A brain infection refers to an infection caused by viruses, bacteria, fungi, or parasites that affects the brain. Encephalitis is one of the most common examples referring to brain inflammation caused by bacteria, amoebas, viruses (such as cytomegalovirus) or parasites, such as Toxoplasma Gondii
[32]. It has been reported that NC functional coating can improve NC transport, absorption and accumulation in brain areas as demonstrated on in vivo studies in rats via intravenous administration. Studies showed increased brain absorption using coating agents, such as polysorbates, poloxamers and/or peptides. It has been demonstrated, for example, that the modification of NC surface with polysorbate 80 allowed to bind the lipoproteins that act as receptor ligands for LDL receptors at the BBB level, inducing a better formulation absorption in the brain
[33][34][35]. In the study of Dibaei et al., the researchers demonstrated an improvement of curcumin biodistribution in the brain thanks to the design of coated nanosuspension due to the presence of Tween
® 80 or TPGS as a coating agent. The results revealed that the best coating agent was found to be polysorbate 80, which allowed drug absorption and targeting to the brain, confirmed by the plasma absorption of the protein ApoE on Tween
® 80. Curcumin NCs were recognized as LDL and interacted with endothelial cells in the capillaries of the brain and were absorbed via endocytosis into the brain. The literature suggested that peptides could serve as coating agents in order to improve drug targeting to the brain
[35][36]. Accordingly, this strategy was investigated in some studies focused on atovaquone, used for brain toxoplasmosis. Toxoplasmosis is a zoonosis caused by the
Toxoplasma gondii parasite and this pathology also affects the CNS. Two different studies were performed on atovaquone by using different coating systems to improve its brain targeting. The first study involved patients with AIDS, which were affected by manifestations of abscesses in the CNS (brain and cerebellum) and neurotoxicosis (Toxoplasma brain infection) with acute symptoms, such as seizures, paresis, or comatose states. Atovaquone NCs were formulated with three different surfactants Tween
® 80, poloxamer 184 or poloxamer 338 as absorption enhancers and the same NCs formulated with ApoE as coating agent, in addition to the three surfactants, and their brain targeting efficacy was investigated. The results showed that the ApoE-coated atovaquone NCs did not achieve the desired absorption in the brain, while the Tween
® 80-coated atovaquone NCs enhanced drug absorption to the brain compartment. The researchers stated that the presence of ApoE improved atovaquone NC accumulation in the brain endothelial cells, but the enhancement of drug absorption in the brain was due to the presence of Tween
® 80 and the mean size of the NCs
[37]. In a following study, the same researchers prepared atovaquone NCs by using sodium dodecyl sulfate (SDS) or Poloxamer 188 for the treatment of toxoplasma encephalitis compared with the commercial drug Wellvone
®. The first difference between atovaquone NCs and Wellvone
® (atovaquone micronized suspension on the market) was the particle size and polydispersity index, which was much higher for the marketed product. Significant differences were found related to the biodistribution of the drug. In particular, on day 12 of infection, mice were treated and drug distribution and absorption in organs, such as brain, lungs and liver, were assessed by HPLC analysis. Poloxamer-coated atovaquone NCs gave similar results to the commercially available Wellvone
® formulation, while SDS-Atovaquone NCs resulted in a very high concentration of the drug in the various districts considered, including the brain, compared to the commercial pharmaceutical form
[38]. In the study of Lemke et al., amphotericin B NCs were investigated against encephalitis caused by the amoeba
Balamuthia mandrillaris. Amphotericin B is characterized by low water solubility and nephrotoxicity. Seven nanosuspensions were prepared differing in the surfactant’s concentration. The most promising formulation was found to be that prepared with Tween
® 80 and sodium cholate (SC), promoting the high absorption of ApoE at the surface of NCs and a low absorption of opsonins, such as fibrinogen and IgG γ. The good absorption of ApoE on the NC surface and a minimization of hepatic absorption (low fibrinogen and IgG γ) indicated a high absorption in the brain
[39]. A coating model was designed for Baicalin NCs, with the aim of obtaining a formulation for both ischemic stroke and Alzheimer’s disease. To improve the passage of the BBB due to the low bioavailability of the molecule, the nanosuspension, addressed to the intravenous route, was prepared using a combination of Tween
® 80 and TPGS as stabilizer agents. The final goal was to obtain a formulation able to absorbs ApoE on the surface, acting as a ligand for the LDL receptors present on the BBB, improving their crossing and leading to their brain-uptake by endocytic processes. As mentioned above, the coating with ApoE led to a lower adsorption of fibrinogen and Ig γ (opsonins) encountered in the blood that can promote phagocytosis and the removal of the drug carriers from the systemic circulation
[40]. Serum albumin and polyethylene glycol 1000 were also investigated as functional coatings for neviparine NCs. Nevirapine is a non-nucleotide reverse transcriptase inhibitor used in the treatment of HIV-associated dementia. The problem with antiretroviral drugs is the difficulty of reaching the “reservoir” site or reaching it at low doses or for short periods of time. To be effective, they need high dosages, which inevitably leads to side effects. Nevirapine NCs were obtained by HPH. Dextran 60, PEG 1000 or serum albumin were absorbed on the NC surface as a functional coating to improve drug brain targeting. The best cellular absorption was obtained with serum albumin, 3.84 times greater than the pure drug and 1.39-fold greater than the uncoated NCs probably due to an increased recognition by macrophage receptors
[41]. Therefore, the use of a coating agents can be defined “functional” when used to increase cellular absorption and drug concentration at the target site, avoiding the massive dosage of antiretroviral drugs.