A mechanistic insight to nanomedicine-mediated adverse cardiopulmonary reactions

Pigs are often used as predictive models of nanomedicine-mediated cardiopulmonary distress reactions in humans. Unlike humans, pulmonary intravascular macrophages (PIM) are abundant in pig lungs. Robust phagocytosis of particles by PIM results in immediate release of large quantities of mediators that correlate with periods of peak cardiopulmonary disturbances. This raises questions on relevance of the pig model to human cases. However, there are suggestions of induction of pulmonary macrophages in certain human diseases (e.g., liver and inflammatory lung diseases). It is conceivable that highly responsive patients may have induced PIM, which could increase sensitivity to blood-borne particles, and the potential risk of pulmonary hemodynamic side effects. Accordingly, it would be necessary to search for constitutive or induced PIM in biopsied or autopsied human lungs, map their phenotype in liver and inflammatory lung diseases, and understand the pathologic implication of phagocyte residency in pulmonary capillaries. In this presentation, I will discuss the roles of PIM and the complement system activation on initiation of adverse cardiopulmonary distress on nanomedicine administration as well as simple strategies that could overcome these problems even in the pig model. Alternative animal models will be suggested for investigating the interplay between induced PIM and the complement system that could closely resemble the human cases and applicable for cardiopulmonary risk assessment in relation to biopharmaceuticals/nanomedicine administration

Temperature-Vegetation-soil Moisture-Precipitation Drought Index (TVMPDI):21-year drought monitoring in Iran using satellite imagery within Google Earth Engine

Remote Sensing (RS) offers efficient tools for drought monitoring, especially in countries with a lack of reliable and consistent in-situ multi-temporal datasets. In this study, a novel RS-based Drought Index (RSDI) named Temperature-Vegetation-soil Moisture-Precipitation Drought Index (TVMPDI) was proposed. To the best of our knowledge, TVMPDI is the first RSDI using four different drought indicators in its formulation. TVMPDI was then validated and compared with six conventional RSDIs including VCI, TCI, VHI, TVDI, MPDI and TVMDI. To this end, precipitation and soil temperature in-situ data have been used. Different time scales of meteorological Standardized Precipitation Index (SPI) index have also been used for the validation of the RSDIs. TVMPDI was highly correlated with the monthly precipitation and soil temperature in-situ data at 0.76 and 0.81 values respectively. The correlation coefficients between the RSDIs and 3-month SPI ranged from 0.07 to 0.28, identifying the TVMPDI as the most suitable index for subsequent analyses. Since the proposed TVMPDI could considerably outperform the other selected RSDIs, all spatiotemporal drought monitoring analyses in Iran were conducted by TVMPDI over the past 21 years. In this study, different products of the Moderate Resolution Imaging Spectrometer (MODIS), Tropical Rainfall Measuring Mission (TRMM), and Global Precipitation Measurement (GPM) datasets containing 15,206 images were used on the Google Earth Engine (GEE) cloud computing platform. According to the results, Iran experienced the most severe drought in 2000 with a 0.715 TVMPDI value lasting for almost two years. Conversely, the TVMPDI showed a minimum value equal to 0.6781 in 2019 as the lowest annual drought level. The drought severity and trend in the 31 provinces of Iran have also been mapped. Consequently, various levels of decrease over the 21 years were found for different provinces, while Isfahan and Gilan were the only provinces showing an ascending drought trend (with a 0.004% and 0.002% trendline slope respectively). Khuzestan also faced a worrying drought prevalence that occurred in several years. In summary, this study provides updated information about drought trends in Iran using an advanced and efficient RSDI implemented in the cloud computing GEE platform. These results are beneficial for decision-makers and officials responsible for environmental sustainability, agriculture and the effects of climate change.</p

Peptide and nucleic acid-directed self-assembly of cationic nanovehicles through giant unilamellar vesicle modification: targetable nanocomplexes for in vivo nucleic acid delivery

One of the greatest challenges for the development of genetic therapies is the efficient targeted delivery of therapeutic nucleic acids. Towards this goal, we have introduced a new engineering initiative in self-assembly of biologically safe and stable nanovesicle complexes (∼90-140 nm) derived from giant unilamellar vesicle (GUV) precursors and comprising plasmid DNA or siRNA and targeting peptide ligands. The biological performance of the engineered nanovesicle complexes were studied both in vitro and in vivo and compared with cationic liposome-based lipopolyplexes. Compared with cationic lipopolyplexes, nanovesicle complexes did not show advantages in transfection and cell uptake. However, nanovesicle complexes neither displayed significant cytotoxicity nor activated the complement system, which are advantageous for intravenous injection and tumour therapy. On intravenous administration into a neuroblastoma xenograft mouse model, nanovesicle complexes were found to distribute throughout the tumour interstitium, thus providing an alternative safer approach for future development of tumour-specific therapeutic nucleic acid interventions. On oropharyngeal instillation, nanovesicle complexes displayed better transfection efficiency than cationic lipopolyplexes. The technological advantages of nanovesicle complexes, originating from GUVs, over traditional cationic liposome-based lipopolyplexes are discussed. STATEMENT OF SIGNIFICANCE: The efficient targeted delivery of nucleic acids in vivo provides some of the greatest challenges to the development of genetic therapies. Giant unilamellar lipid vesicles (GUVs) have been used mainly as cell and tissue mimics and are instrumental in studying lipid bilayers and interactions. Here, the GUVs have been modified into smaller nanovesicles. We have then developed novel nanovesicle complexes comprising self-assembling mixtures of the nanovesicles, plasmid DNA or siRNA, and targeting peptide ligands. Their biophysical properties were studied and their transfection efficiency was investigated. They transfected cells efficiently without any associated cytotoxicity and with targeting specificity, and in vivo they resulted in very high and tumour-specific uptake and in addition, efficiently transfected the lung. The peptide-targeted nanovesicle complexes allow for the specific targeted enhancement of nucleic acid delivery with improved biosafety over liposomal formulations and represent a promising tool to improve our arsenal of safe, non-viral vectors to deliver therapeutic cargos in a variety of disorders

Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration

In Vitro Structural and Functional Evaluation of Gold Nanoparticles Conjugated Antibiotics

Bactericidal efficacy of gold nanoparticles conjugated with ampicillin, streptomycin and kanamycin were evaluated. Gold nanoparticles (Gnps) were conjugated with the antibiotics during the synthesis of nanoparticles utilizing the combined reducing property of antibiotics and sodium borohydride. The conjugation of nanoparticles was confirmed by dynamic light scattering (DLS) and electron microscopic (EM) studies. Such Gnps conjugated antibiotics showed greater bactericidal activity in standard agar well diffusion assay. The minimal inhibitory concentration (MIC) values of all the three antibiotics along with their Gnps conjugated forms were determined in three bacterial strains,Escherichia coli DH5α,Micrococcus luteusandStaphylococcus aureus. Among them, streptomycin and kanamycin showed significant reduction in MIC values in their Gnps conjugated form whereas; Gnps conjugated ampicillin showed slight decrement in the MIC value compared to its free form. On the other hand, all of them showed more heat stability in their Gnps conjugated forms. Thus, our findings indicated that Gnps conjugated antibiotics are more efficient and might have significant therapeutic implications

Liposomes in Biology and Medicine

Drug delivery systems (DDS) have become important tools for the specific delivery of a large number of drug molecules. Since their discovery in the 1960s liposomes were recognized as models to study biological membranes and as versatile DDS of both hydrophilic and lipophilic molecules. Liposomes--nanosized unilamellar phospholipid bilayer vesicles--undoubtedly represent the most extensively studied and advanced drug delivery vehicles. After a long period of research and development efforts, liposome-formulated drugs have now entered the clinics to treat cancer and systemic or local fungal infections, mainly because they are biologically inert and biocompatible and practically do not cause unwanted toxic or antigenic reactions. A novel, up-coming and promising therapy approach for the treatment of solid tumors is the depletion of macrophages, particularly tumor associated macrophages with bisphosphonate-containing liposomes. In the advent of the use of genetic material as therapeutic molecules the development of delivery systems to target such novel drug molecules to cells or to target organs becomes increasingly important. Liposomes, in particular lipid-DNA complexes termed lipoplexes, compete successfully with viral gene transfection systems in this field of application. Future DDS will mostly be based on protein, peptide and DNA therapeutics and their next generation analogs and derivatives. Due to their versatility and vast body of known properties liposome-based formulations will continue to occupy a leading role among the large selection of emerging DDS