Temperature-Sensitive Gels for Intratumoral Delivery of β-Lapachone: Effect of Cyclodextrins and Ethanol

This work evaluated the potential of Pluronics (varieties F127 and P123) in combination with solubilizing agents to be used as syringeable in situ gelling depots of intratumoral β-lapachone (βLAP). Pluronic dispersions prepared at various concentrations in the absence and the presence of ethanol and randomly methylated β-cyclodextrin (RMβCD) were characterized regarding their rheological properties, drug solubilization capacity, and in vitro release. Pluronic F127 (18–23%) formulations combined high ability to solubilize βLAP (enhancement solubility factor up to 50), adequate gel temperature range (over 25°C), and gel strength at 37°C enough to guarantee the permanence of the formulation in the administration site for a period of time. βLAP release rate was finely tuned by the concentration of the polymer and the addition of RMβCD (diffusion coefficient ranging between 9 and 69 μg·cm−2). The ethanol increases βLAP release rate but simultaneously led to weak gels. This paper shows that βLAP formulations involving temperature-reversible Pluronic gels may be suitable for intratumoral drug delivery purposes

Dynamic Ex Vivo Porcine Eye Model to Measure Ophthalmic Drug Penetration under Simulated Lacrimal Flow

Animal models are still used in the research and development of ophthalmic drug products, mainly due to the difficulty in simulating natural physiological conditions with in vitro models, as there is a lack of dynamic protection mechanisms. Therefore, developing alternative ophthalmic models that evaluate drug penetration in the cornea while applying dynamic protection barriers is a contemporary challenge. This study aimed to develop a dynamic ex vivo model using porcine eyes with a simulated lacrimal flow to evaluate the performance of pharmaceutical drug products. A glass donor cell to support a simulated tear flow was designed, optimized, and custom-made. The system was challenged with different formulations (with fluconazole) including excipients with different viscosities (poloxamer 407) and mucoadhesive properties (chitosan). The results were compared to those obtained from a conventional excised cornea model mounted in Franz-type diffusion cells. The dynamic model could differentiate formulations, while the static model did not, overestimating ex vivo drug penetrated amounts. Hence, the dynamic model with simulated tear flow showed to be a simple and promising new alternative method for the drug penetration of ophthalmic formulations that ultimately can reduce the number of animals used in research

CCR2 plays a protective role in Rocio virus–induced encephalitis by promoting macrophage infiltration into the brain

Rocio virus (ROCV) is a highly neuropathogenic mosquito-transmitted flavivirus responsible for an unprecedented outbreak of human encephalitis during 1975-1976 in Sao Paulo State, Brazil. Previous studies have shown an increased number of inflammatory macrophages into the central nervous system (CNS) of ROCV-infected mice, implying a role for macrophages in the pathogenesis of ROCV. Here, we showed that ROCV infection results in increased expression of C-C chemokine ligand 2 (CCL2) in the blood and in infiltration of macrophages into the brain. Moreover, we showed using C-C chemokine receptor 2 (CCR2) knockout mice that CCR2 expression was essential for macrophage infiltration in the brains during ROCV infection and that the lack of CCR2 resulted in increased disease severity and mortality. Thus, our findings show the protective role of CCR2-mediated infiltration of macrophages in the brain during ROCV infection