Principles and applications of nanomaterial-based hyperthermia in cancer therapy.

Over the past few decades, hyperthermia therapy (HTT) has become one of the most promising strategies to treat cancer. HTT has been applied with nanotechnology to overcome drawbacks such as non-selectivity and invasiveness and to maximize therapeutic efficacy. The high temperature of HTT induces protein denaturation that leads to apoptosis or necrosis. It can also enhance the effects of other cancer therapies because heat-damaged tissues reduce radioresistance and help accumulate anticancer drugs. Gold nanoparticles and superparamagnetic iron oxide with different energy sources are commonly used as hyperthermia agents. New types of nanoparticles such as those whose surface is coated with several polymers and those modified with targeting moieties have been studied as novel HTT agents. In this review, we introduce principles and applications of nanotechnology-based HTT using gold nanoparticles and superparamagnetic iron oxide.

Co-delivery of D-(KLAKLAK)2 Peptide and Chlorin e6 using a Liposomal Complex for Synergistic Cancer Therapy.

Nanotechnology-based photo-chemo combination therapy has been extensively investigated to improve therapeutic outcomes in anticancer treatment. Specifically, with the help of a singlet oxygen generated by the photosensitizer, the endocytosed nanoparticles are allowed to escape from the endosomal compartment, which is currently an obstacle in nanotechnology-based anticancer therapy. In this study, a liposomal complex system (Lipo (Pep, Ce6)), composed of a chlorin e6-conjugated di-block copolymer (PEG-PLL(-g-Ce6)) and a D-(KLAKLAK)2 peptide loading liposome (Lipo (Pep)), was developed and evaluated for its anticancer activity. Due to the membrane lytic ability of the D-(KLAKLAK)2 peptide and the membrane disruptive effect of the singlet oxygen generated from chlorin e6, Lipo (Pep, Ce6) accelerated the disruption of the endosomal compartment, and exhibited strong synergistic anticancer activity in vitro. The prepared liposomal complex system could potentially maximize the efficacy of the nanotechnology-based photo-chemo combination therapy, and can be regarded as a novel, versatile strategy in advanced tumor therapy.

A nano-sized blending system comprising identical triblock copolymers with different hydrophobicity for fabrication of an anticancer drug nanovehicle with high stability and solubilizing capacity.

Background: A very common and simple method (known as the blending method) to formulate drug delivery systems with required properties is to physically mix amphiphilic block copolymers with different hydrophobicity. In addition to its simplicity, this blending strategy could help avoid the time and effort involved in the synthesis of block copolymers with the desired structure required for specific drug formulations. Purpose: We used the blending strategy to design a system that could overcome the problem of high hydrophobicity and be a good candidate for drug product development using PEG-PLA-PEG triblock copolymers. Methods: Two types of PEG-PLA-PEG triblock copolymers with similar (long) PLA molecular weights (MWs) and different PEG MWs were synthesized. The micellar formulations were prepared by blending the two block copolymers in various ratios. The size and stability of the blending systems were subsequently investigated to optimize the formulations for further studies. The loading properties of doxorubicin or paclitaxel into the optimized blending system were compared to that in mono systems (systems composed of only a single type of triblock copolymer). In vitro and in vivo anti-cancer effects of the preparations were evaluated to assess the use of the blending system as an optimal nanomedicine platform for insoluble anticancer agents. Results: The blending system (B20 system) with an optimized ratio of the triblock copolymers overcame the drawbacks of mono systems. Drug uptake from the drug-loaded B20 system and its anticancer effects against KB cells were superior compared to those of free drugs (doxorubicin hydrochloride and free paclitaxel). In particular, doxorubicin-loaded B20 resulted in extensive doxorubicin accumulation in tumor tissues and significantly higher in vivo anti-cancer effects compared to free doxorubicin. Conclusion: The blending system reported here could be a potential nanoplatform for drug delivery due to its simplicity and efficiency for pharmaceutical application.

Influence of Staphylococcus aureus on Outcomes after Valvular Surgery for Infective Endocarditis.

BACKGROUND: As Staphylococcus aureus (SA) remains one of the leading cause of infective endocarditis (IE), this study evaluates whether S. aureus is associated with more severe infections or worsened outcomes compared to non-S. aureus (NSA) organisms. METHODS: All patients undergoing valve surgery for bacterial IE between 1995 and 2013 at our institution were included in this study (n = 323). Clinical data were retrospectively collected from the chart review. Patients were stratified according to the causative organism; SA (n = 85) and NSA (n = 238). Propensity score matched pairs (n = 64) of SA versus NSA were used in the analysis. RESULTS: SA patients presented with more severe IE compared to NSA patients, with higher rates of preoperative vascular complications, preoperative septic shock, preoperative embolic events, preoperative stroke, and annular abscess. Among the matched pairs, there were no significant differences in 30-day (9.4% SA vs. 7.8% NSA, OR = 1.20, p = 0.76) or 1-year mortality (20.3% SA vs. 14.1% NSA, OR = 1.57, p = 0.35) groups, though late survival was significantly worse in SA patients. There was also no significant difference in postoperative morbidity between the two matched groups. CONCLUSIONS: SA IE is associated with a more severe clinical presentation than IE caused by other organisms. Despite the clearly increased preoperative risk, valvular surgery may benefit SA IE patients by moderating the post-operative mortality and morbidity.

Early Operation for Endocarditis Complicated by Preoperative Cerebral Emboli Is Not Associated With Worsened Outcomes.

BACKGROUND: Valve operations for patients presenting with infective endocarditis (IE) complicated by stroke are thought to carry elevated risk of postoperative complications. Our aim was to compare outcomes of IE patients who undergo surgical intervention early after diagnosis of septic cerebral emboli with outcomes of patients without preoperative emboli. METHODS: All patients undergoing operations for left-sided IE between 1996 and 2013 at our institution were reviewed. Patients undergoing operations more than 14 days after embolic stroke diagnosis (n = 11) and those with purely hemorrhagic lesions (n = 7) were excluded from the analysis. The study included 308 patients who were stratified according to the presence (STR, n = 54) or absence of a preoperative septic cerebral embolus (NoSTR, n = 254). Primary outcomes of interest were the development of a new postoperative stroke and 30-day mortality. RESULTS: Mean time to surgical intervention from stroke onset was 6.0 ± 4.1 days. Staphylococcus aureus (39% STR vs 21% NoSTR, p = 0.004) infection and annular abscess at operation (52% STR vs 27% NoSTR, p < 0.001) were more prevalent in STR patients. There was no significant difference in 30-day mortality (9.3% STR vs 7.1% NoSTR, p = 0.57) or in the rate of new postoperative stroke (5 [9.4%] STR vs 12 [4.7%] NoSTR, p = 0.19) between groups. In addition, there was no difference in 10-year survival between groups (log-rank p = 0.74). CONCLUSIONS: Early surgical intervention in patients with IE complicated by preoperative septic cerebral emboli does not lead to significantly worse postoperative outcomes. Early surgical intervention for IE after embolic stroke warrants consideration, particularly in patients with high-risk features such as S aureus or annular abscess, or both.

Molecular alterations in the hippocampus after experimental subarachnoid hemorrhage.

Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro-Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation.

Expression patterns of Ephs and ephrins throughout retinotectal development in Xenopus laevis.

The Eph family of receptor tyrosine kinases and their ligands the ephrins play an essential role in the targeting of retinal ganglion cell axons to topographically correct locations in the optic tectum during visual system development. The African claw-toed frog Xenopus laevis is a popular animal model for the study of retinotectal development because of its amenability to live imaging and electrophysiology. Its visual system undergoes protracted growth continuing beyond metamorphosis, yet little is known about ephrin and Eph expression patterns beyond stage 39 when retinal axons first arrive in the tectum. We used alkaline phosphatase fusion proteins of EphA3, ephrin-A5, EphB2, and ephrin-B1 as affinity probes to reveal the expression patterns of ephrin-As, EphAs, ephrin-Bs, and EphBs, respectively. Analysis of brains from stage 40 to adult frog revealed that ephrins and Eph receptors are expressed throughout development. As observed in other species, staining for ephrin-As displayed a high caudal to low rostral expression pattern across the tectum, roughly complementary to the expression of EphAs. In contrast with the prevailing model, EphBs were found to be expressed in the tectum in a high dorsal to low ventral gradient in young animals. In animals with induced binocular tectal innervation, ocular dominance bands of alternating input from the two eyes formed in the tectum; however, ephrin-A and EphA expression patterns were unmodulated and similar to those in normal frogs, confirming that the segregation of axons into eye-specific stripes is not the consequence of a respecification of molecular guidance cues in the tectum.