Due to anatomical and physiologic characteristics of the eye

Due to anatomical and physiologic characteristics of the eye, administration of ophthalmic medicines is difficult and many studies showed that only approximately 5% of the administrated dose are absorbed by intraocular tissues, making the treatment unfeasible for diseases located in posterior segment of the eye. Other available treatments require the use of high drug doses or are too invasive as intravitreal injections, exhibiting great risks and potentially serious side effects to the patient [24], [25], [26]. Seeking to overcome this negative scenario, research has been dedicated to developing new drug delivery systems, such as polymeric implants with the overall goal to be more selective and achieve favorable bioavailability profiles through sustained releasing of the therapeutic cargo [27], [28]. Such systems offer many advantages, including favorable patient compliance, biocompatibility, predictable biodegradation kinetic and mechanical resistance in various intravitreal applications [29], [30], [31]. In order to mitigate the cumulative risks associated with repeated intravitreal injections, some implantable polymeric systems have been approved by FDA and currently available, for example: Ozurdex® (Dexamethasone Intravitreal Implant); Iluvien® (Fluocinolone acetonide intravitreal implant) and Triesence® (Triamcinolone acetonide). In these systems, any cytotoxicity was observed as well as significant antiangiogenic activity were obtained, displaying the applicability of these systems in intravitreal applications. However, at present, no steroid has achieved US FDA approval for the treatment of pathologies associated to angiogenesis (except for ranibizumab, a monoclonal antibody). In this work, we aimed to evaluate the anti-angiogenesis activity of PLGA ocular implants containing the lupeol, a non-steroid compound, in both in vitro and in vivo models.
Experimental
Statistical analysis The mean values and standard deviation were calculated. The statistical parameters were analyzed through ANOVA followed post-test of Tukey or Bonferroni where p≤0.05 was considered as statistically significant. The Mann–Whitney non-parametric test was used to compare outcomes in both groups. The unpaired-test was used to compare outcomes of percent blood vessels in the CAM study. Values of p≤0.05 were considered to be statistically significant. Interrelation between dark-adapted b-wave amplitude and stimuli luminance was modeled using the Naka–Rushton function that yields the parameters: Vmax asymptotic (maximum b-wave amplitude) the light he 5-Azacytidine necessary luminance reaching 50% of Vmax, which is a mark of dark-adapted sensitivity; and is the dynamic working range of photoreceptors.
Results and discussion
Conclusion
Acknowlegdments The authors would like to thank CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais) for their financial support.
Introduction Glioblastoma is the most common and malignant form of primary brain tumor and has a poor prognosis with a 2-year survival rate of 30% and a 5-year survival rate of 10% (Stupp et al., 2009). To date, the standard treatment for newly diagnosed glioblastoma is surgical debulking followed by radiation therapy and temozolomide followed by 6 to 12 cycles of maintenance temozolomide (Stupp et al., 2005). Despite this treatment, relapse is inevitable and the median overall survival is about 15 months (Wen and Kesari, 2008). Given the poor results of cytotoxic therapy over the last few years, new approaches such as antiangiogenic drugs have been analyzed in various studies including newly diagnosed glioblastoma or relapsed patients (Lu-Emerson et al., 2015). Indeed, glioblastomas are highly vascular tumors, with high expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) with the ensuing attachment to its VEGF receptor 2 (VEGFR2) localized to endothelial cells (Wong et al., 2009). Increased levels of VEGF lead to abnormal vasculature and increased tumor vessel permeability; consequently, glioblastomas develop hypoxia which leads to further increase of VEGF expression (Fischer et al., 2005). Moreover, angiogenesis has been demonstrated in preclinical studies to be vital for the proliferation and survival of glioblastoma. Moreover, neoangiogenesis is one of the diagnostic hallmarks of glioblastoma and, according to the WHO classification, it is pivotal for the diagnosis (Norden et al., 2009). Therefore, there is a strong biologic rationale for using antiangiogenic drugs against glioblastoma. Antiangiogenic agents may be classified as direct, indirect or miscellaneous angiogenesis inhibitors depending on their mechanism of action and target (Gasparini et al., 2005a); in fact, antiangiogenic treatments include several mechanisms of action such as targeting VEGF and VEGFR with antibodies or small-molecule tyrosine kinase inhibitors (TKIs) or inhibition of tumor growth and endothelial cell adhesion by integrin inhibitors (Lu-Emerson et al., 2015). Direct angiogenesis inhibitors target the tumor endothelial cells by inhibiting their ability to proliferate, migrate or form new vessels; indirect agents block the production of angiogenic factors and/or downstream angiogenic signalling pathways; mixed angiogenic inhibitors such as multitargeted kinase inhibitors or protein kinase C inhibitors or integrin receptor inhibitors, primarily have a direct cytotoxic function but as a secondary mechanism they also inhibit angiogenesis (Gasparini et al., 2005a).