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The Delphi Method Applied to Nanomedicine for Treating Cancer

The Delphi Method Applied to Nanomedicine for Treating Cancer. Presented to the Minnesota Futurists May 2, 2009 By George Kubik and David Keenan. Cancer Treatment Background.

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The Delphi Method Applied to Nanomedicine for Treating Cancer

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  1. The Delphi Method Applied to Nanomedicine for Treating Cancer Presented to the Minnesota Futurists May 2, 2009 By George Kubik and David Keenan

  2. Cancer Treatment Background • April 15, 2009 Applications with targeted nanoparticles are expected to revolutionize molecular imaging and cancer therapy. • Cancer researchers are looking to nanoparticles as agents in various nanomedicine applications – as a drug carrier capable of localizing, attaching to, and directly releasing drugs into the cell nucleus; as a cellular biomarker; and as imaging and therapy agent in cancer medicine. • In today's chemotherapy, together with radiation and surgery, doctors are pumping the patient full of cytotoxic drugs, that go everywhere in the body, with the hope that enough of the drugs reach the cancer cells and target their nuclear DNA to damage it or destroy the cell. www.nanowerk.com/spotlight/spotid=10099.php

  3. Cancer Treatment Background • Not only do chemotherapeutic techniques have a range of often serious side effects, mainly affecting all the fast-dividing cells of the body, it also has been shown that often less than 1% of the administered drug molecules enter tumor cells and bind to the nuclear DNA. • Complication: Drug resistance of cancer cells. One of the main causes of failure in the treatment of cancer. Dividing cancer cells acquire genetic changes at a high rate, which means that the cells in a tumor that are resistant to a particular drug will survive and multiply. The result is the re-growth of a tumor that is not sensitive to the original drug. • Cancer researchers are experimenting with nanoparticles as both contrast agent and drug carrier capable of pinpointing and destroying individual cancer cells. www.nanowerk.com/spotlight/spotid=10099.php

  4. Nanomedicine Background • One of the greatest challenges in developing and using cancer drugs is delivering them to the diseased tissues without poisoning the patient's entire body. • Size alone gives even simple nanoparticle therapies special properties that determine their movement into and throughout tumors. • Nanoparticles smaller than 10 nm are, like so-called small-molecule drugs, rapidly eliminated through the kidney, whereas particles larger than 100 nm have a difficult time moving through a tumor. • Particles within the 10- to 100-nm range travel throughout the bloodstream to seek out tumors, although they are unable to escape into most healthy tissues through blood vessel walls. http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer

  5. Nanomedicine Background • Because tumors, in contrast, have abnormal blood vessels whose walls are riddled with large pores, nanoparticles can leak into the surrounding tumor tissue. • As a result, nanoparticles have a tendency to accumulate in tumors while minimizing effects on other parts of the body and avoiding the traditional ravishing side effects of cancer drugs. http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer

  6. Research and Markets: Nanotechnology: Vol. 5: Nanomedicine • 30Apr09 www.researchandmarkets.com/research/77b071/nanotechnology_vo Key Topics Covered: • The next waves of medical innovations • IMAGING, DIAGNOSTICS AND DISEASE TREATMENT BY USING ENGINEERED NANOPARTICLES - THE FIRST MEDICAL APPLICATIONS ARE COMING TO THE PATIENTS' BEDSIDE... • Nanoengineered ultrasound and MRI imaging contrast agents • Nanoparticles for cancer detection and therapy • IMAGING AND PROBING THE INNER WORLD OF CELLS - MAJOR ADVANCES IN MEDICINE HAVE ALWAYS BEEN DRIVEN BY NEW TECHNOLOGIES • From molecular machines to cells: imaging with cryoelectron microscopy • Optical imaging at the nanoscale • Nanostructured probes for in vivo gene expression • Analysis of Dynamic Cytoskeleton Functions by Fluorescent Speckle Microscopy • Transport, assembly and proof-reading: harnessing the engineering principles of biological nanomotors • INNOVATIVE DISEASE TREATMENTS AND REGENERATIVE MEDICINE - UNDERSTANDING THE CELLULAR MACHINERY PROVIDES INSIGHTS INTO TOTALLY NEW WAYS OF DETECTING AND TREATING DISEASE, AS WELL AS PROMOTING TISSUE REGENERATION • Mechanical forces matter in health and disease: from cancer to tissue engineering • Stem Cells and Nanomedicine - Nanomechanics of the Microenvironment • Degenerative diseases: manipulating the micro- and nanoscale architecture regulates immunological synapse function • Bone nanostructure and its relevance to mechanical performance, disease and treatment • Nanoengineered systems for tissue engineering and regeneration • Self-assembling synthetic scaffolds for regenerative medicine

  7. Video Links • Cancer Detection with Gold Nanoparticles – May 27, 2007http://www.youtube.com/watch?v=uyhxRIvw_cY&feature=related • Nanoparticle Carrying Capacity – March 27, 2008http://www.youtube.com/watch?v=TVch-fDzet8&feature=related • Nanotechnology In Drug Delivery - March 16, 2008http://www.youtube.com/watch?v=ybK5TIGNNFA&NR=1 • Nanomedicine for Brain Tumors – July 3, 2008http://www.youtube.com/watch?v=gJgmi-D12pk • Nanomedicine Cancer Drug Delivery from PlayGenSeriousGames – sponsored by Wellcome Trust http://www.youtube.com/watch?v=tPAO0WHoaX0(1st)February 11, 2008 http://www.youtube.com/watch?v=DEcof9HlUvk (2nd) February 11, 2008 http://www.nanomission.org/ The Game Site Play

  8. NanoBiotix Example • Inert nanoparticles designed to absorb X-rays are injected into a tumor to cause more targeted treatment compared to surrounding tissue • http://www.nanobiotix.com/ video link • ‘Proof-of-concept’ preclinical study conducted by the French National Institute for Health and Medical Research validated applicability to treatment of glioblastomamultiforme, one of the most prevalent brain tumors. 09Apr09

  9. Gold Nanorod Approach • Raghuraman Kannan, Kattesh Katti, and colleagues at the Univ. of Missouri investigate design and development of targeted gold nanorods. • A recent result: The design of a novel peptide-based nanovector for carrying drug payloads to cancer sites. This vector design exploits the high affinity that bombesin peptides show towards gastrin-releasing peptides (GRP). Since GRP receptors are overexpressed in many cancers, the researchers hypothesized that bombesin peptide can act as a vehicle to deliver gold nanorods specifically to certain tumor cells. www.nanowerk.com/spotlight/spotid=10099.php

  10. Gold Nanorod Approach • These nanovectors show highly selective targeting to cancer cells without harming healthy cells (they don't show any affinity towards them). • Stability and affinity of the nanoparticle towards tumor cells are two important parameters in evaluating the in vivo applicability of an agent. The degree of stability is key in determining whether an agent can be used for in vivo purposes. The degree of affinity of conjugates to tumor cells determines whether it is truly going to attach to the targeted tumor cells. www.nanowerk.com/spotlight/spotid=10099.php

  11. Gold Nanorod Approach • "We investigated the two parameters for our gold nanoconjugates" says Kannan. "With regard to stability, we established that using thioctic acid we can add extraordinary strength to the conjugate, making it stable enough for in vivo purposes. • With regard to affinity, our studies provide quantitative data precisely estimating the affinity of conjugates toward receptors on cells, which in the case of our conjugates is very high." • Kannan explains that one of the most important factors in the development of a nanoparticle as a drug candidate is the so-called IC50 value – the half maximal inhibitory concentration. This value provides crucial information on the effectiveness of a compound in inhibiting a biological or biochemical process. www.nanowerk.com/spotlight/spotid=10099.php

  12. Gold Nanorod Approach • Gold nanorods coated with bombesin attach to GRP receptors and are taken into the cancer cell. NIR laser energy is absorbed by the gold and kills the cell with heat. Gold permits imaging of the process. www.nanowerk.com/spotlight/spotid=10099.php

  13. Polymer Nanoparticles • 23Apr09 An interdisciplinary team of researchers at Brigham and Women's Hospital (BWH) and the Harvard-MIT Division of Health Sciences and Technology has demonstrated a better way to deliver cancer drugs directly to tumors by using specially engineered nanoparticles that can inhibit a signaling pathway and deliver a higher concentration of medication to the specific area. • The team constructed the nanoparticles from a biodegradable, biocompatable, FDA-approved polymer which they chemically engineered to deliver a MAPK inhibitor. By inhibiting the MAPK signaling pathway, which is involved in a majority of human tumors, the nanoparticles hinder the multiplication of cancerous cells and predispose those cells to the cytotoxic effects of chemotherapeutic drugs. The team also modified the polymer to increase drug loading 20 fold www.emaxhealth.com/2/51/30590/delivering-cancer-drugs-directly-tumors.html

  14. Polymer Nanoparticles • The combination of nanoparticles and the cancer drug cisplatin proved successful in preventing the growth of cancerous skin and lung cells and also induced cell death. When researchers gave the same combination to mice with melanoma, it inhibited tumor growth and enhanced the efficacy of the cancer drug. The entire tumors regressed in fifty percent of mice, compared with none in the group receiving cisplatin and the inhibitor without nanoparticles. • In previous work, the group demonstrated that a combination of two drugs delivered with a nanoparticle could exert superior anti-cancer effects. However, most cancers converge into a few pathways for survival and uncontrolled division. “We thought a better strategy might be to target these pathways using nanoparticles, almost like shutting the escape route before exposing the cancer to the drugs,” www.emaxhealth.com/2/51/30590/delivering-cancer-drugs-directly-tumors.html

  15. Magnetic Targeting • April 27, 2009 Dong-Hwang Chen Distinguished Prof. Chemical Engineering at National Cheng Kung University in Tainan, Taiwan, • According to Chen, the type of nanocarrier designed by his group provides several advantages such as 1) magnetic guiding to the desired target area and fixing them at the local site while the medication is released and acts locally; 2) surface functionalization by gum arabic provides an opportunity to allow directing the therapeutic agent to selected cells away from other cells and provides a method for targeting a therapeutic agent into selected cells; 3) the combined properties of fluorescence and magnetism associated with nanoparticles offer new opportunities for in vitro and in vivo imaging; and 4) indirect photo-triggering-on-demand drug release by efficient up-converting energy of the near-IR (NIR) light to higher energy and intraparticle energy transfer from the dye-grafted magnetic nanoparticle to the linker for photo-cleavage." http://www.nanowerk.com/spotlight/spotid=10275.php

  16. Magnetic Targeting • Iron core allows particles to be magnetically guide to tumor. • Chen and group design a new class of drug nanocarriers capable of on demand drug release by efficient up-converting energy of NIR light (skin penetrating near infrared) to higher energy and intraparticle energy transfer for drug release. • The result is a multifunctional nanoparticle that can efficiently absorb the energy of NIR light and emit light of higher energy for triggering drug release by cleavage of a photosensitive linker. http://www.nanowerk.com/spotlight/spotid=10275.php

  17. IT 101 • Newer nanoparticles for example IT-101, which has already undergone human safety testing in phase I trials, have more complex designs that provide multiple functions. • IT-101 is a 30-nm particle assembled from polymers joined to the small-molecule drug camptothecin, which is closely related to two chemotherapy drugs approved by the FDA: irinotecan and topotecan. • The IT-101 particles are designed to circulate in the patient's blood and they remain there for more than 40 hours, whereas camptothecin by itself would circulate for only a few minutes. This long circulation period allows time for IT-101 to escape into tumors and accumulate there. • The particles then enter tumor cells and slowly release the camptothecin to enhance its effects. • As the drug is released, the rest of the nanoparticle components disassemble and the small individual polymer molecules harmlessly exit the body through the kidneys. http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer

  18. IT 101 • Calando’s lead drug candidate, IT-101, is comprised of Cyclosert™ in combination with the anticancer compound camptothecin for systemic treatment of cancer.  • A natural compound found in the bark of the Chinese camptotheca acuminata tree, Camptothecin has potent anticancer properties against a broad spectrum of tumor cell lines. • Method of action: inhibits the enzyme topoisomerase 1, which is key to the winding and unwinding process of DNA that is an essential step in cell division and replication.  • Interrupting this process prevents DNA replication and leads to cell death.   http://www.insertt.com/it-101.html Calando Pharmaceutical, Pasadena, CA site

  19. IT 101 • In the clinical trials, dosages of the drug were achieved that provided high quality of life without the side effects, such as vomiting, diarrhea and hair loss typical of chemotherapeutics, and with no new side effects. • The general high quality of life while on treatment is exciting, and although phase I trials focus on establishing safety, the tests also provided evidence that the drug was active in patients. That is encouraging because patients in phase I cancer trials have had numerous courses of standard therapy that failed before entering the trial. • After completing the six-month trial, several of these patients have remained on the drug on a compassionate use basis, and long-term survivors of approximately one year or more include patients with advanced lung, renal and pancreatic cancers. http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer

  20. IT 101 • Because the side-effect profile of this drug is so low, it will next be tested in a phase II (efficacy) trial in women diagnosed with ovarian cancer who have undergone chemotherapy. Instead of simply "waiting and watching" for the cancer to progress, IT-101 will be given as maintenance therapy in the hope of preventing disease progression. • These observations from IT-101 testing and similarly encouraging news from trials of other nanoparticle-based treatments are beginning to provide a picture of what may be possible with well-designed nanotherapeutics. • Indeed, the next generation of synthetic nanoparticles, which are far more sophisticated, offers a glimpse of the real potential of this technology and the importance these drugs will hold for the systems-based view of disease and treatment. http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer

  21. Nanomedicine Future For cancer, the very exciting promises that should be realized over the next 10 years are: • That presymptomatic blood diagnoses will catch fledgling cancers that can be cured by conventional therapy; • That cancers of a particular tissue (for example, breast or prostate) will be stratified into distinct types that can be matched with drugs that provide very high cure rates; • The identification of disease-perturbed networks will allow more rapid development of drugs that are less expensive and far more effective. • This new approach to medicine therefore has the potential to transform health care for virtually everyone living today.. http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer

  22. Issues for Discussion • Time until Phase III trials complete (5 yr?) • Safety Concerns • Regulatory Approval • Training of Physicians • Price of Treatment • Insurance Coverage • Should cancer be cured?

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