Cutaneous drug delivery offers many advantages over alternative routes of administration with regards to target specific impact, decreased systemic toxicity, avoidance of first pass metabolism, variable dosing schedules, and broadened utility to diverse patient populations.
A complicating factor is that the skin has evolved mechanisms to impede exogenous molecules, especially hydrophilic ones, from safe passage. The horny layer of the stratum corneum (the top most layer of the skin) is tightly bonded to an intercellular lipid matrix making the passage of therapeutics a serious challenge1. This strong barrier to molecular activity is quite effective at blocking large drugs (molecular mass > 500 Da), which of course make up the majority of active therapeutics2.
Mechanical abraders and micro-needles can open a limited number of relatively wide (≥ 103 nm) pores in the skin barrier, that can allow for transient passage of small and even large molecules (or even bacteria)3. Disruption with either ultrasound (phonopheresis) or high-voltage electrical pulsing (electroporation) has been used to force larger materials through this complex barrier. Chemical penetration enhancers are also utilized in order to perturb the epidermal barrier, though safety concerns have limited their efficacy4-6.
Furthermore, many substances that could, in theory, be used as topical therapeutics have several disadvantages in that they are:
1. weakly or not soluble in water;
2. degraded or inactivated prior to reaching the appropriate target;
3. nonspecifically distributed to tissues and organs, resulting in undue adverse side effects and limited efficacy at the target site
Nanotechnology and Delivery Vehicles
Novel delivery vehicles generated through nanotechnology is raising the exciting prospect for controlled and sustained drug delivery across the impenetrable skin barrier. Particles 500 nm and smaller exhibit a host of unique properties that are superior to their bulk material counterparts7-9. Small size is a necessary feature but other properties are needed for nanomaterials to achieve efficacy as a topical delivery vehicle.
Optimally these nanoparticles should:
1. carry drugs through cutaneous pores in the primary skin barrier;
2. release the transported drug spontaneously once penetration is achieved; and
3. exhibit low rates of cutaneous drug clearance allowing for deep/targeted deposition and prolonged action of the carrier-transported drugs.
Additionally, these products should be able to adjust to relevant physiologic variations as part of their design and targeting.
Nanotechnology Becoming a Major Focus in Dermatology Research
Given the potential significant therapeutic benefits listed above, it is no surprise that nanotechnology is becoming a major focus of dermatologically oriented product development7, 10-14. The sixth largest patent holder of nanotechnology in the United States is a cosmetics company15,16. In fact, cosmetic companies are above the curve with respect to their nanotechnology research efforts as compared to industry giants like Motorola and Kodak. While nano-manufacturing can be costly and require sophisticated facilities, mass production, decreasing prices, and exponential growth are expected control costs in the future and allow this science to blossom. Some estimates place nanotechnology by 2012 to be a $2 trillion industry, employing two million in the United States alone7. Applications are underway in medicine and dermatology for the early detection, diagnosis, and targeted therapy of disease7,9,10,12,13,17-24.
As can be expected with any technology in its infancy, of the potential and excitement must be tempered with the realization that there are still pitfalls and remaining concerns regarding safety23,25-35. The skin is the first point of contact for most environmental nanomaterials, regardless of medium in which they are delivered. The risks of nanomaterials in the world of dermatology are therefore extensive, ranging from irritant or allergic contact dermatitis to foreign body reactions to tissue death27.
Theoretically speaking, the toxic potential of any material can be predicted to be exponentially proportional to a decrease in particle size. First, smaller size allows for deeper penetration of encapsulated chemicals, and for enhanced intracellular penetration and systemic absorption. Second, just as a greater surface area to volume ratio confer nanomaterials with significant advantages over their macromolecular counterparts, so too does it dramatically increase the availability of surface groups for interaction with tissues and cells. If the surface groups are chemically reactive and are capable of generating reactive oxygen species, the potential for reactivity increases with decreasing particle size28. Lastly, the toxicity of both insoluble and inert nanoparticles in mammalian cells can be directly related to their cellular uptake. Some cells, such as keratinocytes, have the ability to phagocytose small molecules, and when nanomaterial are internalized, they can accumulate in cells and ultimately result in DNA damage and cytotoxicity through the generation of oxidative stress36.
Therefore, it is of the utmost importance that the toxicology of nanotechnologies be appropriately elucidated to both protect the public from potentially harmful materials, but also to allay public fears and media speculation that can prevent this promising technology from being cultivated and utilized.
The Current State of Nanotechnology in Dermatology
Many areas of medicine, such as oncology37 and diagnostic radiology38 have been incorporating nanotechnology into their teaching, education, and research. Dermatology has been lagging in this area despite the seemingly paradoxical observation that a significant proportion of new developments in nanotechnology have been in consumer skin care. Recent data from a pilot study (Friedman and Nasir, unpublished) revealed that there is a strong agreement among dermatologists nationwide that nanotechnology teaching, education, and research are both necessary and important facets of Dermatology.
Furthermore, respondents indicated that there is a need for improved and more rigorous oversight and regulation of these technologies, though it was unclear either how this could be accomplished or how dermatologists can get involved. In fact, until recently, there have not been any dermatology organizations or groups in the United States dedicated to addressing these issues.
The Nanodermatology Society (NDS)
The Nanodermatology Society was founded in 2010 to bring together individuals from a broad array of linked disciplines who share a common interest in nanotechnology as it relates to dermatology.
The society and members are charged with the following mission:
1. to closely monitor developments in nanotechnology as they relate to dermatology;
2. to meet informally and formally at congresses, scientific conferenceand teaching events with the purpose of educating and informing members on developments in nanotechnology and dermatology;
3. to exchange research and ideas on nanotechnology advances;
4. to sponsor research and education in nanotechnology; and
5. to develop policies and positions to benefit consumers, academia, regulatory bodies, and industry11.
The primary focus of the NDS will be monitoring nanotechnology, studying new developments in the field, and evaluating their potential. The NDS will focus on potential beneficial uses of this new technology, as well as potential dangers. NDS members will critically question the suggested benefits and risks of available and developing nanotechnologies based on the latest available data. The impact on consumers, workers, medical personnel, society, and the environment will all be considered. Most importantly, findings will be shared and distributed as part of the NDS's educational mission through various outlets.
As part of its regulatory mission, the NDS will develop safety guidelines based on current medical and dermatologic understanding and reports from toxicology testing agencies. The NDS will communicate these findings to the society, regulatory bodies, and to law and policy makers.
The dermatologic community is not yet aware of all the benefits and drawbacks to nanotechnology. Yet, dermatology is a vibrant discipline poised to yield new discoveries in the diagnosis and management of disease utilizing nanotechnology. This is the perfect time to educate dermatologists, colleagues, consumers, and workers about nanotechnology.
Hybrid Nanoparticles as a Vehicle for the Delivery of Nitric Oxide
Interest in the therapeutic potential of nitric oxide (NO) has been growing exponentially over the past few decades39-51. This interest is a direct result of findings demonstrating an ever-expanding range of functionalities associated with NO under physiological conditions. These established properties not only have direct therapeutic implications for the treatment of infections, modulation of vasoactivity, angiogenesis, and wound healing, but also provide a basis for our understanding of many diseases ranging from asthma to psoriasis52-55.
Harnessing this potential has proven difficult as reflected by the intense but relatively unsuccessful efforts to develop therapeutically useful NO delivery devices/vehicles56. Clinical use of these materials has been limited due to cost, cytotoxicity, instability of the chemical compounds, potential carcinogenicity, and development of tolerance to the NO releasing substances56. The hybrid nanoparticles overcomes many of the existing limitations associated with the current NO releasing strategies.
It combines the beneficial features of two distinct materials. Firstly, polysaccharide-derived glassy matrices that support the conversion of nitrite to NO as well as retention of NO within the matrix57; Secondly, silane-derived, porous hydrogel that provides a relatively rigid skeleton. Alone, glassy matrices suffer from the limitation that they rapidly dissolve following exposure to water. The hydrogel matrix, though more stable in water, is highly porous, allowing a rapid escape of contents. The hybrid platform overcomes these limitations by using the glassy matrix not only to generate the NO, but also to plug the pores of the hydrogel. The hydrogel component provides structure and stability, slowing the breakdown of the glass in solution58.
The nanoparticle skeleton is formed using alkoxysilanes, which have two key benefits. First, they are already widely used in the production of self-forming nanoparticles. That is, products based on alkoxysilanes do not require any particle size reduction steps in order to create the nanoparticle: they are created during the manufacturing process itself. Second, the physical structure of these types of nanoparticles is that of a highly porous network or skeleton59-63. The NO glassy matrix is a unique concept that capitalizes on well-known chemistries and comprises three main components. Sodium nitrite in the presence of glucose in a glassy matrix undergoes a redox reaction that generates NO gas57,64,65.
In the current platform, the glassy properties are believed to be derived from the strong hydrogen bonding network forged from the interaction between chitosan, a cationic polysaccharide, and the anionic hydrogel side chains. It is this strong hydrogen bonding network that both allows for the glucose-mediated generation of NO, as well as the entrapment of the NO gas. Polyethylene glycol (PEG) polymers of different molecular weights are used to regulate the rate of NO release. As mentioned previously, upon exposure to an aqueous environment, the glassy matrix dissolves allowing release of the NO.
The composition of the nanoparticles allows both for retention of the NO within the dry particles, as well as for slow sustained release of therapeutic levels of NO over long time periods when exposed to moisture/water58. Unlike many of the current NO releasing materials, NO release from nps requires neither chemical decomposition nor enzymatic catalysis. Instead, release of NO from the nps requires only exposure to water56. The release profile for the NO is found to be easily tuned through straightforward manipulation of the relative concentrations of the components used in preparing the hydrogel/glass composites that is basis for the np platform58.
The Application of Nitric Oxide as a Drug Delivery Vehicle
The potential for broad applicability for this NO releasing nanoparticulate platform is emerging though a series of translational projectsa. First and foremost, cutaneous penetration and safety of the hybrid nanoparticles in vivo has thus far been demonstrated. Penetration of fluorescent nanoparticles was visualized both using total body infrared imaging up to twenty four hours following initial application and by histologic sectioning of involved skin in animal models as well nails from human subjects . Repeated applications of the nanoparticles to murine skin demonstrated no pathologic changes to the involved skin, such as thickeneing of the epidermis or increased inflammatory infiltrate. Though these initial studies are promising, continued investigations are underway to fully appreciate any issues with safety.
Because the role of NO in wound healing and antimicrobial activity is well established42,54,66-70, it is a major focus of this work. Treatment with NO-nps results in accelerated wound closure both in fibroblast migration assays and in vivo splinted murine wound model71-73. Antimicrobial in vitro efficacy against Methicillin Resistant S aureus (MRSA)74, Mycobacterium tuberculosis, Acenitobacter baumannii75 has been established .
Topical application of NO nanoparticles to in vivo MRSA and A. baumannii infected excision models results in acceleration of wound healing and clearance of bacterial burden as compared to controls clinically and histologically74,75. To extend these results further, topical application of NO nps in an induced in vivo MRSA abscess model, demonstrating a dose dependent impact on lesion resolution based on wound size, histology, and cytokine profiling from abscess sites76. Therapeutic comparative studies are underway, and preliminary studies have demonstrated that topical and intralesional treatment with NO nps in the MRSA abscess model was significantly more effective than topical Retapamulin and intravenous Vancomycin following four days of treatment based on clinical assessment and wound cultures.
The important role of NO in maintaining vascular health lead to our testing the efficacy of NO nps in addressing conditions associated with endothelial dysfunctions. NO nps increased erectile function when applied topically to the penis of rats that were developed as a model of erectile dysfunction77. In a dose-dependent manner, intravenously (IV) administered, circulating NO nps increased exhaled NO concentrations, decreased mean arterial blood pressure (MAP) and increased microvascular flow over several hours, without inducing an inflammatory response as compared to control nanoparticles78.
When compared to two well known NO donors, DETA NONOate and DPTA NONOate, similar decreases in MAP were witnessed. However, the impact on vascular tone following NONOate use was highly inefficient as compared to NO nps, requiring 30 times more NO release to induce a similar physiological response. This pitfall manifested as a significant effect on methemoglobin formation by NONOate administration with subsequent decrease in hemoglobin oxygen carrying capacity.
Translating these findings, the potential role of the NO-nps in vascular disorders of hemodynamic distress has been investigated. Intravenously administered NO nps are observed both to counteract systemic hypertension following infusion of an NO scavenging hemoglobin based oxygen carrier, improving systemic and microvascular function. Furthermore, IV NO-nps were able to correct the negative, potentially life threatening hemodynamic changes during hemorrhagic shock - the continuous NO released by the NO-nps reverted arteriolar vasoconstriction, recovered functional capillary density and microvascular blood flows, and prevented cardiac decompensation. These data suggests that the NO nps have a clear potential to replenish NO in situations were NO production is impaired, insufficient or consumed (e.g. endothelial dysfunction, metabolic disorders and hemolytic diseases).
Together these data demonstrate the clear potential of the NO nps not only as a therapeutic agent for inflammatory, infectious, and vascular/cardiovascular, but also as a promising tool to promote our understanding of NO signaling mechanisms.
1. Elias PM. Stratum corneum defensive functions: An integrated view. Journal of Investigative Dermatology. Aug 2005;125(2):183-200.
2. Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. Jun 2000;9(3):165-169.
3. Staples M, Daniel K, Cima MJ, Langer R. Application of micro- and nano-electromechanical devices to drug delivery. Pharm Res. May 2006;23(5):847-863.
4. Kupper TS. Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. J Clin Invest. Dec 1990;86(6):1783-1789.
5. Williams IR, Kupper TS. Immunity at the surface: homeostatic mechanisms of the skin immune system. Life Sci. 1996;58(18):1485-1507.
6. Cevc G. Transfersomes, liposomes and other lipid suspensions on the skin: Permeation enhancement, vesicle penetration, and transdermal drug delivery. Critical Reviews in Therapeutic Drug Carrier Systems. 1996;13(3-4):257-388.
7. Nasir A. Nanotechnology and dermatology: Part I-potential of nanotechnology. Clinics in Dermatology. Jul-Aug 2010;28(4):458-466.
8. Cevc G, Vierl U. Nanotechnology and the transdermal route A state of the art review and critical appraisal. Journal of Controlled Release. Feb 2010;141(3):277-299.
9. Farokhzad OC. Nanotechnology for drug delivery: the perfect partnership. Expert Opinion on Drug Delivery. Sep 2008;5(9):927-929.
10. Zippin JH, Friedman A. Nanotechnology in Cosmetics and Sunscreens: An Update. Journal of Drugs in Dermatology. Oct 2009;8(10):955-958.
11. Nasir A, Friedman A. Nanotechnology and the Nanodermatology Society. Journal of Drugs in Dermatology. Jul 2010;9(7):879-882.
12. Mu L, Sprando RL. Application of Nanotechnology in Cosmetics. Pharmaceutical Research. Aug 2010;27(8):1746-1749.
13. Zhang SF, Uludag H. Nanoparticulate Systems for Growth Factor Delivery. Pharmaceutical Research. Jul 2009;26(7):1561-1580.
14. Ochekpe NA, Olorunfemi PO, Ngwuluka NC. Nanotechnology and Drug Delivery Part 1: Background and Applications. Tropical Journal of Pharmaceutical Research. Jun 2009;8(3):265-274.
15. Nasir A. NanoPresent and NanoFuture: The growing role of shrinking technology in dermatology. . Cosmetic Dermatology. 2009;22(4):194-200.
16. Chen H, Roco MC, Li X, Lin Y. Trends in nanotechnology patents. Nat Nanotechnol. Mar 2008;3(3):123-125.
17. Deli G, Hatziantoniou S, Nikas Y, Demetzos C. Solid lipid nanoparticles and nanoemulsions containing ceramides: Preparation and physicochemical characterization. Journal of Liposome Research. Sep 2009;19(3):180-188.
18. Jiang W, Kim BYS, Rutka JT, Chan WCW. Advances and challenges of nanotechnology-based drug delivery systems. Expert Opinion on Drug Delivery. Nov 2007;4(6):621-633.
19. Kumar M, Mumper RJ. Nanotechnology in advanced drug delivery. Journal of Biomedical Nanotechnology. Apr 2007;3(1).
20. Liu XL, Lee PY, Ho CM, et al. Silver Nanoparticles Mediate Differential Responses in Keratinocytes and Fibroblasts during Skin Wound Healing. Chemmedchem. Mar 2010;5(3):468-475.
21. Nasir A. Nanotechnology in Vaccine Development: A Step Forward. Journal of Investigative Dermatology. May 2009;129(5):1055-1059.
22. Petrak K. Nanotechnology and site-targeted drug delivery. Journal of Biomaterials Science-Polymer Edition. 2006;17(11):1209-1219.
23. Somasundaran P, Mehta SC, Rhein L, Chakraborty S. Nanotechnology and related safety issues of or delivery of active ingredients in cosmetics. Mrs Bulletin. Oct 2007;32(10):779-786.
24. Zuo L, Wei WC, Morris M, Wei JC, Gorbounov M, Wei CM. New technology and clinical applications of nanomedicine. Medical Clinics of North America. Sep 2007;91(5):845-+.
25. Brayner R. The toxicological impact of nanoparticles. Nano Today. Feb-Apr 2008;3(1-2):48-55.
26. Hu YL, Gao JQ. Potential neurotoxicity of nanoparticles. International Journal of Pharmaceutics. Jul 2010;394(1-2):115-121.
27. Nasir A. Nanotechnology and dermatology: Part II-risks of nanotechnology. Clinics in Dermatology. Sep-Oct 2010;28(5):581-588.
28. Nasir A. Nanotechnology safety. Journal of Investigative Dermatology. Apr 2008;128:S83-S83.
29. Nohynek GJ, Dufour EK, Roberts MS. Nanotechnology, cosmetics and the skin: Is there a health risk? Skin Pharmacology and Physiology. 2008;21(3):136-149.
30. Nohynek GJ, Lademann J, Ribaud C, Roberts MS. Grey goo on the skin? Nanotechnology, cosmetic and sunscreen safety. Critical Reviews in Toxicology. Mar 2007;37(3):251-277.
31. Panyala NR, Pena-Mendez EM, Havel J. Silver or silver nanoparticles: a hazardous threat to the environment and human health? Journal of Applied Biomedicine. 2008;6(3):117-129.
32. Paschoalino MP, Marcone GPS, Jardim WF. NANOMATERIALS AND THE ENVIRONMENT. Quimica Nova. 2010;33(2):421-430.
33. Sandoval B. Perspectives on FDA's Regulation of Nanotechnology: Emerging Challenges and Potential Solutions. Comprehensive Reviews in Food Science and Food Safety. Oct 2009;8(4):375-393.
34. Stern ST, McNeil SE. Nanotechnology safety concerns revisited. Toxicological Sciences. Jan 2008;101(1):4-21.
35. Tinkle SS. Maximizing safe design of engineered nanomaterials: the NIH and NIEHS research perspective. Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology. Jan-Feb 2010;2(1):88-98.
36. Gorog P, Pearson JD, Kakkar VV. Generation of reactive oxygen metabolites by phagocytosing endothelial cells. Atherosclerosis. Jul 1988;72(1):19-27.
37. Grobmyer SR, Iwakuma N, Sharma P, Moudgil BM. What is cancer nanotechnology? Methods Mol Biol. 2010;624:1-9.
38. Harrington DP. Nanotechnology molecular medicine and radiology. J Am Coll Radiol. Aug 2006;3(8):578-579.
39. Adam L, Bouvier M, Jones TL. Nitric oxide modulates beta(2)-adrenergic receptor palmitoylation and signaling. J Biol Chem. Sep 10 1999;274(37):26337-26343.
40. Ahmadie R, Santiago JJ, Walker J, et al. A high-lipid diet potentiates left ventricular dysfunction in nitric oxide synthase 3-deficient mice after chronic pressure overload. J Nutr. Aug 2010;140(8):1438-1444.
41. Anstey NM, Weinberg JB, Hassanali MY, et al. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med. Aug 1 1996;184(2):557-567.
42. De Groote MA, Fang FC. NO inhibitions: antimicrobial properties of nitric oxide. Clin Infect Dis. Oct 1995;21 Suppl 2:S162-165.
43. Fang FC. Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest. Jun 15 1997;99(12):2818-2825.
44. Fang FC, Vazquez-Torres A. Nitric oxide production by human macrophages: there's NO doubt about it. Am J Physiol Lung Cell Mol Physiol. May 2002;282(5):L941-943.
45. Han G, Zippin JH, Friedman A. From Bench to Bedside: The Therapeutic Potential of Nitric Oxide in Dermatology. Journal of Drugs in Dermatology. Jun 2009;8(6):586-594.
46. Hare JM, Nguyen GC, Massaro AF, et al. Exhaled nitric oxide: a marker of pulmonary hemodynamics in heart failure. J Am Coll Cardiol. Sep 18 2002;40(6):1114-1119.
47. Huang CJ, Wood CE, Nasiroglu O, Slovin PN, Fang X, Skimming JW. Resuscitation of hemorrhagic shock attenuates intrapulmonary nitric oxide formation. Resuscitation. Nov 2002;55(2):201-209.
48. Huang WC, Tsai RY, Fang TC. Nitric oxide modulates the development and surgical reversal of renovascular hypertension in rats. J Hypertens. May 2000;18(5):601-613.
49. Ischiropoulos H, al-Mehdi AB. Peroxynitrite-mediated oxidative protein modifications. FEBS Lett. May 15 1995;364(3):279-282.
50. Misirkic MS, Todorovic-Markovic BM, Vucicevic LM, et al. The protection of cells from nitric oxide-mediated apoptotic death by mechanochemically synthesized fullerene (C(60)) nanoparticles. Biomaterials. Apr 2009;30(12):2319-2328.
51. Seabra AB, Duran N. Nitric oxide-releasing vehicles for biomedical applications. Journal of Materials Chemistry. 2010;20(9):1624-1637.
52. Maskey-Warzechowska M, Przybylowski T, Hildebrand K, et al. [The effect of asthma and COPD exacerbation on exhaled nitric oxide (FE(NO))]. Pneumonol Alergol Pol. 2004;72(5-6):181-186.
53. McKenzie RC, Weller R. Langerhans cells, keratinocytes, nitric oxide and psoriasis. Immunol Today. Sep 1998;19(9):427-428.
54. Weller R, Dykhuizen R, Leifert C, Ormerod A. Nitric oxide release accounts for the reduced incidence of cutaneous infections in psoriasis. J Am Acad Dermatol. Feb 1997;36(2 Pt 1):281-282.
55. Weller R, Ormerod A. Increased expression of inducible nitric oxide (NO) synthase. Br J Dermatol. Jan 1997;136(1):136-137.
56. Friedman A, Friedman J. New biomaterials for the sustained release of nitric oxide: past, present and future. Expert Opin Drug Deliv. Oct 2009;6(10):1113-1122.
57. Ray A, Friedman BA, Friedman JM. Trehalose glass-facilitated thermal reduction of metmyoglobin and methemoglobin. J Am Chem Soc. Jun 26 2002;124(25):7270-7271.
58. Friedman AJ, Han G, Navati MS, et al. Sustained release nitric oxide releasing nanoparticles: characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites. Nitric Oxide. Aug 2008;19(1):12-20.
59. Boettcher SW, Fan J, Tsung CK, Shi Q, Stucky GD. Harnessing the sol-gel process for the assembly of non-silicate mesostructured oxide materials. Acc Chem Res. Sep 2007;40(9):784-792.
60. Coradin T, Boissiere M, Livage J. Sol-gel chemistry in medicinal science. Curr Med Chem. 2006;13(1):99-108.
61. Gupta R, Kumar A. Bioactive materials for biomedical applications using sol-gel technology. Biomedical Materials. Sep 2008;3(3).
62. Radin S, Chen T, Ducheyne P. The controlled release of drugs from emulsified, sol gel processed silica microspheres. Biomaterials. Feb 2009;30(5):850-858.
63. Yilmaz E, Bengisu M. Drug entrapment in silica microspheres through a single step sol-gel process and in vitro release behavior. J Biomed Mater Res B Appl Biomater. Apr 2006;77(1):149-155.
64. Navati MS, Aisen P, Friedman JM. Sugar-mediated protein redox reactions in glassy matrices. Biophysical Journal. Jan 2005;88(1):329A-329A.
65. Navati MS, Friedman JM. Sugar-derived glasses support thermal and photo-initiated electron transfer processes over macroscopic distances. Journal of Biological Chemistry. Nov 2006;281(47):36021-36028.
66. Schwentker A, Vodovotz Y, Weller R, Billiar TR. Nitric oxide and wound repair: role of cytokines? Nitric Oxide. Aug 2002;7(1):1-10.
67. Weller R. Nitric oxide, skin growth and differentiation: more questions than answers? Clin Exp Dermatol. Sep 1999;24(5):388-391.
68. Weller R. Nitric oxide--a newly discovered chemical transmitter in human skin. Br J Dermatol. Nov 1997;137(5):665-672.
69. Evans TG, Thai L, Granger DL, Hibbs JB, Jr. Effect of in vivo inhibition of nitric oxide production in murine leishmaniasis. J Immunol. Jul 15 1993;151(2):907-915.
70. Richardson AR, Libby SJ, Fang FC. A nitric oxide-inducible lactate dehydrogenase enables Staphylococcus aureus to resist innate immunity. Science. Mar 21 2008;319(5870):1672-1676.
71. Han G, Friedman A, Friedman J, Dawkins MC. Wound healing therapy with nitric oxide-releasing nanoparticles. Journal of the American Academy of Dermatology. Mar 2009;60(3):AB203-AB203.
72. Weller RB. Nitric Oxide-Containing Nanoparticles as an Antimicrobial Agent and Enhancer of Wound Healing. Journal of Investigative Dermatology. Oct 2009;129(10):2335-2337.
73. Martinez LR, Han G, Chacko M, et al. Antimicrobial and Healing Efficacy of Sustained Release Nitric Oxide Nanoparticles Against Staphylococcus Aureus Skin Infection. Journal of Investigative Dermatology. Oct 2009;129(10):2463-2469.
74. Martinez LR, Han G, Chacko M, et al. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infection. J Invest Dermatol. Oct 2009;129(10):2463-2469.
75. Mihu MR SU, Han G, Friedman JM, Nosanchuk JD, Martinez LR. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence. 2010;1(2):1-6.
76. Han G, Martinez LR, Mihu MR, Friedman AJ, Friedman JM, Nosanchuk JD. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in a murine model of infection. PLoS One. 2009;4(11):e7804.
77. Han G, Tar M, Kuppam DS, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction. J Sex Med. Jan 2010;7(1 Pt 1):224-233.
78. Cabrales P, Han G, Roche C, Nacharaju P, Friedman AJ, Friedman JM. Sustained release nitric oxide from long lived circulating nanoparticles. Free Radic Biol Med. May 8 2010.
aThe pre-clinical investigations discussed would not have been possible without the following collaborators: George Han, PhD, Luis Martinez, PhD, Joshua Nosanchuk, MD, Moses Tar, PhD, Kelvin Davies, PhD, Pedro Cabrales, PhD, Parimala Nacharaju, PhD, Joel Friedman, MD,PhD
Disclaimer: The views expressed here are those of the interviewee and do not necessarily represent the views of AZoM.com Limited (T/A) AZoNetwork, the owner and operator of this website. This disclaimer forms part of the Terms and Conditions of use of this website.