Nanoparticle-releasing vaccine may help prevent sexually transmitted diseases
Orally delivered nanoparticle-based vaccine could overcome limitations of intrarectaladministration and be a step forward in preventing sexually transmitted diseases
A collaboration of scientists from the National Cancer Institute (NCI, MD, USA), Nanotherapeutics, Inc (FL, USA) and the Air Force General Hospital (Beijing, China) has developed an orally delivered large intestine-targeted nanoparticle vaccine to overcome the limitations presented by intrarectal administration. The researchers, led by Jay Berzofsky, Chief of the Vaccine Branch at the NCI, describe in their recent study published in Nature Medicine that the oral delivery route is often fraught with problems such as destruction by digestive acid, and enzymes and induction of ‘oral tolerance‘. Therefore, the team developed a delivery system to specifically target the oral vaccine to a certain region in the GI tract.
Berzofsky and his colleagues designed the system such that it incorporated nanoparticles in the size range that could be phagocytozed by dendritic cells. Speaking to Future Science, Berzofsky explained the coating strategy that he and his team used to ensure that oral delivery was a possibility: “The nanoparticles were coated in such a way as to protect them from stomach acid and enzymes, and prevent uptake before they reached the large intestine. Both these goals were accomplished by coating the nanoparticles with a polymer (Eudragit®) formulation that protected them from degradation by acid and enzymes, formed microparticles too large to be phagocytosed until they released the nanoparticles, and were pH sensitive to allow selective release of the nanoparticles in the large intestine. Hence, making use of both pH sensitivity and half-time for release at a certain pH relative to transit time in the intestine.”
The team coated the nanoparticles with two different polymer formulations, FS30D and L100-55. They found that nanoparticle vaccines coated with FS30D Eudragit were stable in acid but released their contents in the cecum and colon of the mouse. By contrast, while those coated with Eudragit L100-55 were also stable in acid, they released their contents in the small intestine. Subsequently, the researchers incorporated vaccine peptides and Toll-like receptor ligand adjuvants into the nanoparticles, it was demonstrated that the FS20D formulation allowed induction of T-cell immunity in the large intestine. Only the FS30D formulation led to protection against rectal or vaginal mucosal challenge with a recombinant vaccinia virus expressing an HIV or vaccinia antigen.
The next steps for this research include continuing the studies in larger animals and non-human primates. Berzofsky commented on the impact of the study: “There are both basic and translational implications of this research. From a basic point of view, this technology allows for the first time the selective delivery of vaccine to the small or large intestine, to determine the differences in immunity induced at these sites. We observed, surprisingly, that there was subcompartmentalization within the gastrointestinal mucosal immune system, such that one could induce immunity preferentially in the large intestine and not the small intestine or vice versa. This should allow new studies examining and comparing immunity in these sites. From a translational perspective, this approach should allow more practical vaccination to induce lower gastrointestinal and genital immunity to prevent sexually transmitted diseases. Thus, we are hopeful that this technology can be translated for use in human vaccines to prevent transmission of sexually transmitted diseases.”
– Written by Hannah Stanwix
Source: Zhu Q, Talton J, Zhang G et al. Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection. Nat. Med. doi:10.1038/nm.2866 (2012) (Epub ahead of print).
Sustained drug release using hydrogels could last for up to 6 months
A new technology developed by researchers at the University of Cambridge (Cambridge, UK) could mean that individuals who are currently required to take daily medication, such as diabetic patients or those suffering from HIV, may be able to cut the number of applications to just one every 6 months.
“There has been a lot of research that shows patients who need to take a pill each day for the rest of their lives, especially HIV patients in Africa who do not show any obvious symptoms, will take the pills for a maximum of 6 months before they stop, negating the point of taking the medication in the first place,” explains Eric Appel, who collaborated on the work at the University of Cambridge. “If patients only have to take one shot that will give them 6 months‘ worth of medication, we‘ll have a much greater chance of affecting an entire population and slowing or stopping the progression of a disease.”
The research is published in the journal Biomaterials and the hydrogels, which are up to 99.7% water, were developed by Oren Sherman, Xian Jun Loh and Eric Appel. It reports that the hydrogels developed far surpass those currently available, which can currently deliver for up to 3 months. The material‘s low polymer concentration as well as high water content make the gel highly attractive for biomedical applications due to improved biocompatibility.
As Sherman explained, “The hydrogels protect the proteins so that they remain bio-active for long periods and allow the proteins to remain in their native state. Importantly, all the components can be incorporated at room temperature, which is key when dealing with proteins that denature when exposed to high heat.”
The proteins observed were shown to retain over 80% of their activity when released from the gel, even after 50 days, whilst the bioactivity of those proteins not held in the gel fell to 2% after only 6 days. Protein-based therapeutics is a highly attractive and fast-growing area in comparison to small-molecule drugs, performing highly specific functions as well as having a much lower potential of interfering with biological functions.
The scientists are now working with researchers from the Brain Repair Centre in the Department of Clinical Medicine (Cambridge, UK) on how the technology could be used as a possible treatment for brain cancer. The research has been patented by Cambridge Enterprise (Cambridge, UK), the University‘s commercialization group.
– Written by James Potticary
Sources: New technology delivers sustained release of drugs for up to 6 months: www.cam.ac.uk/research/news/new-technology-delivers-sustained-release-of-drugs-for-up-to-six-months; Appel EA, Loh XJ, Jones ST et al. Sustained release of proteins from high water content supramolecular polymer hydrogels. Biomaterials doi:10.1016/j.biomaterials.2012.02.030 (2012) (Epub ahead of print).
RNA-delivering nanoparticles have potential to target and penetrate tumors
A team of researchers from the USA have developed a tumor-penetrating nanocomplex to target the ID4 protein, overexpressed in approximately one-third of high-grade ovarian tumors.
The tumor-penetrating complex consisted of siRNA complexed with a tandem tumor-penetrating and membrane-translocating peptide. The collaboration of scientists from Massachusetts Institute of Technology (MA, USA), Dana-Farber Cancer Institute (MA, USA), Brigham and Women‘s Hospital (MA, USA) and the Sanford-Burnham Medical Research Institute (CA, USA) evaluated the efficacy of these RNA-delivering nanoparticles in vivo, in a mouse model. Treatment of mice bearing ovarian tumors with the novel nanoparticles significantly improved survival and suppressed growth of the tumors.
The researchers, led by Sangeeta Bhatia, Howard Hughes Medical Institute Investigator and the John J and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at the Massachusetts Institute of Technology, believe that these new RNA-delivering nanoparticles could help target proteins that don‘t have sites for traditional drugs to bind to. According to Bhatia, these novel nanoparticles could, “relieve a significant bottleneck in cancer drug development.”
Looking forward, the team will test the particles in other types of cancer, as well as further developing the ID4-targeting RNA nanoparticles as a treatment for ovarian cancer.
– Written by Hannah Stanwix
Source: Ren Y, Cheung HW, von Maltzhan G et al. Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4. Sci. Transl. Med. doi:10.1126/scitranslmed.3003778 (2012) (Epub ahead of print).
Engineered pancreatic tissue delivers insulin
Researchers at the Technion-Israel Institute of Technology (Haifa, Israel) have recently developed pancreatic islets engineered with a surrounding network of blood vessels, which provide a greater survival rate, as well as producing more insulin and other essential hormones.
The 3D tissue scaffolds have potential to vastly improve tissue transplants in the treatment of Type 1 diabetes, as pancreatic islets are usually transplanted without any accompanying blood vessels. This is usually the primary cause of unsuccessful tissue transplants, as the islets require more time to connect with a patients own vascular system.
Shulamit Levenberg, who created the tissue explained, “We have shown that the 3D environment and the engineered blood vessels support the islets – and this support is important for the survival of the islets and for their insulin secretion activity. The increase in islet survival is correlated with creation of surrounding endothelial tubes.”
The work conducted by research student Keren Francis in Levenberg‘s laboratory and in co-operation with Yuval Dor from the Hebrew University (Jerusalem, Israel), under a joint research grant provided by Juvenile Diabetes Research Foundation International.
While the research is still very much in its infancy, Levenberg and her colleagues are starting to test the 3D scaffolds on human rather than mouse islets, an important next step in seeing whether such engineered tissue could be compatible for future tissue transplants.
– Written by James Potticary
Sources: Technion researchers construct a polymeric scaffold array with pancreatic Islets surrounded by a vascular network: www.technion.ac.il/_local/includes/blocks/news-items/120715-shulamit/news-item-en.htm; Engineered pancreatic tissues could lead to better transplants for diabetics: www.ats.org/site/News2?page=NewsArticle&id=7567&news_iv_ctrl=1161
DNA origami circumvents drug resistance for cancer treatment
DNA origami, a process designed by Paul Rothemund in 2006, is a method of folding a single strand of viral DNA into a desired 3D structure. A new study recently published in the Journal of American Chemical Society demonstrates how researchers from the National Center for Nanoscience and Technology (Beijing, China) have applied the technology to develop a novel drug carrier system and attack breast cancer cells using an anticancer drug, doxorubicin, to which the cancer cells have gained resistance.
The study, jointly-led by Hao Yan at Arizona State University (AZ, USA), reports that the DNA origami structures circumvent drug resistance by both increasing cellular drug uptake and inducing a change in lysosomal pH, redistributing doxorubicin to target sites. The paper states that, “with the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity.” This research was funded by National Basic Research Program of China, 100-Talent Program of Chinese Academy of Sciences, National Science Foundation China, Beijing Natural Science Foundation and the US NIH of Health.
This study provokes particular interest as the DNA origami method could provide benefits over the use of other nanoparticles to delivery chemotherapy – as DNA origami would likely provide faster drug release and, thus, increased anticancer activity, while metal nanoparticles can cause toxicity over an extended time period.
Initial results suggest a safe, biocompatible and efficient drug carrier and delivery tool for future cancer treatment and the researchers are confident that DNA origami can provide a delivery platform for multiple therapeutic drugs – different anti-cancer drugs, small molecules and siRNA could be simultaneously delivered to cells for synergistic therapy.
– Written by James Potticary
Source: Jiang Q, Song C, Nangreave J et al. DNA origami as a carrier for circumvention of drug resistance. J. Am. Chem. Soc. 134(32), 13396–13403 (2012).