Novel Nanoparticle Therapy May Improve Survival After Blood Loss
Nanoparticle-based nitric oxide (NO) therapy has demonstrated potential to preserve cardiac function and improve survival in patients who have experienced blood loss.
The study, published recently in Resuscitation, investigated “the systemic and microvascular hemodynamic changes related to increased NO availability following significant hemorrhage”, utilizing NO-releasing nanoparticles (NO-nps). The authors studied the “hemodynamic responses” to hemorrhagic shock in Hamsters by inducing acute hemorrhage through controlled arterial bleeding. Following this, a subsection of the hamsters were administered with exogenous NO in the form of NO-nps, while the control groups received an equal dose of the nanoparticles without any NO. They found that the animals treated with NO-nps partially maintained systemic and microvascular function during hypovolemic shock. Moreover, NO supplementation after hemorrhage prevented cardiac decompensation, facilitating stabilization of the heart rate.
Human blood loss, which can cause cardiovascular collapse or hemorrhagic shock, is a potentially fatal condition that is currently best treated with intravenous fluids. However, such treatments are confined to the settings of emergency rooms or trauma centers and have limited utility in the field. “It is highly impractical to pack these supplies for use in rural emergencies, mass-casualty disasters or on the battlefield,” explained coauthor Joel Friedman, Professor of Physiology and Medicine at Albert Einstein College of Medicine (NY, USA).
Recently, Friedman and colleagues characterized NO-nps and published studies demonstrating their efficacy in healing antibiotic-resistant wound infections, in addition to treating erectile dysfunction. They used a sol-gel/glass hybrid system that exhibited controlled, sustained release of nitric oxide from a stable, dry powder. The relevance, stability and demonstrated efficacy of NO-nps therapy for hemorrhagic shock will potentially enable use in battlefield and trauma situations. “Our nanoparticle therapy may offer the potential for saving lives in those situations. It‘s lightweight and compact and doesn‘t require refrigeration,” commented Friedman.
Sources: Nachuraju P, Friedman AJ, Friedman JM, Cabrales P: Exogenous nitric oxide prevents cardiovascular collapse during hemorrhagic shock. Resuscitation DOI: 10.1016/j.resuscitation.2010.12.025 (2011) (Epub ahead of print); www.eurekalert.org/pub_releases/2011-02/aeco-nis022211.php
Nanoparticle Shows Promise for The Delivery of Vaccines for HIV, Malaria and Other Infectious Diseases
A team of researchers from Massachusetts Institute of Technology (MIT; MA, USA), have demonstrated the efficacy of a novel nanoparticle vaccine vector, providing new possibilities for therapeutic protein delivery in infectious diseases such as HIV and malaria.
The authors of the study, published in Nature Materials, describe the development of interbilayer-crosslinked multilamellar vesicles (ICMVs), formed by crosslinking headgroups of adjacent lipid bilayers within multilamellar vesicles. These lipid vesicles can carry protein antigens in the vesicle core and immunostimulatory drugs in the vesicle walls, yet exhibit rapid release in the presence of endolysosomal lipases. The study found that these antigen/adjuvant-carrying vesicles serve as a highly effective vaccine, with low doses eliciting strong endogenous T-cell and antibody responses in mice. Indeed, after immunization, up to 30% of all killer T cells in the mice were specific to the vaccine protein. “That is one of the strongest T-cell responses generated by a protein vaccine, and comparable to strong viral vaccines, but without the safety concerns of live viruses,” commented lead author Darrell Irvine, Associate Professor at MIT‘s Department of Biological Engineering.
Vaccines induce active immunity in the body by exposing it to an infectious agent; stimulating a primary response against the antigen. The goal is to invoke at least one of the human body‘s two major immune responses: the T-cell response, which involves attacking infected cells; or the B-cell response, in which secreted antibodies target viruses or bacteria present in the blood and other body fluids. For diseases involving intracellular pathogens, such as HIV, specialized killer T cells are utilized.
At present, the most effective method of stimulating these responses is to use inactivated or attenuated vaccines that contain dead or disabled microorganisms. However, this is difficult to achieve with some viruses, such as HIV, owing to the difficulties of reducing the virulence of the virus. As an alternative, researchers have developed vaccines based on recombinant proteins. However, while the synthetic vaccines avoid the toxicity and antivector immunity associated with live vaccine vectors, their immunogenicity is poor; in particular, they incite only weak CD8+ T-cell responses. Recently, researchers have designed vaccines enclosed in liposomes, which could help promote T-cell responses by packaging the protein in a virus-like particle. However, these vesicles are somewhat unstable in blood and body fluids, preventing them from stimulating an effective T-cell response. Irvine and colleagues elaborated on this design by packaging many of the droplets together in concentric spheres. Following fusion, the adjacent walls of the liposomes are ‘stapled’ to each other, conferring stability and minimizing premature break-down following injection.
The potential of the new vesicles in vaccine delivery is very exciting, but further work is certainly necessary to demonstrate the utility of the particles in the prevention of human disease. “Efforts are underway in our laboratory to translate these promising results into effective vaccines against malaria and HIV,” said co-author James Moon, also at the Department of Biological Engineering at MIT. “In collaboration with researchers at Walter Reed Army Institute of Research, we have thus far achieved very strong humoral responses against malaria parasites with ICMV vaccines carrying candidate malaria antigen, and we are pursuing to demonstrate their efficacy in nonhuman primate models.” As for HIV, we are also working with other investigators at the Ragon Institute of MGH, MIT and Harvard to examine ICMVs as a potent HIV vaccine carrier.”
Sources: Moon JJ, Suh H, Bershteyn A et al.: Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nat. Mater. 10(3), 243–251 (2011); MIT News: Nano-sized vaccines: http://web.mit.edu/newsoffice/2011/nano-sized-vaccines-0222.html
Long-Lasting Immunity Induced by Synthetic Nanoparticles Incorporating Multiple Adjuvants
Nanoparticles targeting more than one Toll-like receptor induce lasting immunity in mice
Researchers at Emory Vaccine Center (GA, USA) have recently demonstrated that nanoparticles designed to resemble viruses and mimic the immunostimulatory effect of the yellow fever vaccine (YF-17D) are able to include lifelong immunity in mice.
The synthetic nanoparticle is composed of biodegradable polymers and is similar in both size and immune composition to viruses. The team, led by senior author Bali Pulendran, Charles Howard Candler, Professor of Pathology and Laboratory Medicine at Emory University School of Medicine, aimed to develop a particle able to induce an immune response similar to the long-lasting and protective response induced by one of the most successful vaccines ever developed, YF-17D. This yellow fever vaccine is capable of protecting against disease-causing forms of the virus for decades and previous investigation by Pulendran and his group into the mechanism of action of YF-17D, revealed that the innate immune system is capable of sensing the vaccine via multiple Toll-like receptors (TLRs) located on dendritic cells, a mechanism responsible for the immune response generated in response to the vaccine.
In order to replicate this effect, the team produced nanoparticles that targeted more than one TLR. In addition to the antigen, the team incorporated two adjuvants into the poly(lactic acid)-co-(glycolic acid) particles, both of which are US FDA approved for use in humans individually: monophosphoryl lipid A, a low-toxicity derivative of the TLR-4 ligand lipopolysaccharide; and imiquimod, which mimics the effects of viral RNA and targets TLR-7. The team found that immunization with these nanoparticles induced increases in antigen-specific neutralizing antibodies in league with those produced in response to immunization with nanoparticles containing antigens and a single TLR ligand.
Furthermore, the group noted an enhanced persistence of germinal centers and of plasma-cell responses within the lymph node that persisted for >1.5 years, a duration similar to the lifetime of the mouse model. The team believes that this ability to induce a long-lasting immune response could benefit future vaccine design as Pulendran explains: “Most of the highly successful vaccines, such as live-attenuated vaccines against smallpox, yellow fever, measles, mumps and rubella, induce immunological memory that can last a lifetime. The ability to do this using a synthetic nanoparticle could facilitate the design of safe vaccines against a host of diseases, such as malaria, HIV and TB. Furthermore, these nanoparticle-based vaccines might offer a strategy to prolong the duration of immunity stimulated by vaccines that typically do not induce long-lived responses, such as the carbohydrate vaccines against meningococcal and pneumococcal diseases, as well as the pertussis vaccine.”
Immunization with the nanoparticles in mice induced complete protection against both lethal avian and swine influenza virus strains. A vaccine that could induce lifelong protection in the recipient would avoid the need for revaccination or booster doses in the future and, as Pulendran notes, “These particles could provide an instant way to stretch scarce supplies when access to viral material is limited, such as pandemic flu or during an emerging infection.”
The team also studied the effects of the nanoparticles in Rhesus macaques (replacing imiquimod with resiquimod) and observed a robust immune response against pandemic H1N1 influenza in these animals.
“The next step is to test the immunogenicity of these particles in nonhuman primates, using a variety of antigens, including antigens from HIV, malaria and dengue,” noted Pulendran. “We hope that this platform would represent a universal adjuvant platform that could be coupled with any antigen. However, the feasibility of using this in humans must await several nonhuman primate studies (which are currently being performed), as well as a safety trial in humans.”
Sources: Emory University Press release: www.eurekalert.org/pub_releases/2011-02/eu-vnc022111.php; Kasturi SP, Skountzou I, Albrecht RA et al.: Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470(7335), 543–547 (2011).
Advances in Treatment of Liver Cancer Aided by Nanotechnology
Hepatocellular carcinoma inhibited by injected nanoscale cerasomes
A recent evaluation of nano-scale ‘cerasomes’ in the treatment of in vitro and in vivo models of human hepatocellular carcinoma has shown these particles to be efficacious antineoplastic agents, suggesting a potential new therapeutic options for this aggressive liver cancer.
The study found that these molecular-scale nanoliposomes containing the tumor-suppressing lipid, C6-ceraminde, induced apoptosis in SK-HEP-1 cells in vitro, corresponding with an accumulation of cells in the G2 phase of the cell cycle and reduced phosphorylation of the serine/threonine protein kinase AKT. Moreover, mice possessing subcutaneous SK-HEP-1 tumors injected with nanoliposomal C6-ceramide, exhibited reduced tumor vascularization and proliferation, tumor cell apoptosis, decreased phosphorylation of AKT and ultimately inhibited tumor growth. “The beauty of ceramide is that it is nontoxic to normal cells, putting them to sleep, while selectively killing cancer cells,” explained Mark Kester, G Thomas Passananti Professor of Pharmacology at Penn State University (PA, USA).
Human hepatocellular carcinoma is becoming increasingly prevalent, yet prognosis remains poor; aggressive and metastatic tumors generally have a poor response rate to currently used treatment methods. One antineoplastic agent commonly in use is ceramide, which is known to be involved in apoptosis and cell-cycle arrest. However, a problem with ceramide is that it is an insoluble lipid and thus cannot be delivered effectively as a drug. The recent development of cerasomes by researchers at Penn State involved the incorporation of ceramide into nanoliposomes, in order to generate a soluble drug-delivery system. These can target cancer cells with high specificity without harming healthy cells. “Cerasomes were designed as a therapeutic alternative to common chemotherapeutics,” said Kester, “and have already been shown to effectively treat cellular and animal models of breast cancer and melanoma. Cerasomes have also been shown to be essentially free of toxic side effects normally associated with anticancer agents.”
Kester was keen to elucidate the significance of this development: “It is plausible that preventing liver tumor vascularization with cerasome treatment could induce widespread apoptosis, a genetically programmed series of events that leads to cell death in tumors.” He added, “The efficacy of our cerasomes in the treatment of diverse cancers lends significant therapeutic promise as it translates from bench to bedside.”
Sources: Tagaram HR, Divittore NA, Barth BM et al.: Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut DOI: 10.1136/gut.2010.216671 (2010) (Epub ahead of print); Penn State Live: Nanotechnology may lead to new treatment of liver cancer: http://live.psu.edu/story/51418
Nanomedicine Senior Editor and Editorial Board Members Listed in Thomson Reuters Top 100 Chemists 2000–2010
The Future Medicine editorial team would like to congratulate Charles R Martin, Senior Editor of Nanomedicine, on his inclusion on a recent list of the world‘s top 100 chemists, ranked by the impact of their published research. The data were compiled and released by Thomson Reuters, for research conducted thus far in the 21st century, and honors their ‘Top 100’ chemists worldwide. It is in support of the International Year of Chemistry.
Also included on the select list are Charles Lieber, Chad Mirkin, Samuel Stupp and Jean MJ Frechet, Editorial Board members of Nanomedicine, as well as several previous and current authors of the journal. The editorial team would also like to congratulate these individuals on this achievement.
“The Top 100 is intended to celebrate chemists who achieved the highest citation impact scores for chemistry papers published since 2000,” Thomson Reuters posted. “Since approximately 1 million chemists were recorded in the journal publications indexed by Thomson Reuters during the last decade, these 100 represent the top hundredth of 1%.”
Source: Science Watch: Top 100 Chemists 2000–2010: www.sciencewatch.com/dr/sci/misc/Top100Chemists2000-10/