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DOI: 10.1089/act.2013.19601 • MARY ANN LIEBERT, INC. • VOL. 19 NO. 6 ALTERNATIVE AND COMPLEMENTARY THERAPIESDECEMBER 2013

Nanomedicine is a new direction in medicine that integrates advances in conventional and complementary and alternative (CAM) therapies. This article focuses on the concepts, advan-tages, and challenges of this emerging modality, and also ex-amines nanomedicine as a possible explanatory mechanism of action for homeopathic remedies.

Historical Background, Concepts, and Terminology

In a 1959 presentation, Richard Feynman, PhD (1918–1988)—a professor of theoretical physics at the California Institute of Technology in Pasadena, who won the Nobel Prize in physics in 1965—predicted the emergence of nano-science and nanotechnology involving the study and applica-tion of extremely small particles.1 However, it was not until the development of the scanning tunneling electron micro-scope in 1981, that enabled the viewing of individual atoms, that modern nanotechnology began. (One use of nanoscale materials in the past had included gold in stained-glass win-dows in medieval Europe.)

Nanomaterials occur both naturally (e.g., in sea spray, smoke, and volcanic ash), and in bioengineered objects. No-tably, the majority of biologic processes occur at the nano-scale level.1 Nanotechnology can be considered biomimicry, in that science learns from and applies solutions from nature to biologic systems.2

Nanomedicine is a new concept that combines advances in the interdisciplinary fields of nanoscience and medicine. Nanomedicines refer to drugs, vaccines, other health prod-ucts, and medical devices developed using nanotechnology for imaging, diagnosing, monitoring, and treating diseases at the molecular level.

Nanomedicines include nanocarriers for facilitating target-ed drug delivery and nanosuspensions to improve drug solu-bility.3 Nanomedicine utilizes nanoparticles (NPs). These are substances that measure 1–100 nanometer (nm) along at least one dimension; 1 nanometer equals 1-billionth of a meter in size. By comparison, a sheet of paper is approxi-

mately 100,000-nm thick. The resulting large ratio of surface area–to-volume in NPs, compared to larger molecular forms, confers unique physical, chemical, biologic, electromagnetic, and quantum properties on these particles.1

Advantages of nanomedicine therapeutic-agent delivery methods, compared to conventional ones, include more pre-cise and personalized disease targeting, improved permeabil-ity (the ability to enter cell membranes and cross the blood–brain barrier), longer-duration drug action, lower dosing with fewer side-effects, support of immune-system function, and use of natural agents for “green” manufacturing of less-toxic NPs. Because of these assets, the development of nanomedi-cines for treating infectious diseases of epidemic propor-tions and acute upper respiratory infections is being sought.4 There is particular interest in multifunctional therapeutic-agent carriers capable of combined targeted drug delivery as treatment modalities for cancer, brain disorders, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS).5 These hybrid treatments can include conventional and/or complementary and alternative medicine (CAM) therapies.

Integrative nanomedicine utilizes NP forms of agents used in conventional and CAM therapies. For example, NP versions of herbs and nutraceuticals can be used to treat infections be-cause of these versions’ improved bioavailability and anti-in-flammatory, antioxidant, and immunomodulatory effects.4

Nanomedicine Model for Homeopathic Remedies’ Mechanism of Action

The homeopathic principle of using minimal doses to evoke a therapeutic response in a patient has been the most controversial aspect of this well-established modality. Previous theories for the effects of classic homeopathic remedies (typically plant, min-eral, or animal in nature) have included: the persistent chemi-cal “memory” of unique water structures; properties of ethanol–water solutions in glass containers used in dilutions; and epitaxy (the growth of a thin layer on the surface of a crystal so that the layer has the same structure as the underlying crystal).6 These theories bear similarities to the ideas behind nanoscience.

Integrative NanomedicineAn Emerging Therapeutic Approach

Sala Horowitz, PhD

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Integrative NanomedicineAn Emerging Therapeutic Approach

Although a fair body of empirical evidence exists for the ef-ficacy of homeopathic medicines for treating certain condi-tions, practitioners and scientists have been unable to explain fully the mechanisms of action for these remedies, because they consist of minutely diluted amounts of products of serial stepwise dilutions (1:100 per step) of a wide variety of sub-stances at high potencies on the “C” (centesimal) scale. In ho-meopathic medicine, the higher the dilution, the more potent the remedy is considered to be.

The classic preparation process for homeopathic remedies involves serial succussions (vigorous shaking of ethanol–water solutions in glass containers) and/or trituration (mechani-cal grinding of a drug powder with an inert diluent, such as lactose, in a definite proportion by weight). In principle, this process leaves progressively fewer and fewer molecules of bulk-form source materials until, eventually, none should persist in the solution.

Critics have argued that, at such levels of dilution, these preparations do not contain any measurable traces of the source materials that could have biologic effects. However,

physiochemical studies of high-potency solutions have es-tablished the presence of the raw source materials and solu-tion silica NPs even in dilutions beyond Avogadro’s number (6 × 1023 molecules), creating, in effect, “top-down” nano-structures. The hypothesis proposed to explain this phenom-enon is that, once the bulk concentration is below a thresh-old level of a few nanograms/mL, at the end of each dilution step, the NPs rise to the surface as a mono-layer at the air–liquid interface. Consequently, dilution concentrations are only apparent rather than real, with the NPs being preserved and carried over at each dilution step.7

The biologic effects of such ultradiluted concentrations of substances are also known as dose-dependent reverse effects or hormesis.8 Hormesis is defined as “a theoretical phenomenon of dose-dependent relationships in which something. . .that produces harmful biological effects at moderate or high doses may produce beneficial effects at low doses.”9

Researchers at the Department of Family and Community Medicine at the University of Arizona’s College of Medicine in Tucson—including Iris R. Bell, MD, PhD, a professor of psychiatry and psychology, who is also the director of research for the university’s Center for Integrative Medicine—have suggested that homeopathic medicine, with its reliance on ex-tremely small molecules, is actually a form of nanomedicine.4 Based on this rationale, a proposed model for the nature and mechanism of action treats homeopathic remedies involving

succussion and/or trituration as containing source material and silica solution NPs. Dilutions of 12 C strength and above are considered to be “ultramolecular dilutions” by homeopaths.10

A systematic review of 67 studies (a third of them replica-tions) that assessed the evidence base for the in-vitro effects of high-potency homeopathic medicines found that nearly 75% of them demonstrated an effect. While the investigators recommended improved methodologies (adoption of random-ization, controls for liquid succussions of remedies, and blind-ing) to strengthen the evidence for future experiments, the researchers concluded that such dilutions had biologic effects, thus countering skeptics’ contention that such remedies consist of nothing but water.11

Rather than producing pharmacologic effects, the NPs of homeopathic remedies are hypothesized to act as low-level stressors that stimulate signals to induce adaptive changes in an organism. These signals, in turn, evoke responses in the com-plex, interconnected biologic stress-response network (e.g., cy-tokines, neuroendocrine pathways, inflammasomes [molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleu-kin], and heat shock proteins). To represent this mechanism of action in the context of nanoscience, it has been proposed that the term “adaptive network nanomedicine” now be used instead of homeopathy.12

This proposed model for homeopathic remedy effects is called the nanoparticle-allostatic cross-adaptation-sensitiza-tion model. The central thesis of this model is that homeo-pathic remedies are a form of nanomedicine, acting as mild stressors to mobilize hormesis and thereby enhancing systemic adaptive responses, long-term resilience, and health. Allostatic refers to the stress-response network’s tendency toward ho-meostasis. Cross-adaptation and sensitization refer to the role of nanodose homeopathic remedies prescribed in intermit-tently spaced doses to act as low-level stressors that can reverse dysfunctional responses to endogenous stressors, depending on a patient’s medical history. Differences in the size, structure, and aggregation of NPs also affect remedy properties and the reproducibility of results.6,13

Analyses of homeopathic medicines by advanced techno-logical methods, including examination under scanning and transmission electron microscopes, showed that the remedies had NPs and conglomerates of them of a crystalline nature. As forms of silica are known to interact with proteins in the im-mune system, the examiners concluded that homeopathy may represent a nanomedicine system.14

Grapefruit-Derived Nanovectors

Although nanotechnology has the potential to deliver a wide range of therapeutic treatments in a manner that reduces adverse effects associated with conventional drug therapy, spe-cifically, targeted drug delivery remains a challenge. NPs made of grapefruit-derived lipids have been demonstrated in experi-mental models to co-deliver, with folic acid, chemotherapeutic

Researchers have suggested that homeopathic medicine, with its

reliance on extremely small molecules, is actually a form of nanomedicine.

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and other therapeutic agents to different types of cells. In such models, drug delivery via these NP-based vectors prompted inhibition of tumor growth.

Huang-Ge Zhang, PhD, a professor of microbiology and immunology at the University of Louisville, Kentucky, commented: “These nanoparticles, which we have named grapefruit-derived nanovectors,. . .are less toxic for patients, result in less hazardous waste for the environment and are much cheaper to produce at large scale than nanoparticles made from synthetic materials.” Considering how our an-cestors selected foods to eat, Dr. Zhang explained that “it made sense for us to consider [edible] plants as a mecha-nism to create medical nanoparticles as a potential nontoxic therapeutic delivery vehicle.”15

Dr. Zhang’s research team validated the potential of grape-fruit-derived NPs further in a phase I clinical trial for treating patients with colon cancer. Thus far, no toxicity has been ob-served in patients who ingested the anti-inflammatory agent curcumin (a component of turmeric; Curcuma longa) encapsu-lated in the grapefruit-derived NPs orally. The team is plan-ning to study if grapefruit-derived NPs can be used to treat inflammation-related autoimmune diseases such as rheuma-toid arthritis.15

Researchers at the University of California, San Diego, have also taken a cue from natural structures in designing NPs. These NPs, likewise, are used to target cancerous and other diseased tissues.16

Nanomedicine for Treating Specific Disorders

Esther Chang, PhD—a professor of oncology and oto-laryngology at the Lombardi Comprehensive Cancer Cen-ter at Georgetown University in Washington, DC, and president of the American Society for Nanomedicine (see Resource)—believes that nanomedicines will revolutionize research into understanding and treating such diseases as cancer and HIV/AIDS. Nanoscale agents, with their unique properties, can facilitate targeted drug delivery with fewer side-effects, and even stimulate the body’s own immune system to fight such diseases.17

Neurodegenerative DisordersNanomedicines may deliver neuroprotective proteins and

alter the antioxidant state of affected neural tissues in de-generative and inflammatory diseases of the central nervous system (CNS). These conditions include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, amyotrophic lateral sclerosis (commonly known as Lou Gehrig’s disease), and neurocognitive disorders associ-ated with HIV/AIDS.18

HIV/AIDS Nanoformulations of existing (or novel) antiretroviral drug

treatments for HIV/AIDS may reduce the wide variability of patient response and reduce the risk of drug resistance. The

Royal Liverpool University Hospital, in the United Kingdom, plans to test new nanoscale treatment approaches that could be used to treat the approximately 34 million adults and children with the disease worldwide.19

Because gold is biocompatible, it is a suitable candidate for use in nanomedical approaches. In the case of therapies for HIV/AIDS, evidence suggests that placing small molecules on the surface of gold NPs can convert inactive agents into po-tent viral inhibitors. Silver NPs have also been demonstrated, in vitro, to interact with the virus causing HIV and inhibit infection in a size-dependent manner. Nanoformulations that can breach the blood–brain barrier are important in CNS dis-orders, because the brain is a sanctuary for a broad range of pathogens, including HIV-1.20

CancerAlthough positively charged gold NPs are usually toxic to

cells, cancer cells were found to be resistant to them. But with the better understanding of basic cellular processes that nano-science has provided, researchers were able to formulate gold NPs with enhanced targeting of ovarian cancer tumor cells while sparing healthy cells.21

Researchers at the University of Central Florida in Orlando have developed an NP-based potential alternative to chemo-therapy for patients diagnosed with cancer. Using Taxol® (pa-clitaxel), a standard chemotherapeutic drug, which produces degradation of noncancerous and cancerous cells, the team en-gineered NPs that increased the specificity of the drug to target only the cancerous cells. The research team was able to increase the agent’s specificity by attaching folic acid (vitamin B9)—which cancer cells consume in large amounts—to the NPs that released their therapeutic “cargos” selectively via cell receptors to cells in tumors, thus sparing patients systemic side-effects.22

Radioactive gold NPs combined with epigallocatechin-gallate—a phytochemical component of green tea with potent antioxidant properties that has been shown to be beneficial for treating various cancers—could spare patients with prostate cancer many of the systemic-side effects of chemotherapy by delivering therapeutic agents with smaller, more precisely tar-geted doses. An additional advantage of this flavonoid is its ability to target the laminin receptor, which is overexpressed in human prostate-cancer cells. This integrative nanomedi-cine approach has been tested successfully in animal models.23 Curcumin, a yellow polyphenol extracted from the rhizome of turmeric, which has been found to be effective against some cancers, has also been shown, in cell cultures, to facilitate more efficient NP-based drug delivery in prostate cancer.24

Cardiovascular DiseasesCardiovascular diseases, including hypertension and heart fail-

ure, are associated with activation of the renin-angiotensin system (RAS) and increased circulating and tissue levels of ANG II, a RAS peptide that plays a major mediating role in the pathogen-esis of cardiovascular disease. ANG II induces vasoconstriction, cardiac and vascular hypertrophy, sodium and water reabsorption in the kidneys, and excitation of the sympathetic nervous system

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and the overall immune system. A new nanomedicine-based strategy for improved treatment of cardiovascular disease is the development of specific antioxidant molecules or proteins.25

Antibiotic-Free Nanotherapeutics

Hypericin is a naturally occurring, potent photosynthesizer found in the common St. John’s wort (Hypericum perforatum) hypericum species. However, its lipophilicity (solubility in fats but not in water) limits its therapeutic applications for photo-dynamic therapy and wound healing. Experimental models of biodegradable nanocarriers for hypericin capable of preserving its antibacterial photoactivity confirmed the healing potential of nanoencapsulated hypericin.26

Health and Safety Concerns

Despite their advantages, nanomedicine-based approaches face several challenges beyond those encountered by con-ventional medicines during clinical development, including methods for the accurate characterization of NPs size, struc-ture, composition, and the design of multifunctional nano-medicines for novel combination therapies with supportable levels of bioaccumulation.27

The unique physical and biologic properties of substances at the nanoscale have raised concerns about toxicity and other po-tential adverse effects of NPs on human health and the environ-ment. These concerns are pressing, as the number of consumer products containing NPs, available in the United States, has been estimated by the Project on Emerging Nanotechnologies as being more than 1000. While that number is rapidly growing, there are also concerns that the U.S. Environmental Protection Agency’s research response strategy has not been keeping pace. It has been pointed out that even naturally occurring NPs can have a deleterious effect on the human body.28 Furthermore, minimal information is currently available on how NPs interact with the body’s systems and their health effects on the body.29

For example, NPs are currently present in many U.S. sun-screens as forms of either titanium dioxide or zinc oxide. Al-though generally scoring well in being protective against skin

cancer and the dermatologic effects of aging, debates exist over whether or not such products should be required to be labeled as containing NPs.30 A survey of sunscreen manufacturers by Friends of the Earth, an environmental group based in Wash-ington, D.C., found that only 9 of 38 respondents, of 128 com-panies, reported that they did not use NPs in their products.31 However, the group cautions that some claims that products do not contain nanoingredients are misleading.

In addition, although sunscreen lotions applied to the skin do not appear to pose skin-penetration problems, inhaled NPs from spray sunscreens may be hazardous. At the very least, the survey author recommended that manufacturers be required to label products that contain NPs.31

Product safety, quality control, and effectiveness can vary as size goes up or down the nanoscale, complicating further the product review process by regulatory agencies.32 To provide a regulatory and funding framework for research into nanoscience to prevent unintended consequences for public health and the environment, the U.S. National Nanotechnology Initiative was created in 2000, published in 2008, and updated in 2011.33

Conclusion

Nanomedicine utilizes materials at a molecular scale that have unique properties and hold promise for treating health problems with greater therapeutic targeting and fewer side-effects than conventional pharmaceuticals. However, further research into the behavior and effects of NPs needs to be con-ducted to have greater clinical utility.

Most nanomedicines at present are nanoscale formulations of conventional pharmaceutical drugs. However, theoretical models suggest approaches for further research into the mech-anisms of action and evidence-based utilization of integrative nanomedicine that combines nanoscience with homeopathic and other CAM modalities. Further research is warranted to corroborate existing empirical evidence indicating that NPs are present in homeopathic remedies. Integrative nanomedi-cine is clearly a promising wave of the future. n

References

1. National Nanotechnology Initiative. Nanotechnology 101. Online docu-ment at: www.nano.gov/nanotech-101 Accessed July 3, 2013.2. Kumar R. The Emerging Therapy of Tomorrow with Nanomedicine: Pres-ent Status. Internet J Neurol 2008;10. Online document at: http://archive.ispub.com/journal/the-internet-journal-of-neurology/volume-10-number-1/the-emerging-therapy-of-tomorrow-with-nanomedicine-present-status.html#sthash.XXRgFyGF.dpbs Accessed July 28, 2013.3. Hock SC, Ying YM, Wah CL. A review of the current scientific and regu-latory status of nanomedicines and the challenges ahead. PDA J Pharm Sci Technol 2011;65:177–195.4. Bell IR, Schwartz GE, Boyer NN, et al. Advances in integrative medicine for improving infectious disease treatment in public health. Eur J Integr Med 2013;5:126–140.5. Muthu MS, Singh S. Targeted nanomedicines: Effective treatment modalities for cancer, AIDS and brain disorders. Nanomedicine (Lond) 2009;4:105–118.

ResourceAmerican Society for Nanomedicine (ASNM)

Georgetown University Medical Center 3970 Reservoir Road NW Washington, DC 20057 Phone: (202) 687-8418 E-mail: estherchang@amsocnanomed.org Website: www.amsocnanomed.org Contact: Esther Chang, PhDThe ASNM is a nonprofit multidisciplinary professional,

academic, and medical organization dedicated to ad-vancing research in the emerging field of nanomedicine.

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22. New Nanoparticles Could Lead to End of Chemotherapy. Science Daily, June 17, 2009. Online document at: www.sciencedaily.com/releases/2009/ 06/090616121343.htm Accessed July 27, 2013. 23. Shukla R, Chanda N, Zambre A, et al. Laminin receptor specific thera-peutic gold nanoparticles (198AuNP-EGCg) show efficacy in treating prostate cancer. Proc Natl Acad Sci U S A 2012;109:12426–12431. 24. Yallapu MM, Dobberpuhl MR, Maher DM, et al. Design of curcumin loaded cellulose nanoparticles for prostate cancer. Curr Drug Metab 2012;13: 120–128. 25. Rosenbaugh EG, Savalia KK, Manickam DS, Zimmerman MC. Antioxi-dant-based therapies for angiotensin II-associated cardiovascular diseases. Am J Physiol Regul Integr Physiol 2013;304:R917–R928. 26. Nafee N, Youssef A, El-Gowellli H, et al. Antibiotic-free nanotherapeu-tics: Hypericin nanoparticles thereof for improved in vitro and in vivo antimi- crobial photodynamic therapy and wound healing. Int J Pharm 2013;454:249–258.27. Wei A, Mehtala JG, Patri AK. Challenges and opportunities in the ad-vancement of nanomedicines. J Control Release 2012;164:236–246.28. Editors. Nano-Risks: A Big Need for a Little Testing: The EPA Must Act Swiftly to Evaluate the Possible Health Risks of Nanotechnology. Scientific American, December 23, 2009. Online document at: www.scientificamerican.com/article.cfm?id=big-need-for-a-little-testing Accessed September 17, 2013.29. Centers for Disease Control and Prevention. Workplace Health & Safety Issues: Nanotechnology. Online document at: www.cdc.gov/niosh/topics/nanotech/ Accessed September 17, 2013.30. Environmental Working Group. Nanoparticles in Sunscreens. Online doc- ument at: www.ewg.org/2013sunscreen/nanoparticles-in-sunscreen/ Accessed July 8, 2013.31. Biello D. Do Nanoparticles and Sunscreen Mix? Your First Encounter With “Better” Living Through Nanotechnology May Be Your Sunscreen. Scientific American, August 2007. Online document at: www.scientifi camerican.com/article.cfm?id=do-nanoparticles-and-sunscreen-mix Accessed July 8, 2013.32. U.S. Food and Drug Administration. Science & Research: FDA Readies for More “Nanoscale” Challenges. Online document at: http//www.fda.gov/ ScienceResearch/SpecialTopics/Nanotechnology/ucm153723.htm Accessed July 8, 2013. 33. National Nanotechnology Initiative. Nanotechnology and You: Environ-mental, Health, and Safety Issues. Online document at: www.nano.gov/you/environmental-health-safety Accessed July 6, 2013.

To order reprints of this article, e-mail Karen Ballen at: Kballen@liebertpub.com or call (914) 740-2100.

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