Using gold nanoparticles for enhanced intradermal delivery of poorly soluble auto-antigenic peptides

Ultra-small 1-2 nm gold nanoparticles (NP) were conjugated with a poorly-soluble peptide auto-antigen, associated with type 1 diabetes, to modify the peptide pharmacokinetics, following its intradermal delivery. Peptide distribution was characterized, in vivo, after delivery using either conventional intradermal injection or a hollow microneedle device. The poorly-soluble peptide was effectively presented in distant lymph nodes (LN), spleen and draining LN when conjugated to the nanoparticles, whereas peptide alone was only presented in the draining LN. By contrast, nanoparticle conjugation to a highly-soluble peptide did not enhance in vivo distribution. Transfer of both free peptide and peptide-NPs from the skin to LN was reduced in mice lacking lymphoid homing receptor CCR7, suggesting that both are actively transported by migrating dendritic cells to LN. Collectively, these data demonstrate that intradermally administered ultra-small gold nanoparticles can widen the distribution of poorly-soluble auto-antigenic peptides to multiple lymphoid organs, thus enhancing their use as potential therapeutics

Cinema 3D: large scale automultiscopic display

While 3D movies are gaining popularity, viewers in a 3D cinema still need to wear cumbersome glasses in order to enjoy them. Automultiscopic displays provide a better alternative to the display of 3D content, as they present multiple angular images of the same scene without the need for special eyewear. However, automultiscopic displays cannot be directly implemented in a wide cinema setting due to variants of two main problems: (i) The range of angles at which the screen is observed in a large cinema is usually very wide, and there is an unavoidable tradeoff between the range of angular images supported by the display and its spatial or angular resolutions. (ii) Parallax is usually observed only when a viewer is positioned at a limited range of distances from the screen. This work proposes a new display concept, which supports automultiscopic content in a wide cinema setting. It builds on the typical structure of cinemas, such as the fixed seat positions and the fact that different rows are located on a slope at different heights. Rather than attempting to display many angular images spanning the full range of viewing angles in a wide cinema, our design only displays the narrow angular range observed within the limited width of a single seat. The same narrow range content is then replicated to all rows and seats in the cinema. To achieve this, it uses an optical construction based on two sets of parallax barriers, or lenslets, placed in front of a standard screen. This paper derives the geometry of such a display, analyzes its limitations, and demonstrates a proof-of-concept prototype

A phase 1, open-label, randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly

AbstractBackgroundInfluenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity.MethodsA total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60–63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months.ResultsIntradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%).ConclusionsIntradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45μg) virosomal vaccine did not demonstrate any benefit on vaccine’s immunogenicity over 15μg commercial presentation. All treatments were generally safe and well-tolerated

Fine-needle aspiration biopsy of the lymph node: a novel tool for the monitoring of immune responses after skin antigen delivery

Assessment of immune responses in lymph nodes (LNs) is routine in animals, but rarely done in humans. We have applied minimally invasive ultrasound-guided fine-needle aspiration of the LN to a before-and-after study of the immune response to intradermally delivered Ag in healthy volunteers (n = 25). By comparison with PBMCs from the same individual, LN cells (LNCs) were characterized by reduced numbers of effector memory cells, especially CD8+ TEMRA cells (3.37 ± 1.93 in LNCs versus 22.53 ± 7.65 in PBMCs; p = 0.01) and a marked increased in CD69 expression (27.67 ± 7.49 versus 3.49 ± 2.62%, LNCs and PBMCs, respectively; p < 0.0001). At baseline, there was a striking absence of IFN-γ ELISPOT responses to recall Ags (purified protein derivative, Tetanus toxoid, or flu/EBV/CMV viral mix) in LN, despite strong responses in the peripheral blood. However, 48 h after tuberculin purified protein derivative administration in the ipsilateral forearm resulting in a positive skin reaction, a clear increase in IFN-γ ELISPOT counts was seen in the draining LN but not in PBMCs. This response was lost by 5 d. These data suggest that the low levels of effector memory cells in the LN may explain the low background of baseline ELISPOT responses in LNs as compared with PBMCs, and the appearance of a response after 48 h is likely to represent migration of effector memory cells from the skin to the LN. Hence, it appears that the combination of intradermal Ag administration and draining LN sampling can be used as a sensitive method to probe the effector memory T cell repertoire in the skin

Skin Vaccination against Rotavirus Using Microneedles: Proof of Concept in Gnotobiotic Piglets.

Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P[8]) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P[8] human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route

Synthesis, characterisation, electronic spectra and electrochemical investigation of ferrocenyl-terminated dendrimers

Two new dodecaferrocenyl dendrimers have been prepared using a sixfold Sonogashira coupling reaction and sixfold Huisgen cycloaddition, respectively. In addition, a dendron containing four ferrocenyl groups has been synthesised by conventional synthetic methods. Electrochemical studies have shown that all the ferrocene units are electrochemically equivalent. Moreover, when treated with acid these compounds form multicharged methylium near-infrared-absorbing dendritic dyes with a high extinction coefficient

Public Concerns during the COVID-19 Lockdown: A Multicultural Cross-Sectional Study among Internet Survey Respondents in Three Countries

(1) Background: this study aimed to evaluate the worries, anxiety, and depression in the public during the initial coronavirus disease 2019 (COVID-19) pandemic lockdown in three culturally different groups of internet survey respondents: Middle Eastern (Israel), European (Poland), and North American (Canada). (2) Methods: a cross-sectional online survey was conducted in the mentioned countries during the lockdown periods. The survey included a demographic questionnaire, a questionnaire on personal concerns, and the Patient Health Questionnaire-4 (PHQ-4). A total of 2207 people successfully completed the survey. (3) Results: Polish respondents were the most concerned about being infected. Canadian respondents worried the most about their finances, relations with relatives and friends, and both physical and mental health. Polish respondents worried the least about their physical health, and Israeli respondents worried the least about their mental health and relations with relatives and friends. Canadian respondents obtained the highest score in the PHQ-4, while the scores of Israeli respondents were the lowest. (4) Conclusions: various factors should be considered while formulating appropriate solutions in emergency circumstances such as a pandemic. Understanding these factors will aid in the development of strategies to mitigate the adverse effects of stress, social isolation, and uncertainty on the well-being and mental health of culturally different societies

Intradermal Delivery of Synthetic mRNA Using Hollow Microneedles for Efficient and Rapid Production of Exogenous Proteins in Skin

In recent years, synthetic mRNA-based applications to produce desired exogenous proteins in cells have been gaining importance. However, systemic delivery of synthetic mRNA can result in unspecific uptake into undesired cells or organs and, thereby, fail to target desired cells. Thus, local and targeted delivery of synthetic mRNA becomes increasingly important to reach the desired cell types and tissues. In this study, intradermal delivery of synthetic mRNA using a hollow microneedle injection-based method was evaluated. Furthermore, an ex vivo porcine skin model was established to analyze synthetic mRNA-mediated protein expression in the skin following intradermal delivery. Using this model, highly efficient delivery of synthetic mRNA was demonstrated, which resulted in detection of high levels of secretable humanized Gaussia luciferase (hGLuc) protein encoded by the microinjected synthetic mRNA. Interestingly, synthetic mRNA injected without transfection reagent was also able to enter the cells and resulted in protein expression. The established ex vivo porcine skin model can be used to evaluate the successful production of desired proteins after intradermal delivery of synthetic mRNAs before starting with in vivo experiments. Furthermore, the use of microneedles enables patient-friendly, painless, and efficient delivery of synthetic mRNAs into the dermis; thus, this method could be applied for local treatment of different skin diseases as well as for vaccination and immunotherapy