A collaboration between scientists at the Nanotechnology Center of Memorial Sloan-Kettering (MSK) Cancer Center, Cornell University and Hybrid Silica Technologies Inc., has resulted in an inorganic silica nanoparticle with the potential for the targeted molecular imaging of cancer. The researchers have received approval from the US FDA for an Investigational New Drug application and are about to launch a first-in-human trial of the particle in melanoma patients, a first-of-its-kind trial for an inorganic nanoparticle approved as a drug. Lead investigator Michelle Bradbury commented, “This is a very exciting and important first step for this new particle technology that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers”.
The purpose of the trial is to investigate the distribution, uptake and safety of the particles in humans by positron emission tomography (PET) imaging. This resulting data could serve as a guideline for future trials and oncologic clinical applications.
Oula Penate Medina, a nanochemist at MSK, speaking exclusively to Therapeutic Delivery on the importance of this news for the progression of nanotechnology into human trials for cancer treatment said, “I think that nanotechnology and the advanced drug-delivery systems have great potential for future therapy and imaging. There is a deep lack of knowledge in how these systems work in humans. This study will highlight a class of particles that will circulate relatively rapidly (cleared in 24 h) through the body and leave without being metabolized. During this time they can be targeted to the tumors. These kinds of inorganic particles are ideal for targeted imaging and for delivery of highly toxic compounds like radionuclides or chemotherapeutic agents”.
The nanoparticles, otherwise known as Cornell dots (C dots), are small spheres of silica that enclose a dye that glows up to three-times brighter than free dye when excited by a particular wavelength of light. C dots were initially synthesized by Ulrich Wiesner at Cornell University in conjunction with Hybrid Silica Technologies, to be used as optical probes.
The C dots have been modified by nanotechnologists at MSK for use in PET imaging. C dots can be used to illuminate cancer cells, trace circulating tumor cells and optically diagnose tumors near the surface of the skin.
Further advancement of the technology involved attaching radioactive labels to the C dots to produce a new generation of probes that allow for more in-depth imaging and monitoring of drug delivery using 3D PET techniques. The team at MSK also tailored the particles to target receptors (or other molecules) expressed on tumor surfaces
Tracking the particles using PET scans, the C dots can be used to monitor tumor accumulation and metastasis, as well as response to therapy and other properties. This information may eventually aid physicians in mapping the disease, assessing the extent of a tumor‘s spread and other necessary visualizations.
In terms of the future potential of these particles to progress from imaging to therapy, Medina said, “These particles have potential in [the] targeting of highly toxic compounds like chemotherapeutic agents”. On the future of nanotechnology in the imaging and treatment of cancers over coming years she continued, “Personalized medicine can be achieved by imaging nanocarriers that can give relevant biological information about the primary tumors and the metastatic hidden tumors. I think that the concept of drug delivery and controlled release provided by nanoparticles will reduce the side effects of chemotherapy agents and result [in] a situation where optimal amount of effective therapeutic drug will be delivered to each tumor”.
Source: Novel cancer-targeting investigational nanoparticle receives FDA IND approval for first-in-human trial: www.nanotech-now.com/news.cgi?story_id=41554
Researchers at the Medical Center of the University of Munich, Germany, have shown that chemically modified mRNA could be a promising alternative to current gene-delivery vectors such as DNA-based systems or nonviral vectors. In a study published in Nature Biotechnology, the scientists, led by Carsten Rudolph, used chemically altered mRNA molecules synthesized in the body from a DNA-template to deliver functioning copies of a defective gene to mice in a murine model of a lethal congenital lung disease.
Gene therapy replaces mutant genes present in the host, with functioning copies of that gene, thereby providing a way to correct the expression of the defective gene. The therapy has great potential for treating both acquired and congenital diseases, which may otherwise have limited or no treatment options. In order for the functioning gene to be expressed, and thereby for the treatment to have therapeutic effect, the ‘healthy‘ gene must be delivered into the host‘s cellular genome. Current vectors for delivery include DNA-based systems and a variety of nonviral vectors such as inorganic nanoparticles. Viral vectors are associated with serious safety concerns, which include a risk of cancer or severe immune response, whereas nonviral vectors, while generally associated with lower risk, are limited by poor gene-transfer efficiency.
To circumvent these issues, the researchers modified mRNA, which was then used as the delivery platform. The nucleotide modifications on the mRNA meant that the vehicle did not interact with Toll-like receptor (TLR)3, TLR7, TLR8 or the retinoid-inducible gene I (RIG-I) in mice, which resulted in low immunogenicity and a high stability in the murine model. Being a viral delivery method, the mRNA platform did not suffer from the low gene-transfer efficiency seen for non-viral systems. “Chemical modification of the mRNA prevents it from activating the immune system, so that no inflammatory reaction ensues”, commented Rudolph. “Furthermore, in contrast to conventional mRNA, the modified mRNA can be administered repeatedly, is more stable and is effective at very low doses.”
For the study, mice making up the model of lethal congenital lung disease, which is characterized by a lack of surfactant protein B (SP-B), were exposed to a twice-weekly application of modified SP-B mRNA via an aerosol. This treatment restored over 70% of the functional SP-B expression, and the treated mice survived the 28 days until the end of the study.
In addition, mice injected intramuscularly with modified erythropoetin mRNA, the gene that codes for the production of a hormone that stimulates the differentiation of red blood cells, showed an increase in erythrocyte count from 51.5 to 64.2% 4 weeks later. “These results clearly demonstrate the therapeutic potential of our mRNAs”, explained Rudolph, demonstrating the scope for this therapy in the treatment of genetic diseases. It is hoped that modified mRNAs will be tested in clinical trials over the next few years.
Sources: Kormann MS, Hasenpusch G, Aneja MK et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat. Biotechnol. 29(2), 154–157 (2011); Save messengers – modified mRNAs open up new therapeutic possibilities: www.eurekalert.org/pub_releases/2011-02/lm-sm020711.php
Scientists at Eindhoven University of Technology, The Netherlands, and Royal Philips Electronics, The Netherlands, have recently announced a development in their collaboration on a drug-delivery system that can be visualized and measured in real-time by MRI. The technology formed a proof-of-concept study in image-guided drug delivery currently undergoing pre-clinical trials.
The research, led by Holger Grüll at the Eindhoven University of Technology and Philips Research, involved injection of tailored, heat-sensitive liposomes – small particles containing a chemotherapeutic and an MRI contrast agent – into the bloodstream. These liposomes, once in the systemic circulation, carried the drug around the body and, eventually, to the tumor site. A combination of MRI and ultrasound technology was then used to effect local chemotherapy drug delivery. A focused ultrasound beam was directed onto the tumor site, causing the liposomes present to release their payload of the cytotoxic drug. MRI was conducted simultaneously in order to locate the tumor and guide the ultrasound beam. On heating, as well as releasing the chemotherapy, the liposomes also co-release the contrast agent. This allows for MRI measurement of the uptake of the contrast agent into the tumor and surrounding tissue, giving an indication of drug uptake. This technology would potentially allow the measurement of dose received by a tumor and, therefore, if additional and/or alternative therapy is required to treat the tumor.
Image-guided drug delivery, which offers a way to monitor the drug delivery to a tumor site, is a hot topic of research. The blood supply to a tumor is highly variable, thus, tumors poorly perfused with blood vessels are not exposed to the same dose of chemotherapy as those that are well supplied with blood. As a result, these tumors, or regions of the tumor, will receive a suboptimal dose of therapy and, therefore, remain ineffectively treated. Image-guided drug delivery would help elucidate the dose of drug a particular tumor receives, and, thus, enable increased drug delivery to the tumor, increasing efficacy without the usual corresponding increase in side effects, thereby representing the potential for greater patient comfort and compliance. When asked what this proof-of-concept study could mean in terms of treatment options in the future, Henk van Houten, Senior Vice President at Philips Research replied, “Image-guided drug delivery technology has the potential to improve chemotherapy cancer treatment for certain types of cancer”.
The research will appear in the Journal of Controlled Release. The technology is currently undergoing further preclinical studies to assess the therapeutic efficacy, with the long-term aim being human clinical trials.
Sources: Philips and Eindhoven University of Technology measure and visualize local chemotherapy delivery to tumors: www.ttkn.com/health/philips-and-eindhoven-university-of-technology-measure-and-visualize-local-chemotherapy-delivery-to-tumors-8233.html; Proof of concept demonstrated for MRI-guided chemodelivery: www.healthimaging.com/index.php?option=com_articles&view=article&id=26164:proof-of-concept-demonstrated-for-mri-guided-chemo-delivery
The Welch Foundation, one of the largest private funding sources of chemical research in the USA, has awarded its annual Hackerman Award to Jason Hafner at Rice University, TX, USA. Hafner was dubbed a ‘rising star‘ this year by the foundation in light of his research, which straddles the disciplines of physics and chemistry. The US$100,000 award and a commemorative glass statuette was presented at a prize-giving luncheon. Ernest Cockrell, chair of The Welch Foundation said of Hafner, “His creative thinking, careful experiments and willingness to tap into research tools from a variety of disciplines have led to breakthroughs in several areas and epitomize the type of scientist this award was created to recognize”. The Hackerman Award is named in honor of Norman Hackerman, a revered scientist and previous chair of The Welch Foundation‘s Scientific Advisory Board. Describing his passion for science Hafner commented, “I‘ve always known I wanted to be a scientist; nothing gets me more excited than figuring out how things work”, he continued, “To be recognized for doing what I love – especially with an award named after Norman Hackerman, a man who gave so much to science – is a very special honor”.
Hafner, earned his undergraduate degree in physics at Trinity University, TX, USA, and went on to study a postgraduate degree at Rice University. He continued to Harvard University, MA, USA where he carried out postdoctoral work before returning to Rice University in 2001 as an assistant professor in chemistry, physics and astronomy. Hafner has an interest in nanomaterials and nanoscale tools and their potential to study biological systems, in particular he studies the effect of the surface chemistry of metal nanoparticles on their growth and interaction with living cells.
One of his main discoveries includes a nanostructure dubbed ‘gold nanostars‘. These complex metallic nanostructures have elongated points and absorb/scatter light at varying wavelengths, thereby proving useful for sensing and medical imaging. The gold nanostars are also expected to have therapeutic applications. In collaboration with Dmitri Lapotko, the nanostars have been used in conjunction with lasers to create nanosized bubbles that can target and kill cancer cells. Hafner is also pursuing more analytical research, using atomic force microscopy to investigate the nature of lipid membranes, which are vital for cell function.
The Welch Foundation, based in Houston, TX, USA, contributes research grants, departmental programs and endowed chairs for the chemical sciences in Texas. In light of the emphasis placed by the foundation on the importance of teaching chemistry for the advancement of research, James Kinsey, current chair of The Welch Foundation‘s Scientific Advisory Board, states of Hafner, “He also gives back to science beyond his own research as an inspiring teacher and mentor to the next generations of scientists”.
Sources: The Welch Foundation honors ‘rising star‘ for stellar work on nanoparticles, cell membranes: www.medicalnewstoday.com/articles/215097.php; Rice scientist recognized for stellar work on nanoparticles, cell membranes: www.welch1.org/NewsRoomReports/PressReleases/HoustonScientistHon16E9.asp