Sustained release property is also
Sustained release property is also associated with side effects reduction  that could be confirmed by histopathological analyzes. Massive infiltrating inflammatory cells, hyperproliferation of skin layers and keratin pearls, caused by DMBA and croton oil application  are attenuated in Imq-loaded nanoparticles treated mice compared to other groups (Section 3.4).
Similar results were described by REHMAN and colleagues . In this report, chemopreventive potential of imiquimod-loaded fish oil bigel colloidal system were also evaluated in murine model of skin cancer. Such system led to the reduction of histopathological changes, control of tumor growth and significant inhibition of VEGF (vascular endothelial growth factor) compared to carcinogenic control group. However, the formulation was applied daily on mice dorsal skin at a concentration of 5 mg / g formulation, the same as commercial product. In the present study, a 20-fold lower concentration of Imq than commercial products was used and formulations were applied 3 times a week. The efficacy of nanocarriers developed system even at low concentrations could be an advantage over the low skin permeation and adverse effects of the market Imq, commonly reported [18,19,20].
Since the final number of papillomas can be considered as a parameter for evaluating tumor initiation, and the growth of these tumors is an indicator of clonal expansion of "initiated" Poly (A) Tailing , our results suggests that Imq-loaded nanoparticles were able to inhibit or reverse these two carcinogenic steps and its chemopreventive action may occurred in a formulation dependent manner.
Acknowledgements The authors wish to thank CNPq/MCT (Brazil) and Fapemig (Brazil) for financial support. This work was developed within the framework of National Institute of Science and Technology of Pharmaceutical Nanotechnology (INCT-Nanofarma), which is supported by “Fundação de Amparo à Pesquisa do Estado de São Paulo” (FAPESP, Brazil) Grant #14/50928-2, and by “Conselho Nacional de Pesquisa” (CNPq, Brazil) Grant #465687/2014-8).
Introduction Angiogenesis is a natural process that occurs in the human body during fetal development or as a response to tissue damage, as part of wound healing process and renewing the blood flux in damage areas , . When the human body loses its capacity to maintain adequately the equilibrium of angiogenic mediators, some diseases can develop, including arthritis, cancer, endometriosis, psoriasis, macular degeneration related to age and proliferative diabetic retinopathy , . Macular degeneration related to age is the main cause of blindness in persons older than 60 years in industrialized countries . The prevalence of blindness can vary between 10 and 15% among affected persons and estimates have shown a significantly rates increase until 2030 . Currently, available treatments are limited to palliatives such as photodynamic therapy, intravitreal injections with corticoids, antiangiogenic compounds applied directly into eye and laser photocoagulation , , , . The proliferative diabetic retinopathy is characterized by new important vascularization in retina, following to intravitreal interface, with possible loses of normal visual characteristics mainly due to traditional retinal detachment. In this sense, the inhibition of angiogenesis can be considered an important strategy to treat these intraocular diseases and have been explored in many published works , , , . Lupeol is a natural pentaciclic triterpene with a lupane scaffold that can be found in diverse vegetables, including white cabbage, red pepper, cucumber, tomatoes, carrots, peas, and soy. Moreover, administration of lupeol does not result in systemic toxicity in animal models in doses ranging from 30 to 2000mgkg−1. Triterpene can be isolated from medicinal plants, i.e. Celastraceae family plants, displaying clinically relevant biological properties related to inflammation, arthritis, cardiovascular disorders, cancer and wound healing processes , , . You et al.  evaluated the antiangiogenic activity of lupeol on a tube-like formation assay using HUVEC cells (Human umbilical vein endothelial cells). The results revealed lupeol capacity to inhibit 80% of angiogenic processes at a non-toxic dose of 50μgmL−1, whereas lower doses showed a significant reduction in antiangiogenic activity reaching only 40% of initial values. Other studies using an endothelial cell model have indicated that triterpenes can modulate growth factors such VEGF (Vascular endothelial growth factor) and are capable of inducing cellular differentiation, seeking to inhibit the vascular tissue growth, displaying an important antiangiogenic effect , , , .