Table 1.
Examples of in vivo studies with the aim to neuroprotect and functionally recover the damaged brain using nanoparticle- and hydrogel-based biomaterials.
| Stroke Model, Species | Therapeutic Molecule, Main Properties | Biomaterial and Format, Administration Route, Time Window of Application | Main Therapeutic Effects | References |
|---|---|---|---|---|
| MCAO (permanent), rat | Superoxide dismutase/Catalase, anti-oxidant enzymes | PGA NPs, intravenous injection, ~ 1 min post-stroke | Reduction of infarct volume | [49] |
| MCAO (transient), mouse | BDNF, neuroprotective, neurogenic, and regenerative factor | PEG/PGA NPs, intravenous injection, 3–24 h post-stroke | Reduction in cerebral tissue loss | [134] |
| MCAO (transient), rat | Osteopontin, anti-inflammatory, anti-apoptotic, and neurogenic roles | Gelatin microspheres, intrastriatal delivery, 1–12 h post-stroke | Reduced infarct volume | [199] |
| Photothrombotic stroke model (permanent), mouse | Edaravone, antioxidant compound/ROS scavenger | PEG-PLA micelles, intravenous injection, 6 h post-stroke | Higher efficiency of Edaravone delivery. Reduction of ROS, decreasing of ischemic area that leads to behavioural improvement | [152] |
| Endothelin-1 model, rat | Cyclosporin-A, immunosuppressant and anti-inflammatory compound. Neurogenic and regenerative properties | PLGA microparticles encapsulated in hyaluronan and methylcellulose hydrogels, epicortical delivery, immediately after entothelin-1 injection | Sustained delivery of Cyclosporin-A for 14 days. Decreasing infarct volume. Neuroprotective effect even with the hydrogel formulation alone. | [153] |
| Endothelin-1 model, mouse | EGF/erythropoietin, stimulators of neural precursors formation and neuroprotective properties | PLGA-PEG NPs encapsulated in hyaluronan and methylcellulose hydrogels, epicortical administration, 4 days post-stroke | Attenuation of injury response and cell death. Reduction of infarct cavity. Increasing content of mature neurons in damage and peri-lesional areas | [154] |
| Focal aspiration brain injury model, rat | Neurotrophin-3, neurogenic, angiogenic, and anti-inflammatory factor | Chitosan particles, intracerebral delivery (lesion cavity, cortex), immediately after tissue aspiration | Reduction of inflammation (peripheral leukocytes and microglia) | [169] |
| Hypoxia-ischemia exposure model, neonatal rat | Erythropoietin, enhances oxygen delivery, neurogenesis, anti-oxidant properties (decreases ROS formation) | PLGA NPs, intraperitoneal, 1, 24, and 48 h after hypoxia | Reduction of infarct volume and improvement of behavioral deficits with lower doses than the administration of free Erythropoietin | [196] |
| MCAO (transient), rat | Osteopontin, anti-inflammatory, anti-apoptotic, and neurogenic roles | Gelatin microspheres, intranasal, 6 h post-stroke | Reduction of infarct volume | [200] |
| MCAO (transient), rat | Superoxide dismutase, anti-oxidant enzyme | PLGA NPs, arterial (intracarotid), immediately after reperfusion (1 h post-ischemia) | Reduction of infarct volume leading to functional recovery | [203] |
| MCAO (transient), mouse | Superoxide dismutase, anti-oxidant enzyme | Polyion-cationic complexes-PEG, intravenous injection, immediately after reperfusion (1 h post-ischemia) | Reduction of infarct volume (no effect with superoxide dismutase alone) | [205] |
| MCAO (transient), rat | Thymoquinone, anti-inflammatory and anti-oxidant factor | PLGA-Chitosan NPs, intranasal, administration for 12 days: from -5 (pre-stroke) to 7 (post-stroke) days | Reduction of infarct volume and significant motor improvement associated with stronger scavenging and anti-oxidant capacity | [208] |
| Control (healthy), rat | Venlafaxine, antidepressant molecule | Chitosan NPs, intranasal delivery | Efficient delivery of Venlafaxine into the brain via the intranasal route in comparison with the intranasal or intravenous delivery of free Venlafaxine | [209] |
| MCAO (transient), rat | Acetyl-11-keto-β-boswellic acid, anti-oxidant and anti-inflammatory effects | Chitosan NPs, intravenous injection, 1 h after reperfusion (2 h post-ischemia) | Higher rates of delivery in the brain with respect to the administration of the free molecule. Reduction of infarct volume that leads to behavioral improvements. Positive outcomes related with decreasing oxidative stress/inflammation and reduced neuronal mortality post-ischemia | [210] |
| MCAO (transient), rat | Fenofibrate, activator of Peroxisome Proliferator Activated Receptors (anti-inflammatory and anti-oxidative receptors) | PLGA microparticles, intracerebral administration, 24 h before ischemia | Moderate (non-significant) decrease of infarct volume with respect to the effect of free Fenofibrate. Evolution of infarct volume on untreated MCAO animals is non-determined | [211] |
| MCAO (transient), rat | ONO-1301, prostacyclin agonist with thromboxane synthase inhibitory activity | PLGA microspheres, subcutaneous injection, immediately after MCAO | Significant reduction in the infarct volume and cerebral edema. Oral administration of the free molecule produced similar neuroprotective efficacy, although repetitive doses were needed. | [214] |
| Global cerebral (transient), rat | Curcumin, antioxidant and anti-inflammatory effects | Polysorbate 80/lecithin-based NPs, oral administration, starting 5 days before ischemia for 3 days | Motor and cognitive improvement. No positive effect with the free molecule | [215] |
| MCAO (transient), rat | NR2B9, prevents the excitotoxocity and hyperproduction of NO by disrupting NMDA-PSD-95 signaling | PLGA-PEG nanoparticles decorated with wheat germ agglutinin (WGA) to target olfactory epithelium receptors, intranasal delivery, immediately after reperfusion (2 h post-ischemia) | Increasing content of NR2B9 in the brain with respect to the intranasal administration of free molecule. Significant reduction in infarct size and better neurological improvement | [117] |
| MCAO (transient), rat | NR2B9, prevents the excitotoxocity and hyperproduction of NO by disrupting NMDA-PSD-95 signaling | Dextran NPs decorated with ROS-responsive boronic ester and red blood shell membrane, intravenous injection, immediately after reperfusion (2 h post-ischemia) | NR2B9: Increasing time in circulation and highly efficient to target NR2B9 in the brain. Significant reduction in infarct size and better neurological outcome | [140] |
| MCAO (transient), rat | ZL006, prevents the excitotoxocity and hyperproduction of NO by disrupting NMDA-PSD-95 signaling | Soybean-lecithin-cholesterol-based liposome-PEG decorated with peptides against transferring receptor of the brain endothelium, intravenous injection | Reduction of infarct volume. Behavioural improvement | [216] |
| MCAO (transient), rat | Riluzole, variable effects antagonizing NMDA receptors or/and blocking voltage-gated Calcium/sodium channels | Chitosan NPs formulated with N-isopropyl acrylamide/tween80, intraperitoneal injection, 1 h post-ischemia | Decreasing content of lipid peroxide and increasing levels of glutathione and ROS detoxification enzymes. Reduction of lesion and improvement of behavioral deficits | [219] |
| MCAO (transient), mouse | Cilostazol, vasodilatating, anti-inflammatory with anti-oxidant properties | Zirconia/Methylcellulose NPs, intravenous delivery, 3 h after reperfusion (5 h post-ischemia) | Reduction of infarct size | [223] |
| MCAO (transient), mouse | NEP1-40, antagonist of the Nogo-66 receptor,. enhances neural plasticity and suppresses cell death after injury | PLGA NPs decorated with chlorotoxin to target MMP-2 and lexiscan to transiently increase the BBB permeability, intravenous injection, 3 doses (0, 24, and 48 h after MCAO) | Reduction of infarct volume and better neurological outcome | [222] |
| MCAO (transient), rat | Heme oxygenase-1, anti-oxidant enzyme | R3V6-peptide -based micelles stabilized with Dexamethasone, intracerebral injection (striatum), 1 h before ischemia | Reduction of infarct volume | [225] |
| MCAO (transient), rat | siRNA against HMGB1, (HMGB1 is a pro-inflammatory signal) | PAMAM-based dendrimers, intracerebral injection (cortex). 6–24 h before ischemia | Reduction of neuronal mortality and infarct volume | [226] |
| Photothrombotic stroke model (permanent), mouse | siRNA to silence PHID2, (PHD2 is a factor involved in the up-regulation of genes related to a cellular response to hypoxia) | Polyethylenimine superparamagnetic iron oxide NPs delivered from endothelial progenitor cells, intra-cardiac injection, 24 h after stroke | Significant reduction of infarct volume at 7 days after treatment. Stimulation of endogenous vascularization and neurogenesis. Significant Improvement of behavioral deficits (at 2 weeks after treatment) | [227] |
| MCAO (permanent), rat | Cxcl12, a chemoattractant and neuroprotective molecule | pH-responsive copolymer poly (urethane amino sulfamethazine) (PUASM) micelles, intracerebral delivery, 24 h after ischemia | Significant angiogenesis and neurogenesis, lack of a neuroprotective effect | [229] |
| MCAO (transient), rat | VEGF, an angiogenic and neuroprotectant molecule | Alginate-based hydrogels, intracerebral injection (striatum), 15 min before ischemia | Higher content of VEGF administrated in the striatum than delivery of the free molecule. Behavioral recovery and significant reduction of infarct volume | [168] |
| Focal aspiration brain injury model, rat | Neurotrophin-3, neuroprotective, neurogenic, and anti-inflammatory factor | Chitosan particles, intracerebral administration (cortex), immediately after injury | Increasing neurogenesis and synaptogenesis, anti-inflammatory effects, and behavioral improvement | [169] |
| Endothelin-1 model, rat | BDNF, a neuroprotector molecule and inductor of plasticity | PLGA NPs dispersed on the hyaluronan and methylcellulose hydrogels, epi-cortical administration (brain surface), immediately after stroke | Significant behavioral recovery and reduced cortical lesions (these positive effects were seen even with the biomaterial alone) | [170] |
| Endothelin-1 model, mouse | Dual delivery of EGF and EPO, neurogenic, anti-inflammatory, and neuroprotective factors | PLGA NPs dispersed on the hyaluronan and methylcellulose hydrogels, epi-cortical administration (brain surface), 4 days after stroke | Increasing neurogenesis and reduction of injury response, inflammation and cell death (attenuation of inflammation and injury were also observed, even with the biomaterial alone) | [154] |
| MCAO (transient), hyperglycemic rat | Carbon-HCCs, antioxidant potential | Carbon-PEG NPs, intravenous administration, two doses (immediately before reperfusion and 2 h after reperfusion) | Reduction in infarct size and behavioral improvement | [183] |
| MCAO (transient), rat | Selenium, modulator of neurogenesis with anti-oxidant properties | Selenium-PEG NPs decorated with Anti-transferrin receptor antibody, intraperitoneal injection, 1 h before stroke | Reduction in infarct size, high levels of myelination, neural, and axonal density. Behavioral improvement. No toxicity concerns at therapeutic doses | [184] |
| MCAO (permanent), mouse | Hyaluronic acid hydrogel (porous), promotes cell neural stem cell infiltration and reduces inflammation | MAP-HA-based hydrogels, intracerebral delivery (stroke cavity), 5 days post-stroke | Reduction of inflammation and astrogliosis, increasing neurogenesis and angiogenesis. Remarkable neural progenitor cell migration to lesional and peri-lesional areas | [161] |
| MCAO (transient), rat | Porcine urinary bladder ECM, promotes cell neural stem cell infiltration and reduces inflammation | Porcine urinary bladder ECM hydrogels, intracerebral administration (stroke cavity), 14 days post-stroke | Increasing microglia polarization towards anti-inflammatory phenotypes | [181] |
| MCAO (transient), macaque monkey | Hemoglobin, oxygen carrier supporting tissue oxygenation | Phosphatidylcholine-cholesterol-liposome decorated with PEG, intravenous injection, 5 min after ischemia | Reduction of infarct area, behavioral improvement | [235,236] |
| MCAO (transient), macaque monkey | BDNF, neuroprotective, neurogenic, and regenerative factor | HA-PEG based hydrogel, intracerebral administration (stroke cavity), 3 months post-stroke | Significant increase of BDNF content in peri-infarct tissue in relation to the delivery of free BDNF | [156] |
| Control (healthy), St. Kitts green monkey | No therapeutic compound | PEG-PLA-based hydrogel, intracerebral injection (cortex and striatum) | Moderate inflammation and astrogliosis. Full degradation of material four months after implantation | [155] |
Table abbreviations; NPs: nanoparticles; PGA: poly(glycolic acid); PLGA: poly(Lactide-co-Glycolide); PLA: Poly (Lactic Acid); PEG: Polyethylene glycol; HA: hyaluronic acid; NO: Nitric oxide; MCAO: middle cerebral artery occlusion; BNDF: brain-derived neurotrophic factor; EGF: Epidermal Growth Factor; VEGF: Vascular endothelial growth factor; EPO: Erythropoietin; ROS: Reactive oxygen species; NMDA: N-methyl-D-aspartate receptor; PSD-95: postsynaptic density protein 95; WGA: Wheat germ agglutinin; MMP-2: Matrix Metallopeptidase 2; BBB: blood–brain barrier; HMGB1: high mobility group box 1; PAMAM: Polyamidoamine; siRNA: Small interfering RNA; Cxcl12: stromal cell-derived factor 1 or C-X-C motif chemokine 12; PHD2: hydroxylase domain protein 2; ECM: extracellular matrix.