**4. Nanotechnology and nanoscience**

Although acute graft failure after transplantation has improved over the last two decades, the same cannot be said in the long run where achievements have been less pronounced. Graft vascular disease appears as the main complication after the first year of transplantation and lacks specific and effective therapy. The importance of this entity can be observed in the comparative analysis of the survival curves presented by the International Society for Heart and Lung Transplantation, in which patients who developed vasculopathy had a higher mortality rate than the others.13 The graft vascular disease is responsible for 17% of the deaths and can be detected as early as the first year after transplantation, reaching in the third year figures in the order of 42% by cinecoronariography and 75% by intravascular

The "graft vascular disease" designation has received greater acceptance rather than the other ones—post-transplant atherosclerosis, chronic rejection, accelerated atherosclerosis, graft vasculopathy and others—because it expresses more appropriately the immunological phenom-

Graft vascular disease is a form of accelerated coronary vasculopathy of immune origin that has not yet been completely clarified, in which nonimmunological factors also take place. However, the most likely entrance door is the endothelial dysfunction, as it allows the aggression of the subintimal layer and stimulates the myointimal proliferation in the wall of the artery. The inflammatory process extends to the entire arterial bed and, occasionally, to the

In the initial phase of the lesion, there is a discrete thickness of the intima, with little hyperplastic fibrosis and an increase in extracellular matrix proteins. At this stage, the internal elastic lamina is still intact, and the involvement is limited to the proximal arteries. Subsequently, the thickness proceeds diffusely through the coronary vasculature, with the appearance of plaques of fibroadiposal tissue and gradual deposition of calcium with the future formation of isolated plaques of atheroma [19, 20]. The first intimal changes can be observed as early as

In the late phase of the disease, it is observed that the thickness of the intima is diffuse, with hyperplasia and concentric fibrosis. A detailed study of the coronary arteries has shown the incorporation of lipids and focal plaques of atheromas interspersed with diffuse arteritis [19, 20]. The arteries thickness occurs by the infiltration of mononuclear inflammatory cells in response to alloimmune stimuli or by infection, and in this last situation, the participation of the cytomegalovirus deserves special attention. In a more advanced stage, the medial layer may be totally or partially replaced by fibrous tissue. Only vessels with little or no

The participation of acute rejection is controversial in the development of graft vascular disease [24–26]. Among the nonimmunological factors considered to be at risk for graft vascular disease, we highlight those that may compromise the integrity of the endothelium, as classi-

The donor risk factors encephalic death etiology, age, sex, atherosclerotic disease, and his or

ultrasonography [13–17].

174 Heart Transplantation

enon that is common to transplants of solid organs [9].

veins, sparing only the recipient's native vessels [8, 18].

the sixth month after transplantation [15, 16, 19].

muscle layer can be spared [21–23].

fied below [24–29]:

her clinical characteristics.

Nanotechnology and nanoscience, ranging from 1 to 100 nanometers (nm), focus on materials of atomic size, molecular, and supramolecular, which point to the control and manipulation of these new materials precisely by configuring atoms and molecules, producing new molecular aggregates and designing self-aggregation systems to create supramolecular devices at the cellular or minor scale.

The nanoscale is prevalent in natural systems, as several functional components of living cells fit into this anthropometric classification, but few drugs or diagnostic, therapeutic, and repair devices have been developed on this scale.

The properties of the nanoscale allow high density of function in small packages to minimize invasiveness and facilitate intelligent therapeutic interventions with increased specificity of release and action, decrease of side effects, and ability to respond to external stimuli and to refer to external receptors.

Nanotechnology and nanomedicine are two areas of great growth that have provided new diagnostic and therapeutic opportunities for cardiovascular, pulmonary, hematological, and sleep diseases. In the near future, nanotechnology will play an increasingly significant role in the day-to-day practice of cardiologists, pneumonologists, and hematologists.

The use of nanoparticles in medicine was first performed in the treatment of cancer and progressed rapidly, being well used to address the limitations of conventional drug delivery systems, such as nonspecific and target biodistribution, water solubility, poor oral bioavailability, and low therapeutic indexes.

An effective way to achieve drug delivery efficiency will be to reasonably develop nanosystems based on their knowledge of their interactions with the biological environment, target cell population, changes in cellular receptors that occur with disease progression, mechanism and site of drug action, drug retention, multiple drug administration, molecular mechanism, and pathobiology of the disease under consideration [39].

In the area of biomedical nanotechnology, the group led by Maranhão has made pioneering contributions in the world: they described the first system of nanoparticles (non liposomal) produced in the laboratory, capable of directing and concentrating drugs at the drug targeting site for treatment for the treatment of proliferative diseases such as cancer and atherosclerosis [21, 40, 41] (**Pictures 1** and **2**).

A fascinating field of impact applications has been opened with the discovery that LDE, after injection into the circulatory system, is concentrated in the tumor tissues and can be used in the treatment of cancer as a vehicle to direct chemotherapeutics to the neoplastic cells [42]. The cell probably due to the need for greater lipid content required by accelerated proliferation has a marked increase in the expression of LDL receptors. This enables the use of LDE as a vehicle to concentrate neoplastic neoplastic tissue associated with the particles. Chemotherapeutics are thus diverted from the normal tissues of the organism. Thus, it is possible to increase the therapeutic efficacy of these agents and to reduce the side effects that constitute an important limitation to chemotherapy. The initial finding was described in patients with acute myelocytic leukemia, [40, 41] in whom overexpression of receptors reached up to 100-fold. More recently, it has been found that LDE can also be concentrated in tissues where there are nonneoplastic proliferative processes [43]. Then, in rabbits with

cholesterol-induced diet atherosclerosis, the inflammatory process in atherosclerosis also led to the concentration of nanoemulsion in injured arteries. These findings broadened the range of potential applications of nanoemulsion as a drug vehicle not only in neoplasias but also in

**Picture 2.** Structure of lipid nanoemulsion (LDE). Modified from www.foodspace.wordpress.com

**Picture 1.** Structure of low density lipoprotein (LDL). Modified from www.foodspace.wordpress.com

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http://dx.doi.org/10.5772/intechopen.79631

The incorporation and stability of drugs within the LDE were optimized with drug modification without loss of pharmacological effect. Thus, with the modification of these drugs, it was possible to proceed with the assembly of a therapeutic arsenal associated with nanoemulsions.

atherosclerosis and other chronic inflammatory processes.

of these new materials precisely by configuring atoms and molecules, producing new molecular aggregates and designing self-aggregation systems to create supramolecular devices at

The nanoscale is prevalent in natural systems, as several functional components of living cells fit into this anthropometric classification, but few drugs or diagnostic, therapeutic, and repair

The properties of the nanoscale allow high density of function in small packages to minimize invasiveness and facilitate intelligent therapeutic interventions with increased specificity of release and action, decrease of side effects, and ability to respond to external stimuli and to

Nanotechnology and nanomedicine are two areas of great growth that have provided new diagnostic and therapeutic opportunities for cardiovascular, pulmonary, hematological, and sleep diseases. In the near future, nanotechnology will play an increasingly significant role in

The use of nanoparticles in medicine was first performed in the treatment of cancer and progressed rapidly, being well used to address the limitations of conventional drug delivery systems, such as nonspecific and target biodistribution, water solubility, poor oral bioavail-

An effective way to achieve drug delivery efficiency will be to reasonably develop nanosystems based on their knowledge of their interactions with the biological environment, target cell population, changes in cellular receptors that occur with disease progression, mechanism and site of drug action, drug retention, multiple drug administration, molecular mechanism,

In the area of biomedical nanotechnology, the group led by Maranhão has made pioneering contributions in the world: they described the first system of nanoparticles (non liposomal) produced in the laboratory, capable of directing and concentrating drugs at the drug targeting site for treatment for the treatment of proliferative diseases such as cancer and atherosclerosis

A fascinating field of impact applications has been opened with the discovery that LDE, after injection into the circulatory system, is concentrated in the tumor tissues and can be used in the treatment of cancer as a vehicle to direct chemotherapeutics to the neoplastic cells [42]. The cell probably due to the need for greater lipid content required by accelerated proliferation has a marked increase in the expression of LDL receptors. This enables the use of LDE as a vehicle to concentrate neoplastic neoplastic tissue associated with the particles. Chemotherapeutics are thus diverted from the normal tissues of the organism. Thus, it is possible to increase the therapeutic efficacy of these agents and to reduce the side effects that constitute an important limitation to chemotherapy. The initial finding was described in patients with acute myelocytic leukemia, [40, 41] in whom overexpression of receptors reached up to 100-fold. More recently, it has been found that LDE can also be concentrated in tissues where there are nonneoplastic proliferative processes [43]. Then, in rabbits with

the day-to-day practice of cardiologists, pneumonologists, and hematologists.

the cellular or minor scale.

176 Heart Transplantation

refer to external receptors.

ability, and low therapeutic indexes.

[21, 40, 41] (**Pictures 1** and **2**).

and pathobiology of the disease under consideration [39].

devices have been developed on this scale.

**Picture 1.** Structure of low density lipoprotein (LDL). Modified from www.foodspace.wordpress.com

**Picture 2.** Structure of lipid nanoemulsion (LDE). Modified from www.foodspace.wordpress.com

cholesterol-induced diet atherosclerosis, the inflammatory process in atherosclerosis also led to the concentration of nanoemulsion in injured arteries. These findings broadened the range of potential applications of nanoemulsion as a drug vehicle not only in neoplasias but also in atherosclerosis and other chronic inflammatory processes.

The incorporation and stability of drugs within the LDE were optimized with drug modification without loss of pharmacological effect. Thus, with the modification of these drugs, it was possible to proceed with the assembly of a therapeutic arsenal associated with nanoemulsions. LDE preparations, associated with modified forms of etoposide chemotherapeutic agents, paclitaxel 18 and methotrexate, are ready and efficiently tested in vitro and in vivo. In all cases, comparing these associations with nanoemulsions to the respective commercial preparations, a greater therapeutic action at higher doses was shown in culture of neoplastic cells and models of tumors implanted in animals (Walker's tumor and B-16 melanoma). In clinical trials with carmustine, etoposide, and paclitaxel [18, 20, 42], it was found that in the use of these drugs associated with LDE, even at higher doses than those usually used in the clinic, the toxicity was practically absent.

[5] Griepp RB, Stinson EB, Clark DA, Shumway NE. A two-year experience with human

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[6] Rider AK, Copeland JG, Hunt SA, Mason J, Specter MJ, Winkle RA, et al. The status of car-

[7] Miller LW, Granville DJ, Narula J, Mcmanus BM. Apoptosis in cardiac transplant rejec-

[8] Rogers NJ, Lechler RI. Allorecognition. American Journal of Transplantation. 2001;**1**:97-102 [9] Jukes JP, Jones ND. Immunology in the clinic review series; focus on host responses: Invariant natural killer T cell activation following transplantation. Clinical and Experimental

[10] Weis M, Von Scheidt W. Coronary artery disease in the transplanted heart. Annual Review

[11] Diujvestijn AM, Derhaag JG, Van Breda Vriesman PJ. Complement activation by antiendothelial cell antibodies in MHC-mismatched and MHC-matched heart allograft rejection: Anti-MHC-but not anti non-MHC alloantibodies are effective in complement

[12] Lourenço-Filho DD, Maranhão RC, Méndez-Contreras CA, Tavares ER, Freitas FR, Stolf NA. An artificial nanoemulsion carrying paclitaxel decreases the transplant heart vascular disease: A study in a rabbit graft mod el. The Journal of Thoracic and Cardiovascular

[13] Rora P, Edwards LB, Kucheryavaya AY, Christie JD, Dobbels F, Kirk R, et al. The registry of the International Society for Heart and Lung Transplantation: Thirteenth official pediatric lung and heart-lung transplantation report—2010. The Journal of Heart and Lung

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The results described above then directed us to the application of these nanoemulsions in the treatment of patients with heart transplantation, in which two main problems predominate: rejection of the receptor to the transplanted organ and the SVD. These are two entities that are difficult to manage clinically, which seriously compromise the success of heart transplants and which require new therapeutic solutions. For DVE, in general, there is no conventional treatment, only retransplantation. The inflammatory and proliferative bases of SVD are similar to those of atherosclerotic cardiovascular disease. Thus, the fact that an antiproliferative agent associated with LDE has been effective in promoting the regression of experimental atherosclerosis suggests that it is equally efficient as a therapeutic approach to PVD.
