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The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread (CPT-DNA-NT), mediated by scavenger receptors into HeLa cells. DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT. Atomic force microscopy (AFM) characterization of the DNA-NT showed uniformity in the structure with a diameter of 50–150 nm and length of 300–600 nm. The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis, as large the molecular-weight (polymeric) DNA-NT did not split into constituting strands under applied current and voltage. The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration (512 nM) with a viability of 92% as evidence of its biocompatibility for drug delivery. MTT assay showed superior cytotoxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT internalization. The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT (from DNA-NT), as illustrated in confocal images. Therefore, in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis (72.7%) with CPT-DNA-NT (compared to free CPT; 64.4%). CPT-DNA-NT, being poly-anionic, showed enhanced endocytosis via scavenger receptors. [Display omitted] • Development of effective and safe vehicles for cytotoxic drug delivery into targeted tumor cells remained a significant challenge in the modern medicine. • Circular DNA nanotechnology is a tool to design architects with stiffer topology and geometry based on Watson-Crick base pairing for potential applications including drug delivery. • Cisplatin is loaded in DNA Nanothread (DNA NT) to achieve enhanced cytotoxicity and CPT-DNA-NT shows controlled/prolonged CPT release and enhanced cytotoxic activity through scavenger receptors facilitated endocytosis, making this a promising candidate for anticancer therapy. [ABSTRACT FROM AUTHOR]

In recent years, indocyanine green (ICG) encapsulated in different kinds of nano-carriers have been developed to overcome its short lifetime in vivo and non-selectivity in cancer cells. However, these nanoparticles are still easily recognized and captured by the reticuloendothelial system (RES) and the low singlet oxygen quantum (0.08) of ICG inevitably leads to a limited efficacy of phototherapy. To overcome these limitations, a novel oxygen self-enriched biomimetic red blood cell (RBC) was developed by cloaking albumin nanoparticles which contained ICG and perfluorocarbon (PFC) with RBC membranes. Due to the high oxygen capacity of PFC, the oxygen self-enriched nanoparticles can enhance photodynamic therapy (PDT) by generating more singlet oxygen ( 1 O 2 ). After successfully coated RBC membranes onto nanoparticles, the novel oxygen self-enriched biomimetic RBCs remained the characteristics of photothermal therapy (PTT) and enhanced PDT in vitro . Importantly, it can effectively reduce immune clearance in macrophage cells (RAW264.7) and significantly prolong blood circulation time, achieving high accumulation in tumor. In addition, the tumor growth was effectively inhibited after intravenous injection to tumor-bearing mice. Altogether, this oxygen self-enriched RBCs with long circulation time and high oxygen capacity as natural RBCs provide a new strategy to design biomimetic nano-system for clinical cancer phototherapy treatment. Statement of Significance Near-infrared (NIR) dyes encapsulated in nanocarriers have been achieved great interest in cancer phototherapy treatment. However, the low singlet oxygen ( 1 O 2 ) quantum of NIR dyes and short circulation time of nanoparticles lead to unsatisfactory efficacy, limiting their applications. In this study, a novel oxygen self-enriched biomimetic red blood cell (bio-RBC) was developed to produce fluorescence, imaging-guided for photothermal therapy (PTT) and enhanced photodynamic therapy (PDT). It was composed of RBC membranes and albumin nanoparticles (IPH) which contained indocyanine green (ICG) and perfluorocarbon (PFC). After RBC membranes successfully being coated on nanoparticles, bio-RBC can effectively reduce immune clearance in macrophage cells and achieve longer circulation time in vivo , due to the protein retention in RBC membranes. In addition, PFC with high oxygen capacity can provide more oxygen to generate more 1 O 2 and dissolve 1 O 2 to enhance its life-time, enhancing PDT cancer treatment. In summary, the novel bio-RBC with longer lifetime and higher oxygen capacity as natural RBCs can significantly accumulate on tumor and effectively enhance phototherapy. It could serve as a novel strategy to overcome the problems of NIR dyes encapsulated nanoparticles, promising for future clinical application. [ABSTRACT FROM AUTHOR]

Bladder cancer is one of the most frequent malignancies in the urinary system. Radical cystectomy is inevitable when bladder cancer progresses to a muscle-invasive disease. However, cystectomy still causes a high risk of death and a low quality of life (such as ureter-abdomen ostomy, uroclepsia for ileal-colon neobladder). Therefore, more effective treatments as well as bladder preservation are needed. We developed self-assembled tumor-targeting hyaluronic acid-IR-780 nanoparticles for photothermal ablation in over-expressing CD44 (the receptor for HA) bladder cancer, which show high tumor selectivity, high treatment efficacy, good bioavailability, and excellent biocompatibility. The nanoparticles demonstrated a stable spherical nanostructure in aqueous conditions with good mono-dispersity, and their average size was 171.3 ± 9.14 nm. The nanoparticles can be degraded by hyaluronidase when it is over-expressed in bladder cells; therefore, they appear to have a hyaluronidase-responsive “OFF/ON” behavior of a fluorescence signal. HA-IR-780 NPs also showed high photothermal efficiency; 2.5, 5, 10 and 20 μg/mL of NPs had a maximum temperature increase of 11.2 ± 0.66 °C, 18.6 ± 0.75 °C, 26.8 ± 1.11 °C and 32.3 ± 1.42 °C. The in vitro cell viability showed that MB-49 cells could be efficiently ablated by combining HA-IR-780 NPs with 808 nm laser irradiation. Then, in vivo biodistribution showed the HA-IR-780 NPs are targeted for accumulation in bladder cancer cells but have negligible accumulation in normal bladder wall. The photothermal therapeutic efficacy of HA-IR-780 NPs in the orthotopic bladder cancer model showed tumors treated with NPs had a maximum temperature of 48.1 ± 1.81 °C after 6 min of laser irradiation. The tumor volume was approximately 65–75 mm 3 prior to treatment. After 12 days, the tumor sizes for the PBS, PBS plus laser irradiation and HA-IR-780 NPs-treated groups were 784.75 mm 3 , 707.5 mm 3 , and 711.37 mm 3 , respectively. None of the tumors in the HA-IR-780 NPs plus laser irradiation-treated group were visible to the naked eye. A toxicity study showed HA-IR-780 NPs (2.5–20 mg/kg, i.v.) were nontoxic and safe for in vivo applications. HA-IR-780 nanoparticles address current clinical challenges, treating locally aggressive lesions and preserving the bladder. They have enormous potential to improve the bladder cancer treatment strategies in clinic. Statement of Significance 1) Bladder cancer is one of the most frequent malignancies in the urinary system. Radical cystectomy is inevitable while bladder cancer progress to muscle-invasive disease. 2) We developed self-assembled tumor-targeting hyaluronic acid-IR-780 nanoparticles for photothermal ablation in over-expressing CD44 (the receptor for HA) bladder cancer. 3) Photothermal therapeutic efficacy of HA-IR-780 NPs in orthotopic bladder cancer model showed tumors were completely ablated. 4) HA-IR-780 nanoparticles address current clinical challenges, treating locally aggressive lesions as well as for bladder preservation. [ABSTRACT FROM AUTHOR]

Application of photodynamic therapy for treating cancers has been restrained by suboptimal delivery of photosensitizers to cancer cells. Nanoparticle (NP)-based delivery has become an important strategy to improve tumor delivery of photosensitizers; however, the success is still limited. One problem for many NPs is poor penetration into tumors, and thus the photokilling is not complete. We aimed to use chemical conjugation method to engineer small NPs for superior cancer cell uptake and tumor penetration. Thus, Chlorin e6 (Ce6) was covalently conjugated to PAMAM dendrimer (generation 7.0) that was also modified by tumor-targeting RGD peptide. With multiple Ce6 molecules in a single nanoconjugate molecule, the resultant targeted nanoconjugates showed uniform and monodispersed size distribution with a diameter of 28 nm. The singlet oxygen generation efficiency and fluorescence intensity of the nanoconjugates in aqueous media were significantly higher than free Ce6. Targeted nanoconjugates demonstrated approximately 16-fold enhancement in receptor-specific cellular delivery of Ce6 into integrin-expressing A375 cells compared to free Ce6 and thus were able to cause massive cell killing at low nanomolar concentrations under photo-irradiation. In contrast, they did not cause significant toxicity up to 2 μM in dark. Due to their small size, the targeted nanoconjugates could penetrate deeply into tumor spheroids and produced strong photo-toxicity in this 3-D tumor model. As a result of their great cellular delivery, small size, and lack of dark cytotoxicity, the nanoconjugates may provide an effective tool for targeted photodynamic therapy of solid tumors. [ABSTRACT FROM AUTHOR]

It has been reported that IR780 iodide, a near-infrared dye, can be applied for cancer imaging, photodynamic therapy (PDT) and photothermal therapy (PTT). However, the hydrophobicity and toxicity of IR780 severely limit its further clinical applications. In this study, human serum albumin was used to load IR780 to form nanoparticles (HSA-IR780 NPs) by protein self-assembly. Compared to free IR-780, the solubility of HSA-IR780 NPs was greatly increased (1000-fold) while the toxicity was decreased (from 2.5 mg kg −1 to 25 mg kg −1 ). Moreover, both PTT and PDT could be observed in HSA-IR780 NPs, as determined by increased temperature and enhanced generation of singlet oxygen after laser irradiation at a wavelength of 808 nm. In vivo studies also showed a great tumor inhibition by the injection of HSA-IR780 NPs into tumor-bearing mice. Therefore, HSA-IR780 NPs may serve as a promising substitute for IR780 in further clinical PDT and PTT. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent hepatic disease characterized as lipid accumulation, yet without any approved drug. And development of therapeutic molecules is obstructed by low efficiency and organ toxicity. Herein, we develop a long-term, low-toxic and liver-selected nano candidate, nabCK, to alleviate NAFLD. NabCK is simply composed by natural compound ginsenoside compound K (CK) and albumin. As a major metabolite of ginseng, ginsenoside CK has excellently modulating functions for lipid metabolism, but accompanied by an extremely poor bioavailability <1%. Albumin is a key lipid carrier secreted and metabolized by livers. Thereby, it can improve solubility and liver-localization of CK. In adipocytes and hepatocytes, nabCK prevents lipid deposition and eliminates lipid droplets. Transcriptomic analysis reveals that nabCK rectifies various pathways that involved in steatosis development, including lipid absorption, lipid export, fatty acid biosynthesis, lipid storage and inflammation. All these pathways are modulated by mTOR, the pivotal feedback sensor that is hyperactive in NAFLD. NabCK suppresses mTOR activation to restores lipid homeostasis. In high-fat diet (HFD) induced NAFLD mice, nabCK retards development of steatosis and fibrosis, coupling a protective effect on cardiac tissues from lipotoxicity. Together, nabCK is a safe and potent candidate to offer benefits for NAFLD treatment. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is the combination of light and photosensitizer (PS) to kill tumor cells, which has the potential to meet many currently unmet medical needs. However, the whole body distribution and activatability by sunlight of photosensitizers to induce skin photosensitivity have limited the extensive clinic application of PDT. Herein, a novel strategy is presented to overcome these limitations by using a hydrophobic Near-infared (NIR) dye IR-780 iodide (IR780) to induce the self-assembly of albumin-PS conjugates, as a switchable PDT (Switch-PDT) agent. The PDT effect of PS is effectively inhibited by IR780 and recovered by NIR light irradiation in vitro . This quench/recovery strategy dose not sacrifice the anti-tumor ability in vivo , and the combined PDT and PTT (photothermal) effect contributes a very effective tumor inhibition rate of 100%. More importantly, the PDT effect is significantly suppressed after intravenous administration in mice or subcutaneous administration in rabbits as exhibited by the negligible skin response, while traditional PDT agent arouses severe skin erythema and edema. To the best of our knowledge, the switchable PDT is the first time to be used to eradicate the skin photosensitization of PS in vivo . [ABSTRACT FROM AUTHOR]

Protein-based nanoparticles hold great promise in both preclinical and clinical practices due to their high biocompatibility and biodegradability. However, the complicated preparations often denature proteins, which subsequently diminish their bioactivity. To overcome these drawbacks, we developed a one-step self-assembling method for preparing protein-based nanoparticles. Transferrin (Tf), a targeting protein, was mixed with 2-mercaptoethanol to break disulfide bonds. Using this method, Tf-PTX-NPs (paclitaxel-loaded Tf nanoparticles) could be readily obtained. Tf-PTX-NPs were round and their diameter could be controlled in the range of 5-200 nm. The bioactivity of Tf to its receptor after forming nanoparticles was also confirmed in vitro . Tf-PTX-NPs also could inhibit the tumor growth to some extent in a mice tumor xenograft model. Therefore, using this self-assembling method, we fabricated this antitumor Tf-based nanoparticle, in which Tf acted as both the targeting moiety and drug carrier. [ABSTRACT FROM AUTHOR]

Bitterness-suppressing molecules have drawn ever-increasing attention these years for some unique advantages like low molecular weight, tastelessness and no interference on drug bioavailability. l -Arg was reported to suppress the bitterness of quinine, and we happened to find that the suppressing effects could be demonstrated by isothermal titration calorimeter (ITC). In this study, we investigated the possibility of using ITC to screen bitterness-suppressing molecules for quinine. Among the amino acids we screened, l -Lys bond quinine with high affinity. The results of ITC correlated well with the results of human sensory experiments. l -Arg and l -Lys could suppress the bitterness of quinine while other amino acids could not. Therefore, ITC has the potential to screen bitterness-suppressing molecules. [ABSTRACT FROM AUTHOR]

Iron is indispensable for cancer cell survival and cancer cells are more vulnerable to ferroptosis than normal cells. Ferroptosis holds promise for overcoming chemoresistance and inducing tumor immunogenic cell death, which offers new possibilities for cancer immunotherapy. However, the prevalence of immunogenic ferroptosis in cancer cells is diminished because of the high levels of reducing substances within tumor microenvironments. Ferroptosis-needed iron is overdose for livings, which is also an obstacle for effective immune responses. In this study, we construct self-assembled carrier-free nanoscale coordination polymers based on iron and methotrexate (MFe-NCPs). The low-dose-iron-induced immunogenic ferroptosis is obviously enhanced by methotrexate via inhibiting dihydrofolate reductase and abating substance reduction, respectively. Of note, MFe-NCPs sequentially promoted antigen presentation, immune activation, T cell infiltration and boosted the therapeutic effect of immune checkpoint blockade therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Adipose derived mesenchymal stem cells (AdMSCs) have been demonstrated to have ability to differentiate into several cell lineages, including endothelial cells. The low endothelial differentiation efficiency, however, limits further clinical application of AdMSCs for therapeutic angiogenesis. This study was designed to investigate the feasibility to promote endothelial differentiation efficacy of AdMSCs using microwell array as a 3-D culture system. AdMSCs aggregates were prepared using photocrosslinkable polyethylene glycol dimethacrylate (PEGDM) derived microwell. AdMSCs aggregated and formed well defined 3-D aggregates following seeding. The microwell was effective in regulating the size of AdMSCs aggregates with low variation. AdMSCs within the 3-D aggregates maintained the cell surface epitopes of AdMSCs with high viability. Endothelial growth medium was used to induce the in vitro endothelial differentiation of AdMSCs. Both gene expression results from real time PCR and protein expression data from immunofluorescent staining revealed that 3-D cultured aggregates significantly promote the endothelial differentiation efficacy of AdMSCs. AdMSCs or AdMSCs aggregates were injected into the subcutaneous space of nu/nu mice to investigate the endothelial differentiation in vivo. The immunofluorescent staining data indicated promoted endothelial differentiation of 3-D aggregates compared with 2-D AdMSCs. Aggregates dissociated cells were obtained by transferring 3-D aggregates onto the adherent surfaces. Cells dissociated from induced aggregates were still positive for endothelial specific markers and were able to form endothelial-like tube structures on matrigel, indicating the endothelial properties. We conclude that microwell is an ideal 3-D culture system for promoting endothelial differentiation efficacy of AdMSCs. [ABSTRACT FROM AUTHOR]

IR-780, a representative hydrophobic near-infrared (NIR) fluorescence dye, is capable of fluorescently imaging and photothermal therapy in vitro and in vivo . However, insolubility in all pharmaceutically acceptable solvents limits its further biological applications. To increase solubility, we developed a novel self-assembled IR-780 containing micelle (PEG-IR-780-C13) based on the structural modification of IR-780. Briefly, a hydrophilic PEG 2000 was modified on the one side of IR-780, and the hydrophobic carbon chain on the other side was extended from C3 to C16 (additional C13 carbon chain). The modification provides a better self-assemble capability, improved water solubility and higher stability. In addition, PEG-IR-780-C13 micelles are specifically targeted to the tumor after intravenous injection and can be used for tumor imaging. The in vitro cell viability assays and in vivo photothermal therapy experiments indicated that CT-26 cells or CT-26 xenograft tumors can be effectively ablated by combining PEG-IR-780-C13 micelles with 808 nm laser irradiation. More importantly, no significant toxicity can be observed after intravenous administration of the therapeutic dose of generated micelles. Overall, our micelles may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications. [ABSTRACT FROM AUTHOR]

The detection of exogenous plant microRNAs in human/animal plasma/sera lies at the foundation of exploring their cross-kingdom regulatory functions. It is necessary to establish a standard operation procedure to promote study in this nascent field. In this study, 18 plant miRNAs were assessed in watermelon juice and mixed fruits by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). C T values, no-template controls and standard curves for each miRNA were used to evaluate the specificity and sensitivity of qRT-PCR and to obtain concentrations. Sixteen miRNAs were selected and measured in human plasma from volunteers after drinking juice. The C T values of 6 plant miRNAs in human plasma fell outside the linear ranges of their standard curves. The remaining 10 miRNAs were present at high basal levels, and 6 of them showed a dynamic physiological pattern in plasma (absorption rates of 0.04% to 1.31%). Northern blotting was used to confirm the qRT-PCR results. Critical issues such as RNA extraction and internal controls were also addressed. [ABSTRACT FROM AUTHOR]

Natural Killer T (NKT) cells are a unique type of innate immune cells which exert paradoxical roles in animal models through producing either Th1 or Th2 cytokines and activating dendritic cells. Alpha-galactosylceramide (αGalCer), a synthetic antigen for NKT cells, was found to be safe and immune stimulatory in cancer and hepatitis patients. We recently developed microparticle-formulated αGalCer, which is selectively presented by dendritic cells and macrophages, but not B cells, and thus can avoid the anergy of NKT cells. In this study, we have examined the immunogenicity of microparticles containing αGalCer and protein vaccine components through sublingual injection in mice. The results showed that sublingual injection of microparticles containing αGalCer and ovalbumin triggered IgG responses in serum (titer >1:100,000), which persisted for more than 3 months. Microparticles containing ovalbumin alone also induced comparable level of IgG responses. However, immunoglobulin subclass analysis showed that sublingually injected microparticles containing αGalCer and ovalbumin induced 20 fold higher Th1 biased antibody (IgG2c) than microparticles containing OVA alone (1:20,000 as compared to 1:1000 titer). Sublingual injection of microparticles containing αGalCer and ovalbumin induced secretion of both IgG (titer >1:1000) and IgA (titer = 1:80) in saliva secretion, while microparticles containing ovalbumin alone only induced secretion of IgG in saliva. Our results suggest that sublingual injection of microparticles and their subsequent trafficking to draining lymph nodes may induce adaptive immune responses in mucosal compartments. Ongoing studies are focused on the mechanism of antigen presentation and lymphocyte biology in the oral cavity, as well as the toxicity and efficacy of these candidate microparticles for future applications. [ABSTRACT FROM AUTHOR]

Protein-based nanoparticles hold great promises in both preclinical and clinical practices, such as oncology diagnosis and treatment, because of their high biocompatibility and biodegradability. However, the complicated preparation and lack of targeting specific cells or tissues may limit their further uses. To overcome these limitations, we developed a novel replacing method for preparing dual-functional protein nanocarrier, such that one function is capable of encapsulating small molecule into protein, whereas the other function is cable of recognizing CD163 receptor [hemoglobin (Hb) scavenger receptor]. In this study, Hb was chosen as the targeting drug carrier. First, the heme group in the Hb was removed and replaced by paclitaxel (PTX) to form nanoparticles (Gb-NPs-PTX). The resulted Gb-NPs-PTX showed spherical shape and their diameter could be controlled in the range of 120-160 nm by altering the ratio of PTX to Hb. The binding activity of Gb-NPs-PTX to CD163 was confirmed by cell uptake in CD163+ Chinese hamster ovary cells. Results in vivo also showed a CD163-dependent tissue accumulation of Gb-NPs-PTX in mice. In summary, by using the novel replacing method, PTX could be easily encapsulated into Hb nanoparticles and the targeting effects of Hb could also be kept. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1045-1055, 2015 [ABSTRACT FROM AUTHOR]

Drug solution is commonly used in conventional intravesical instillation. However, most of them would be easily eliminated by voiding, which significantly limit their efficacy. Recent advances in intravesical drug delivery are to use hydrogels as drug reservoir to extend the drug residence time in bladder. However, because of the high viscosity of hydrogel, urinary obstruction is usually existed during the intravesical instillation. To overcome these, we developed a floating hydrogel for the delivery of Adriamycin ( ADR). The floating hydrogel was made of ADR, thermosensitive polymer ( Poloxamer 407) and Na HCO3, which was liquid at low temperature, whereas formed gel at high temperature. In the presence of H+, Na HCO3 decomposed and produced CO2 that attached on the surface of hydrogel and helped the hydrogel float on the urine. Hence, the urinary tract will not be blocked. Meanwhile, the encapsulated ADR released in a controlled manner. These results suggest that the floating gel may have promising applications in intravesical therapy for bladder cancer. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:927-936, 2014 [ABSTRACT FROM AUTHOR]

Exposed chronic wounds are usually covered by hypoxic tissues accompanied with necrosis, persistent inflammation and anaerobic infections. Since atmospheric oxygen air can only penetrate about 0.3 mm tissues, meanwhile oxygen from the circulation is difficult to reach chronic wounds through the destroyed blood vessels, a solution to deliver oxygen locally and permeably is urgently needed. Herein we report a technique to reform traditional gel-based wound dressings by adding lyophilized oxygen encapsulated nanoparticles, which can deliver dissolved oxygen locally into wound surface. This delivery technique can potentially evaluate the therapeutic effects on hypoxic epithelial, endothelial and fibroblasts in vitro. Further experiments confirm the effects on both open wounds bearing and flap transplanted diabetic mice models. Considering its biocompatibility, effectiveness and practicality, we believe our hydrogel has significant transformation value to care and accelerate the healing of various clinical wounds, especially chronic wound. [ABSTRACT FROM AUTHOR]

Highlights: [•] The HSP gene-chip consists of ninety-six hot point mutations. [•] We have used this diagnostic gene chip to detect ninety-six HSP patients. [•] The call rate of the diagnostic gene chip is 97.7% and the consistency is 99.0%. [•] We genetically diagnosed a HSP patient with a c.316G>C substitution in SPG6. [•] The HSP gene-chip is a useful technique for preliminary screening of this disease. [Copyright &y& Elsevier]

Doxorubicin is an antitumor drug commonly used against a wide spectrum of tumors. However, the clinical application of DOX is restricted by its cardiotoxicity. To reduce the cardiotoxicity, we develop an albumin-based nanocarrier via a new molecular switch method for DOX delivery. Spherically shaped DOX-loaded HSA nanoparticles (NPs-DOX) are prepared with a drug-loading capacity and particle size of 4.3% and 120.1 ± 26 nm, respectively. In vivo studies demonstrate that NPs-DOX is able to preferentially accumulate in tumor and show great tumor inhibition on H22 hepatocellular-carcinoma-bearing mice. As for the toxicity, compared with free DOX, the maximum tolerated dose of NPs-DOX is increased from 10 to over 30 mg/kg, indicating the reduced systematic toxicity. More importantly, the cardiotoxicity induced by NPs-DOX is also significantly reduced because both left ventricular ejection fraction and left ventricular fractional shortening are almost not changed and other cardiotoxicity markers such as serum creatine kinase-MB, lactate dehydrogenase, superoxide dismutase, and malonaldehyde are kept constant. The reduced cardiotoxicity of NPs-DOX is also confirmed by nonhistological changes in the heart tissue. Therefore, such albumin-based nanocarrier can be one of the most promising strategies for the delivery of DOX. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1626-1635, 2013 [ABSTRACT FROM AUTHOR]

Near-infrared (NIR) dyes, small organic molecules that function in the NIR region, have received increasing attention in recent years as diagnostic and therapeutic agents in the field of tumor research. They have been demonstrated great successes in imaging and treating tumors both in vitro and in vivo. And their different applications in clinical practices have made rapid gains. This review primarily focuses on the progress of the application of NIR dyes in tumor imaging and therapy. In particular, advances in the use of different NIR dyes in tumor-specific imaging, photothermal, and photodynamic therapies are discussed. Limitations and prospects associated with NIR dyes in diagnostic and therapeutic application are also reviewed. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:6-28, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Combination of tirapazamine (TPZ) with cisplatin has been studied extensively in clinical trial for tumor therapy. However, in phase III clinical trial, the combination therapy did not show overall survival improvement in patients. To decrease the side effects and increase the efficacy of the combination therapy, TPZ was conjugated with transferrin (Tf-G-TPZ) for targeted delivery and co-administered with cisplatin. In vitro toxicity study showed that the combination of Tf-G-TPZ with cisplatin induced substantially higher cytotoxicity of tumor cells than the combination of TPZ and cisplatin. After Tf-G-TPZ was intravenously injected into tumor-bearing mice, its total accumulation in tumor was 2.3 fold higher than that of the unmodified TPZ, suggesting transferrin-mediated target delivery of TPZ into the tumor tissue. With the increased accumulation of Tf-G-TPZ in tumor, the synergistic anti-tumor effects of Tf-G-TPZ and cisplatin were also enhanced as showed by the 53% tumor inhibition rate. Meanwhile, the side effects such as body weight lost were not significantly increased. Therefore, Tf-G-TPZ holds great promise to a better substitute for TPZ in the combination therapy with cisplatin. [Copyright &y& Elsevier]

Abstract: The emergence of combinatorial chemistries and the increased discovery of natural compounds have led to the production of expansive libraries of drug candidates and vast numbers of compounds with potentially interesting biological activities. Despite broad interest in high throughput screening (HTS) across varied fields of biological research, there has not been an increase in accessible HTS technologies. Here, we present a simple microarray sandwich system suitable for screening chemical libraries in cell-based assays at the benchtop. The microarray platform delivers chemical compounds to isolated cell cultures by ‘sandwiching’ chemical-laden arrayed posts with cell-seeded microwells. In this way, an array of sealed cell-based assays was generated without cross-contamination between neighbouring assays. After chemical exposure, cell viability was analyzed by fluorescence detection of cell viability assays on a per microwell basis using a standard microarray scanner. We demonstrate the efficacy of the system by generating four hits from toxicology screens towards MCF-7 human breast cancer cells. Three of the hits were identified in a combinatorial screen of a library of natural compounds in combination with verapamil, a P-glycoprotein inhibitor. A fourth hit, 9-methoxy-camptothecin, was identified by screening the natural compound library in the absence of verapamil. The method developed here miniaturizes existing HTS systems and enables the screening of a wide array of individual or combinatorial libraries in a reproducible and scalable manner. We anticipate broad application of such a system as it is amenable to combinatorial drug screening in a simple, robust and portable platform. [ABSTRACT FROM AUTHOR]

Hypoxia exists in most malignant tumors and often contributes to therapy resistance, especially for aerobic treatments such as photodynamic therapy (PDT) and radiotherapy. Here, we developed a novel light-controlled sustainable PDT in which light was used to help photosynthetic microorganisms (Chlorella) produce oxygen, and perfluorocarbon was used to enrich oxygen around the photosensitizer for sustained oxygen supply. After light stops, Chlorella further acts as an adjuvant to promote dendritic cell (DC) activation, promoting the antitumor immune response. We showed that sustainable PDT could continuously provide oxygen for photosensitizers and avoid PDT-induced local hypoxia. More importantly, sustainable PDT also promoted the activation of DCs and amplified the antitumor immune effects. Therefore, this novel strategy provides an effective but simple method for improving PDT in both tumor hypoxia and normoxia, and enhancing the antitumor immunity may be a new anti-resistance strategy for treating patients with advanced-stage cancer. Image 1 [ABSTRACT FROM AUTHOR]

Abstract: Strong evidence has shown that a defect in the Parkin gene is known to be a common, genetic cause of Parkinson disease (PD). The E3 ubiquitin ligase Nrdp1 is shown to interact with the N terminal of Parkin (the first 76 amino acids) and catalyze degradation of Parkin via the ubiquitin–proteasome pathway, suggesting that Nrdp1 may be involved in the development of PD via the regulation of Parkin, We believe we are the first to have screened PD patients for mutations in the Nrdp1 gene to determine the association between these variants and PD. By direct sequencing, we analysed the entire coding regions and 5′ UTR of Nrdp1 in 209 Chinese PD patients and 302 unrelated healthy individuals. No variant was detected in the coding regions (exons 3–7); only 2 variants (c.−206 T > A and c.−208–8 A > G) were identified in the 5′ UTR (exon 2) and intron 1. Furthermore, a study of the allelic and genotypic association between patients and controls showed no significant association between the c.−206 T > A polymorphism and PD; c.−208–8 A > G was identified in one PD patient and not in controls. Our data do not support the hypothesis of a major role for the Nrdp1 gene in PD development in the Chinese population. [Copyright &y& Elsevier]