Grapefruit-derived nanoparticles could be less toxic for patients and less expensive to produce on a large scale than conventional nanomedicines.
A team of scientists at the University of Louisville (KY, USA) have used grapefruit to develop nanoparticles that can be used to deliver medicines. Led by Huang-Ge Zhang, Professor of Microbiology and Immunology at the university, the researchers demonstrated that the nanoparticles, made of grapefruit-derived lipids, can deliver chemotherapeutic agents, siRNAs, DNA expression vectors and proteins to various types of cells. They also reported enhanced inhibition of tumor growth in two tumor animal models, which caused less adverse effects when compared with drugs encapsulated in synthetic lipids.
“These nanoparticles, which we have named grapefruit-derived nanovectors (GNVs), are derived from an edible plant, and we believe they are less toxic for patients, result in less biohazardous waste for the environment and are much cheaper to produce at large scale than nanoparticles made from synthetic materials,” commented Zhang, whose team also analyzed nanoparticles derived from tomatoes and grapes, choosing grapefruits owing to the larger quantities of lipids that can be obtained. “Our GNVs can be modified to target specific cells – we can use them like missiles to carry a variety of therapeutic agents for the purpose of destroying diseased cells. Furthermore, we can do this at an affordable price.”
The group further validated the therapeutic potential of the GNVs through a Phase I clinical trial for the treatment of colon cancer patients. Thus far, the researchers have observed no toxicity in patients who took the anti-inflammatory agent curcumin encapsulated in the GNVs orally.
Zhang explained that he began the study by considering how human ancestors selected food to eat. “The fruit and vegetables we buy from the grocers today were passed down from generation to generation as favorable and nutritious for the human body. On the flip side, outcomes were not favorable for our ancestors who ate poisonous mushrooms, for example. It made sense for us to consider edible plants as a mechanism to create medicinal nanoparticles as a potential nontoxic therapeutic delivery vehicle.”
The scientists now plan to study whether the GNVs can be used in the treatment of inflammation-related autoimmune diseases, such as rheumatoid arthritis.
Sources: Wang Q, Zhuang X, Mu J et al. Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids. Nat. Commun. 4, 1867 (2013); University of Louisville press release. Grapefruits provide a secret weapon in medical drug delivery: http://louisville.edu/uofltoday/campus-news/grapefruits-provide-a-secret-weapon-in-medical-drug-delivery
A team of researchers, at the University of California, San Diego (CA, USA), has designed spherical nanoparticles that, within diseased tissue, can assemble into net-like structures to specifically target cancerous or other diseased cells. The group, led by Nathan Gianneschi, a Professor of Chemistry and Biochemistry at the university, took inspiration from biological systems that use shape to alter the ability of something to lock in place, or slip away and escape. “We wanted to come up with a new approach,” commented Gianneschi. “Specifically, we wanted to design switchable materials that we could inject in one shape and have them change to another between the blood and tumors.”
With each nanoparticle made up of many detergent-like molecules – one end of the molecule is hydrophobic and the other is hydrophilic – they self-assemble within the solution into spheres that have the hydrophobic ends on the inside, producing a configuration that is easily injected. The team then looked to change the shape of the nanoparticles specific to endogenous, enzymatic biochemical signals that are associated with tumor tissue, in this case matrix metalloproteinases (MMPs).
When mixed with MMPs in vitro, the enzymes cut peptides on the surface of the spherical nanoparticles, which then reassembled into the net-like structures. The scientists then took the concept further, by injecting the nanoparticles into mice with human fibrosarcomas, a cancer that produces high levels of MMPs. They used fluorescent dyes present in the spheres to detect that the nanoparticles reassembled at the site of the tumors within 1 day, and remained for at least 1 week. They also observed that the structures did not affect the liver or kidneys, the organs that are usually most susceptible to damage following treatment because they are responsible for the clearance of toxins from the body.
While the treatment itself is not toxic to tumors, variations of the nanoparticles could be engineered to carry drugs or diagnostic probes, and also respond to signals unique to other cancer types and inflamed tissue. The researchers intend to next develop nanoparticles that carry an infrared dye, enabling them to visualize tumors deep inside the body with instruments commonly available in a clinical setting.
Sources: Chien MP, Thompson MP, Barback CV, Ku TH, Hall DJ, Gianneschi NC. Enzyme-directed assembly of a nanoparticle probe in tumor tissue. Adv. Mater. doi:10.1002/adma.201300823 (2013) (Epub ahead of print); University of California, San Diego press release. Shape-shifting nanoparticles flip from sphere to net in response to tumor signal: http://ucsdnews.ucsd.edu/pressrelease/shape_shifting_nanoparticles_flip_from_sphere_to_net_in_response_to_tu
Researchers at Northwestern University (IL, USA) have developed a new method, named nanofountain-probe electroporation (NFP-E), which allows the delivery of molecules into targeted cells through temporary nanopores in the cell membrane created by a localized electric field applied to a small portion of the cell. In the study, the scientists demonstrated NFP-E of single HeLa cells within a population, delivering molecules to a target cell with over 95% transfection efficiency, qualitative dosage control and high viability (92%) of transfected cells.
Horacio Espinosa, Professor at Northwestern University‘s McCormick School of Engineering, and lead author of the work, commented, “This is really exciting. The ability to precisely deliver molecules into single cells is needed for biotechnology researchers to advance the state of the art in therapeutics, diagnostics and drug delivery toward the promise of personalized medicine.”
Bulk electroporation is an increasingly popular technique used to deliver molecules, such as nucleic acids or proteins, into cells through reversible nanopores caused by exposure to electric pulses. However, it is not without its problems; one issue is that there is often low cell viability because it applies electric pulses to a bulk cell solution.
NFP-E is based on nanofountain-probe technology developed in Espinosa‘s lab, and has previously been used for high-speed nanopatterning of proteins and nanoparticles for drug delivery studies. The NFP-E technology couples the probe with an electrode and fluid control system, which, according to the university‘s press release, can easily be connected to a micromanipulator or atomic force microscope for position control.
The NFP-E system is now being developed for commercialization by iNfinitesimal LLC (IL, USA), a Northwestern University spin-off company that was founded by Espinosa. It is expected to be available in late 2013.
Sources: Kang W, Yavari F, Minary-Jolandan M et al. Nanofountain probe electroporation (NFP-E) of single cells. Nano Lett. doi:10.1021/nl400423c (2013) (Epub ahead of print); Northwestern University press release. Single-cell transfection tool enables added control for biological studies: www.mccormick.northwestern.edu/news/articles/2013/05/single-cell-transfection-tool-enables-added-control-for-biological-studies.html
Scientists at the University of Munich (Munich, Germany) have developed a nanoparticle system for the targeted delivery of a range of drug cargos to various types of cancer cells. The group, jointly led by Christoph Bräuchle and Thomas Bein, professors at the university, utilized colloidal mesoporous silica nanoparticles, which can be safely biodegraded and offer large pores that are ideal for the storage of a large cargo volume. A red-light photosensitizer was attached to the particle surface, and targeting ligands specific to certain cancer cell types were inserted into the lipid bilayer.
The team tested the system using ligands specific for hepatoma and cervical cancer cells, demonstrating specific uptake of the delivery vehicle and also controlled cargo release by photoactivation in vitro. “The particles can be easily loaded with a variety of chemical agents and equipped with labels recognized by specific cell types,” said Bräuchle. “Thus, they bind specifically to certain cancer cells and release their cargo only after uptake by the cell.”
Bein added, “It is extremely difficult to design a particle that meets all these criteria at once. But we have now developed a system that, in principle, achieves this goal, and provides a generally applicable platform that is compatible with different cargos and target cells.”
The researchers point out that an important advance from this work is the incorporation of a photosensitizer that responds to red light, rather than blue light, as it is less toxic to cells and also penetrates deeper into tissues. It is also noted that as the photosensitizer is bound directly to the drug carrier, its effects are restricted to the vicinity of the nanoparticle itself, avoiding a destructive impact on larger regions of the cell interior.
This latest study represents a further step in a long-term collaboration, which developed the basic method for triggering the release of cargo from nanoparticles after their uptake by target cells in 2010.
Sources: Mackowiak SA, Schmidt A, Weiss V et al. Targeted drug delivery in cancer cells with red-light photoactivated mesoporous silica nanoparticles. Nano Lett. doi:10.1021/nl400681f (2013) (Epub ahead of print); University of Munich press release. Taking the fight into the enemy‘s territory: www.en.uni-muenchen.de/news/newsarchiv/2013/f-m-41-13.html
Researchers have developed a drug delivery system that combines nanoparticles and siRNA to help treat lung cancer, demonstrating “Efficient suppression of tumor growth” in a mouse model of human lung cancer. The group, which included Oleh Taratula (Oregon State University, OR, USA) and Tamara Minko (Rutgers University, NJ, USA), used nanostructured lipid carriers to deliver an anticancer drug (either doxorubicin or paclitaxel, functioning as a cell-death inducer) and two types of siRNA, which served as suppressors of cellular drug resistance in cancer cells.
Previously, the scientists had identified MRP1 and BCL2 mRNA as significant targets to suppress both pump and nonpump cellular resistance in lung cancer cells, respectively. As such, in order to suppress both types of resistance, two types of siRNA were incorporated into the nanostructured lipid carrier to target MRP1 and BCL2 mRNA. The group then attached a modified synthetic analog of the LHRH peptide, whose receptors are overexpressed in lung cancer cells, as a cancer-targeting moiety. Local delivery by inhalation was subsequently used to target the nanocarrier to the lungs, which delivered 83% to the target organ in comparison with 23% by intravenous injection. When further compared with intravenous treatment, the researchers demonstrated an almost complete regression of the tumor, as well as the prevention of adverse side effects on healthy lung tissue and other organs.
Taratula commented on the benefits of the new approach, “Lung cancer damage is usually not localized, which makes chemotherapy an important part of treatment. However, the drugs used are toxic and can cause organ damage and severe side effects if given conventionally through intravenous administration,” he explained. “A drug delivery system that can be inhaled is a much more efficient approach, targeting just the cancer cells as much as possible. Other chemotherapeutic approaches only tend to suppress tumors, but this system appears to eliminate it.”
According to the press release, a patent is being applied for on the new technology, while the group notes that further research is required before the system is ready for human clinical trials.
Sources: Taratula O, Kuzmov A, Shah M, Garbuzenko OB, Minko T. Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA. J. Control. Release doi:10.1016/j.jconrel.2013.04.018 (2013) (Epub ahead of print); Oregon State University press release. Research offers promising new approach to treatment of lung cancer: http://oregonstate.edu/ua/ncs/archives/2013/may/research-offers-promising-new-approach-treatment-lung-cancer
– All stories written by James Potticary