Increasing the density of nanomedicines improves their ultrasound-mediated delivery to tumours

AbstractNanomedicines have provided fresh impetus in the fight against cancer due to their selectivity and power. However, these agents are limited when delivered intravenously due to their rapid clearance from the bloodstream and poor passage from the bloodstream into target tumours. Here we describe a novel stealthing strategy which addresses both these limitations and thereby demonstrate that both the passive and mechanically-mediated tumour accumulation of the model nanomedicine adenovirus (Ad) can be substantially enhanced. In our strategy gold nanoparticles were thoroughly modified with 2kDa polyethyleneglycol (PEG) and then linked to Ad via a single reduction-cleavable 5kDa PEG. The resulting Ad–gold–PEG construct was compared to non-modified Ad or conventionally stealthed Ad–poly[N-(2-hydroxypropyl)methacrylamide] (Ad–PHPMA). Notably, although Ad–gold–PEG was of similar size and surface charge to Ad–PHPMA the increase in density, resulting from the inclusion of the gold nanoparticles, provided a substantial enhancement of ultrasound-mediated transport. In an in vitro tumour mimicking phantom, the level and distance of Ad–gold–PEG transport was shown to be substantially greater than achieved with Ad–PHPMA. In in vivo studies 0.1% of an unmodified Ad dose was shown to accumulate in tumours, whereas over 12% of the injected dose was recovered from the tumours of mice treated with Ad–gold–PEG and ultrasound. Ultimately, a significant increase in anti-tumour efficacy resulted from this strategy. This stealthing and density-increasing technology could ultimately enhance clinical utility of intravenously delivered nanoscale medicines including viruses, liposomes and antibodies

Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma

Iron-based compounds coordinated with phospho-polymers as biocompatible probes for dual 31P/1H magnetic resonance imaging and spectroscopy

Abstract In this work, we present the synthesis and evaluation of magnetic resonance (MR) properties of novel phosphorus/iron-containing probes for dual 31P and 1H MR imaging and spectroscopy (MRI and MRS). The presented probes are composed of biocompatible semitelechelic and multivalent phospho-polymers based on poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) coordinated with small paramagnetic Fe3+ ions or superparamagnetic maghemite (γ-Fe2O3) nanoparticles via deferoxamine group linked to the end or along the polymer chains. All probes provided very short 1H T 1 and T 2 relaxation times even at low iron concentrations. The presence of iron had a significant impact on the shortening of 31P relaxation, with the effect being more pronounced for probes based on γ-Fe2O3 and multivalent polymer. While the water-soluble probe having one Fe3+ ion per polymer chain was satisfactorily visualized by both 31P-MRS and 31P-MRI, the probe with multiple Fe3+ ions could only be detected by 31P-MRS, and the probes consisting of γ-Fe2O3 nanoparticles could not be imaged by either technique due to their ultra-short 31P relaxations. In this proof-of-principle study performed on phantoms at a clinically relevant magnetic fields, we demonstrated how the different forms and concentrations of iron affect both the 1H MR signal of the surrounding water molecules and the 31P MR signal of the phospho-polymer probe. Thus, this double contrast can be exploited to simultaneously visualize body anatomy and monitor probe biodistribution

Specific Inhibition of VanZ-Mediated Resistance to Lipoglycopeptide Antibiotics

Teicoplanin is a natural lipoglycopeptide antibiotic with a similar activity spectrum as vancomycin; however, it has with the added benefit to the patient of low cytotoxicity. Both teicoplanin and vancomycin antibiotics are actively used in medical practice in the prophylaxis and treatment of severe life-threatening infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, Enterococcus faecium and Clostridium difficile. The expression of vancomycin Z (vanZ), encoded either in the vancomycin A (vanA) glycopeptide antibiotic resistance gene cluster or in the genomes of E. faecium, as well as Streptococcus pneumoniae and C. difficile, was shown to specifically compromise the antibiotic efficiency through the inhibition of teicoplanin binding to the bacterial surface. However, the exact mechanisms of this action and protein structure remain unknown. In this study, the three-dimensional structure of VanZ from E. faecium EnGen0191 was predicted by using the I-TASSER web server. Based on the VanZ structure, a benzimidazole based ligand was predicted to bind to the VanZ by molecular docking. Importantly, this new ligand, named G3K, was further confirmed to specifically inhibit VanZ-mediated resistance to teicoplanin in vivo

Decline in sexually transmitted infection prevalence and HIV incidence in female barworkers attending prevention and care services in Mbeya Region, Tanzania.

OBJECTIVE: To assess trends in sexually transmitted infection (STI) prevalence and HIV incidence and associated factors in a cohort of female barworkers exposed to behavioural interventions and STI screening and treatment. METHODS: An open cohort of 600 female barworkers in Mbeya Region, Tanzania was offered 3-monthly information and education sessions on HIV/STI and reproductive health, voluntary HIV counselling and testing and clinical health check-ups including STI syndromic management with simple STI laboratory support. Outcome assessments included HIV, herpes simplex virus type 2 (HSV-2) and syphilis serology, polymerase chain reaction for Neisseria gonorrhoeae, Chlamydia trachomatis and ulcerative STI, microscopy for Trichomonas vaginalis, Candida albicans and bacterial vaginosis and interviews on sociodemographic and behavioural characteristics. RESULTS: Over a period of 30 months 600 barworkers were enrolled at the baseline examination round and 153 thereafter as replacements for losses to follow-up. At 3-monthly examinations the prevalence of gonorrhoea declined steadily from 22.2 to 6.8% (odds ratio for trend per quarter: 0.81; P < 0.001). The prevalence of all other STI/RTI, except for genital herpes and bacterial vaginosis, also decreased significantly. HIV incidence declined from 13.9/100 to 5.0/100 person-years over three consecutive 9-month periods. HIV incidence was significantly associated with genital ulcers and positive syphilis serology, but not with genital herpes or HSV-2 seropositivity. CONCLUSION: A relatively simple intervention consisting of regular 3-monthly STI screening and syndromic management in combination with HIV/STI information and counselling sessions was well accepted and effective in reducing STI among barworkers. Such interventions should be implemented more widely in high-risk environments in sub-Saharan Africa

Alcohol use, mycoplasma genitalium, and other STIs associated With HIV incidence among women at high risk in Kampala, Uganda.

BACKGROUND: In 2008, the first clinic for women involved in high-risk sexual behavior was established in Kampala, offering targeted HIV prevention. This article describes rates, determinants, and trends of HIV incidence over 3 years. METHODS: A total of 1027 women at high risk were enrolled into a closed cohort. At 3-monthly visits, data were collected on sociodemographic variables and risk behavior; biological samples were tested for HIV and other reproductive tract infections/sexually transmitted infections (RTI/STIs). Hazard ratios for HIV incidence were estimated using Cox proportional hazards regression among the 646 women HIV negative at enrolment. RESULTS: HIV incidence was 3.66/100 person-years (pyr) and declined from 6.80/100 pyr in the first calendar year to 2.24/100 pyr and 2.53/100 pyr in the following years (P trend = 0.003). Sociodemographic and behavioral factors independently associated with HIV incidence were younger age, younger age at first sex, alcohol use (including frequency of use and binge drinking), number of paying clients in the past month, inconsistent condom use with clients, and not being pregnant. HIV incidence was also independently associated with Mycoplasma genitalium infection at enrolment [adjusted hazard ratio (aHR) = 2.28, 95% confidence interval (CI): 1.15 to 4.52] and with Neisseria gonorrhoeae (aHR = 5.91, 95% CI: 3.04 to 11.49) and Trichomonas vaginalis infections at the most recent visit (aHR = 2.72, 95% CI: 1.27 to 5.84). The population attributable fractions of HIV incidence for alcohol use was 63.5% (95% CI: 6.5 to 85.8) and for treatable RTI/STIs was 70.0% (95% CI: 18.8 to 87.5). CONCLUSIONS: Alcohol use and STIs remain important risk factors for HIV acquisition, which call for more intensive control measures in women at high risk. Further longitudinal studies are needed to confirm the association between M. genitalium and HIV acquisition

Thermoresponsive Polymer Micelles as Potential Nanosized Cancerostatics

An effective chemotherapy for neoplastic diseases requires the use of drugs that can reach the site of action at a therapeutically efficacious concentration and maintain it at a constant level over a sufficient period of time with minimal side effects. Currently, conjugates of high-molecular-weight hydrophilic polymers or biocompatible nanoparticles with stimuli-releasable anticancer drugs are considered to be some of the most promising systems capable of fulfilling these criteria. In this work, conjugates of thermoresponsive diblock copolymers with the covalently bound cancerostatic drug pirarubicin (PIR) were synthesized as a reversible micelle-forming drug delivery system combining the benefits of the above-mentioned carriers. The diblock copolymer carriers were composed of hydrophilic poly­[<i>N</i>-(2-hydroxypropyl)­methacrylamide]-based block containing a small amount (∼5 mol %) of comonomer units with reactive hydrazide groups and a thermoresponsive poly­[2-(2-methoxyethoxy)­ethyl methacrylate] block. PIR was attached to the hydrophilic block of the copolymer through the pH-sensitive hydrazone bond designed to be stable in the bloodstream at pH 7.4 but to be degraded in an intratumoral/intracellular environment at pH 5–6. The temperature-induced conformation change of the thermoresponsive block (coil–globule transition), followed by self-assembly of the copolymer into a micellar structure, was controlled by the thermoresponsive block length and PIR content. The cytotoxicity and intracellular transport of the conjugates as well as the release of PIR from the conjugates inside the cells, followed by its accumulation in the cell nuclei, were evaluated in vitro using human colon adenocarcinoma (DLD-1) cell lines. It was demonstrated that the studied conjugates have a great potential to become efficacious in vivo pharmaceuticals

Treatment of sexually transmitted infections for HIV prevention: end of the road or new beginning?

Observational and biological data provide compelling evidence of the importance of sexually transmitted infections (STIs) in HIV transmission, but only one of nine intervention trials has shown an effect. This article reviews the observational studies, critically examines the nine randomized controlled trials evaluating the impact of STI treatment interventions on HIV incidence, and discusses implications for HIV prevention policy, programs and future research. The role of other vaginal infections is also briefly considered. In aggregate, the evidence strongly supports the concept that STI treatment prevents HIV infection. However, issues in trial design and conduct, including HIV epidemic phase, STI prevalence, intervention in comparison groups, and power have affected five of the six trials of treatment of curable STIs. In the three herpes intervention trials, antivirals for HSV suppression were insufficiently potent to alleviate persistent genital inflammation in HIV-negative HSV2-positive persons, and the reduction in HIV levels in HIV-positive persons was insufficient to reduce HIV transmission. It is time for a new phase of exploration of how, when, and in whom to include STI control as a key component of HIV prevention, driven by basic research to elucidate the mechanisms by which STIs and vaginal infections facilitate HIV transmission. From a policy perspective, treatment of curable STIs is an essential part of primary healthcare and is a cheap, simple, and effective intervention when appropriately targeted and delivered. It should be promoted as an essential component of HIV control programs in communities in which the burden of STIs is substantial