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Posted: Feb 12th, 2007
Plant extracts as nontoxic nanoparticle coating for nanomedicine applications
(Nanowerk Spotlight) Gold nanoparticles have gained significant prominence in the design and development of nanoscale devices and nanosensors. The ubiquitous place of gold in nanoscience stems from its unique chemical property of serving in the unoxidized state at the nanoparticulate level. In sharp contrast, most of the surfaces of the less-noble metals are susceptible to oxidation to a depth of several
nanometers or more, often obliterating the nanoscale properties. The high surface reactivity of gold nanoparticles, coupled with their biocompatible properties, has spawned major interest in the utility of gold nanoparticles for in vivo molecular imaging and therapeutic applications (see for instance our recent Nanowerk Spotlight "Medical nanotechnology: Killing cancer with gold nanobullets and nanobombs"). The core of nanomedicine embodies high surface area and the size relationship of nanoparticles to cellular domains so that individual cells can be targeted for diagnostic imaging or therapy of cancer and other diseases. The development of biocompatible and non-toxic nanoparticles is of paramount importance for their utility in nanomedicine applications. Despite the huge potential for gold nanoparticle-based nanomedicinal products, nontoxic gold nanoparticle constructs and formulations that can be readily administered are still rare. Hypothesizing that the ability of plants to absorb and assimilate metals will provide opportunities to utilize plant extracts as nontoxic vehicles to stabilize and deliver nanoparticles for in vivo nanomedicinal applications, researchers now have used Gum Arabic as a plant-derived, nontoxic construct for stabilizing gold nanoparticles. The development of readily injectable, in vivo stable and non-toxic gold nanoparticulate vectors, especially built from currently accepted human food ingredients, would be pivotal in their many uses (e.g. in vivo sensors, photoactive agents for optical imaging, drug carriers, contrast enhancers in computer tomography, X-ray absorbers).
When you read the ingredients list of your yogurt, marshmallows, Big Mac or soda, or even the lickable adhesive on postage stamps, you inevitably find something called "E-414" listed. This is the E-number code for Gum Arabic, or Gum Acacia, a substance that is taken from several species of the acacia tree. Gum Arabic, a complex mixture of saccharides and glycoproteins, is used primarily in the food industry as a stabilizer.
Dr. Kattesh V. Katti, professor of radiology and physics and director of the National Cancer Institute funded University of Missouri Cancer Nanotechnology Platform, and his colleagues were intrigued by plants' ability to absorb and assimilate metals and they proposed that this ability could be exploited to synthesize nontoxic gold nanoparticles.
"In fact, the current level of understanding of the roles and applications of naturally occurring nontoxic substances derived from plant origins, for stabilizing nanoparticles for subsequent use in clinical settings, is largely superficial and conjectural" Katti explains to Nanowerk.
Gum arabic has unique structural features that attracted the researchers' attention. It has a highly branched polysaccharide structure consisting of a complex mixture of potassium, calcium, and magnesium salts derived from arabic acid.
"As part of our ongoing research on the design and development of metal- and nanoparticle-containing diagnostic and therapeutic agents, the main objective of our investigation was to examine whether the complex polysaccharides and protein structures within the Gum Arabic backbone can effectively lock gold nanoparticles to produce nontoxic, nanoparticulate constructs that are stable under in vivo conditions for potential applications in nanomedicine" says Katti. "As a result we succeeded in developing a new class of hybrid gold nanoparticles that are stable in vivo and can be administered either orally or through intravenous injection within the biological system."
Katti and his team found that the hydrophilic polysaccharide arabinogalactan framework juxtaposed with hydrophobic pockets of glycoprotein networks within the structure of Gum Arabic forms an effective coating around the gold nanoparticles. Thus, the branched saccharide-protein structural units in Gum Arabic reduce the reactivity of the coated nanoparticles, resulting in enhanced kinetic inertness and high in vivo stability, due to limited binding with blood plasma proteins. The result is a high in vitro and in vivo stability of the gold nanoparticles. The fact that the nanoparticulate properties of gold nanoparticles remain intact for several months in aqueous/saline/phosphate buffered solutions, as well as in the solid state, makes this an interesting technique for gold nanoparticle-based nanomedicine products that can be shipped and stored in storage worldwide.
(Graphic: Dr. Katti)
Generally, the transition from basic to clinical cancer research for a number of experimental diagnostic or therapeutic agents is hampered by the lack of a genetically suitable, large animal model. Although mice and rats are always convenient to work with, they do not serve as genetically malleable animal for extension of translational research findings into human beings. In order to test the stability suitability of their hybrid gold nanoparticles for in vivo imaging and therapy applications, Katti's team performed biodistribution studies of the Gum Arabic-coated gold nanoparticles in pigs. Pigs are excellent animal models because of their similar physiological and anatomical characteristics to those in human beings.
"The accumulation and clearance of gold nanoparticles in various organs demonstrated clearance of gold nanoparticles from non-target organs" Katti points out. "The significant uptake of gold nanoparticles in swine lung and liver provides solid proof that the nanoparticles are not only bound tightly with the Gum Arabic framework but its complex polysaccharide-protein network serves as a vehicle to deliver gold nanoparticles to lungs and liver with minimal distribution of gold nanoparticles to other non-target organs."
The selective delivery of the Gum Arabic gold nanoparticles to lungs and liver provides an unprecedented approach for the molecular imaging of target organs via X-ray contrast computer tomography imaging. Katti adds that their experiments showed that the nanoparticle matrix clears via the kidney (although very slowly) and that they didn't find serious hematologic or renal side effects in the pigs.
Katti notes that, by designing target organ specific and cancer cell specific gold nanoparticles, doctors will be in a position to diagnose/treat the disease well before the disease has progressed to untreatable levels. "The natural affinity of gold nanoparticles toward open protein structures manifested by leaky tumor vasculatures makes our gold nanoparticle-mediated imaging and therapy approach so much more specific to tumors."
Dr. Mansoor Amiji, Professor of Pharmaceutical Sciences in the School of Pharmacy, Bouve College of Health Sciences and Co-Director of the Nanomedicine Education and Research Consortium, Northeastern University in Boston, and expert in biomedical nanotechnology commented: "Dr. Katti's work represents a major scientific discovery on the application of the non-toxic trimeric alanino phosphine peptide ('Katti Peptides') as an initiator for the generation of biocompatible gold nanoparticles within the non-toxic Gum Arabic phytochemical matrix. The excellent in vivo stability profiles of such gold nanoconstructs will open up new pathways for the intratumoral delivery of gold nanoparticles in diagnostic imaging and therapeutic applications for cancer."
Dr. Jagadese J. Vittal, associate professor in the chemistry department of National University of Singapore, agrees: "Dr. Katti's work represents a ground-breaking discovery. This is a unique process to produce readily injectable biocompatible gold nanoparticles for use in the design and development of gold-based nanoceuticals."
Like so many other nanoscientists, Katti acknowledges that the potential toxic side effects of nanoparticles administered via intravenous or oral pathways cannot be discounted. He emphasizes that concerted efforts must be invested in gaining new insights and knowledge base on the near and long term pharmacology and toxicology of a wide spectrum of nanoparticles that are being considered for medical use.
Looking ahead, Katti and his team will continue to focus on the design and development of disease or cell specific gold nanoparticles. However, they will also invest their efforts toward the development of appropriate animal models for understanding the pharmacokinetics of nanoconstructs in vivo.
"Most of the animal models being currently used in translational research have been standardized for use toward testing traditional pharmaceuticals" he says. "However, the kinetics and thermodynamics of nanoparticles under in vitro/in vivo conditions may not be similar to those of their macro counterparts. Therefore, it remains to be seen weather commonly used animal models can provide meaningful pharmacokinetic information when subjected to interactions with nanoparticles in vivo.
Katti points out the indispensable contributions of his extensive research team, which included: Kattesh Katti (Director of Cancer Nanotechnology Platform); Professor Stan Casteel (Animal experiments in pigs); Dr.Raguraman Kannan (nanoparticle production and their bioconjugation); Professor David Robertson (neutron activation analysis of tissue samples for accurate gold analysis); Dr. Evan Boote (X-Ray CT imaging experiments); Kavita Katti (nanoparticle production and optimization); Dr. Vijaya Kattumuri (nanoparticle production and characterization); Professor Meera Chandrasekhar (optical physics measurements of nanoparticles).
This work has been supported by the generous support from the National Institutes of Health/National Cancer Institute under the Cancer Nanotechnology Platform program (grant number: 1R01CA119412-01: Kattesh Katti Principal Investigator)