK(DR) inactivation with a KD value of 14.7 µM. The steady-state inactivation curve of IK(DR) was shifted to hyperpolarization by 10 mV. Pretreatment of chlorotoxin (1 µM) or iloprost (100 nM) did not alter the magnitude of ART-induced inhibition of IK(DR) in GH3 cells. ART also decreased the peak amplitude of voltage-gated Na+ current (INa) with a concentration-dependent slowing in inactivation rate. Application of KMUP-1, an inhibitor of late INa, was effective at reversing ART-induced prolongation in inactivation time constant of INa. Under current-clamp recordings, ART alone reduced the amplitude of APs and prolonged the duration of APs. CONCLUSION: Under ART exposure, the inhibitory actions on both IK(DR) and INa could be a potential mechanisms through which this drug influences membrane excitability of endocrine or neuroendocrine cells appearing in vivo.

A Formulation Study of 5-Aminolevulinic Encapsulated in DPPC Liposomes in Melanoma Treatment.

Photodynamic therapy (PDT) is a widely used technique for epithelial skin cancer treatment. 5-aminolevulinic acid (5-ALA) is a drug currently used for PDT and is a hydrophilic molecule at its physiological pH, and this limits its capacity to cross the stratum corneum of skin. Since skin penetration is a key factor in the efficacy of topical 5-ALA-mediated PDT, numerous strategies have been proposed to improve skin penetration. Yet this problem is still ongoing. The results of a previous study showed a low rate of 5-ALA encapsulated in liposomes (5.7%) that were 400 nm in size. In the present study, we used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes as vehicles and tested their delivery efficacy of 5-ALA-medicated PDT both in vitro and in vivo. Our data shows that 5-ALA encapsulated in 0.1 or 0.5% DPPC liposomes (5-ALA/DPPC) had a better encapsulated rate (15~16%) and were smaller in size (84~89 nm). We found the 5-ALA/DPPC formulation reduced cell viability, mitochondria membrane potential, and enhanced intracellular ROS accumulation as compared to 5-ALA alone in melanoma cells. Furthermore, the 5-ALA/DPPC formulation also had better skin penetration ability as compared to the 5-ALA in our ex vivo data by assaying 5-ALA converted into protoporphyrin IX (PpIX) in the skin of the mice that were experimented on. In melanoma xenograft models, 5-ALA/DPPC enhanced PpIX accumulation only in tumor tissue but not normal skin. In conclusion, we found DPPC liposomes to be good carriers for 5-ALA delivery and believe that they may prove useful in 5-ALA-mediated PDT in the future.

Syntheses of Platinum-Sulindac Complexes and Their Nanoparticles as Targeted Anticancer Drugs.

Platinum(II)-sulindac complexes [{η2 -C5 H4 SN(O)}Pt(DMSO){O(C=O)Sulindac}], [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac}], [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac-succinimide}], and [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac-thymidine}] were synthesized that exhibited IC50 values of 2.9-4.8 µm against human oral cancer cells OECM1. The poly(lactic-co-glycolic acid) (PLGA) encapsulated [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac}] also showed cytotoxic activity although less potent than the pristine species.

Advances in noninvasive functional imaging of bone.

The demand for functional imaging in clinical medicine is comprehensive. Although the gold standard for the functional imaging of human bones in clinical settings is still radionuclide-based imaging modalities, nonionizing noninvasive imaging technology in small animals has greatly advanced in recent decades, especially the diffuse optical imaging to which Britton Chance made tremendous contributions. The evolution of imaging probes, instruments, and computation has facilitated exploration in the complicated biomedical research field by allowing longitudinal observation of molecular events in live cells and animals. These research-imaging tools are being used for clinical applications in various specialties, such as oncology, neuroscience, and dermatology. The Bone, a deeply located mineralized tissue, presents a challenge for noninvasive functional imaging in humans. Using nanoparticles (NP) with multiple favorable properties as bioimaging probes has provided orthopedics an opportunity to benefit from these noninvasive bone-imaging techniques. This review highlights the historical evolution of radionuclide-based imaging, computed tomography, positron emission tomography, and magnetic resonance imaging, diffuse optics-enabled in vivo technologies, vibrational spectroscopic imaging, and a greater potential for using NPs for biomedical imaging.

The anticancer properties of iron core-gold shell nanoparticles in colorectal cancer cells.

Previously, iron core-gold shell nanoparticles (Fe@Au) have been shown to possess cancer-preferential cytotoxicity in oral and colorectal cancer (CRC) cells. However, CRC cell lines are less sensitive to Fe@Au treatment when compared with oral cancer cell lines. In this research, Fe@Au are found to decrease the cell viability of CRC cell lines, including Caco-2, HT-29, and SW480, through growth inhibition rather than the induction of cell death. The cytotoxicity induced by Fe@Au in CRC cells uses different subcellular pathways to the mitochondria-mediated autophagy found in Fe@Au-treated oral cancer cells, OECM1. Interestingly, the Caco-2 cell line shows a similar response to OECM1 cells and is thus more sensitive to Fe@Au treatment than the other CRC cell lines studied. We have investigated the underlying cell resistance mechanisms of Fe@Au-treated CRC cells. The resistance of CRC cells to Fe@Au does not result from the total amount of Fe@Au internalized. Instead, the different amounts of Fe and Au internalized appear to determine the different response to treatment with Fe-only nanoparticles in Fe@Au-resistant CRC cells compared with the Fe@Au-sensitive OECM1 cells. The only moderately cytotoxic effect of Fe@Au nanoparticles on CRC cells, when compared to the highly sensitive OECM1 cells, appears to arise from the CRC cells' relative insensitivity to Fe, as is demonstrated by our Fe-only treatments. This is a surprising outcome, given that Fe has thus far been considered to be the "active" component of Fe@Au nanoparticles. Instead, we have found that the Au coatings, previously considered only as a passivating coating to protect the Fe cores from oxidation, significantly enhance the cytotoxicity of Fe@Au in certain CRC cells. Therefore, we conclude that both the Fe and Au in these core-shell nanoparticles are essential for the anticancer properties observed in CRC cells.