PLGA nanoparticles modified with a BBB-penetrating peptide co-delivering Aβ generation inhibitor and curcumin attenuate memory deficits and neuropathology in Alzheimer's disease mice

Abstract

Alzheimer's disease (AD) is the most common form of dementia, characterized by the formation of extracellular senile plaques and neuronal loss caused by amyloid β (Aβ) aggregates in the brains of AD patients. Conventional strategies failed to treat AD in clinical trials, partly due to the poor solubility, low bioavailability and ineffectiveness of the tested drugs to cross the blood-brain barrier (BBB). Moreover, AD is a complex, multifactorial neurodegenerative disease; one-target strategies may be insufficient to prevent the processes of AD. Here, we designed novel kind of poly(lactide-co-glycolic acid) (PLGA) nanoparticles by loading with Aβ generation inhibitor S1 (PQVGHL peptide) and curcumin to target the detrimental factors in AD development and by conjugating with brain targeting peptide CRT (cyclic CRTIGPSVC peptide), an iron-mimic peptide that targets transferrin receptor (TfR), to improve BBB penetration. The average particle size of drug-loaded PLGA nanoparticles and CRT-conjugated PLGA nanoparticles were 128.6 nm and 139.8 nm, respectively. The results of Y-maze and new object recognition test demonstrated that our PLGA nanoparticles significantly improved the spatial memory and recognition in transgenic AD mice. Moreover, PLGA nanoparticles remarkably decreased the level of Aβ, reactive oxygen species (ROS), TNF-α and IL-6, and enhanced the activities of super oxide dismutase (SOD) and synapse numbers in the AD mouse brains. Compared with other PLGA nanoparticles, CRT peptide modified-PLGA nanoparticles co-delivering S1 and curcumin exhibited most beneficial effect on the treatment of AD mice, suggesting that conjugated CRT peptide, and encapsulated S1 and curcumin exerted their corresponding functions for the treatment.

PLGA-PEG-ANG-2 Nanoparticles for Blood–Brain Barrier Crossing: Proof-of-Concept Study

“…Representative results were already visible, qualitatively demonstrating penetration of the Ang-2-NPs across the BBB at 1 h (data not shown), similar to those results obtained at 4 h. With respect to control samples (unmodified labeled NPs) not showing significant signals related to NPs (Figure S1), the presence of Ang-2 NPs was uniform throughout the dentate gyrus, cortex, and hippocampus ( Figure 5A, red channel), suggesting a robust, uniform passage of the NPs across the BBB. The clear accumulation of Ang-2 NPs in brain parenchyma is remarkable in consideration of the inability of unmodified NPs and modified NPs used as controls (data not shown) to cross BBB alone (data not shown), which was also broadly assessed from other outputs in literature of NPs of similar composition and size [30,32]. In analyzing the images, Ang-2-NPs colocalized with the various cell types present in the brain, evidenced only with DAPI, but were often also in close proximity to the neuronal cells ( Figure 5B, red and yellow arrows respectively).…”

Hepato therapeutic Efficacy of Native Curcumim and Nano –curcumin : A Novel Therapy Against Hyperthyroidism Induced Liver Oxidative and Inflammatory Damage in Rats

“…Likewise, compared to native curcumin, curcumin nanoparticles exhibited stronger inhibitory properties against cell proliferation in lung A549, liver HepG2 and skin A431 cells [11]. PLGA nanoparticles encapsulating curcumin and amyloid-beta generating inhibitor attenuated memory deficit and neuropathology in a mice model [6].…”

“…Curcumin longa, commonly referred as turmeric, is used widespread as an essential spice in food preparations mainly due to its medicinal properties. Curcumin exhibits a number of medicinal properties including anti-diabetic [1], anti-arthritic [2], anti-oxidant [3], anti-inflammatory [4], antimicrobial [5], anti-neurodegenerative [6]and anticancer [7]. Despite the widespread applications, the beneficial effects of curcumin are hampered by its poor bioavailability which results from its high metabolic and excretion rates, poor absorption and minimal water insolubility [8].…”

Multifunctional Polymeric Nanoplatforms for Brain Diseases Diagnosis, Therapy and Theranostics

“…Increased activity of superoxide dismutase (SOD) and synapse numbers in the AD mouse brains [119] PBCA-P80 Dalargin Efficient delivery of drugs into the brain [138] P(HDCA-co-RCA-co-MePEGCA) and 14 C-P(HDCA-co-MePEGCA) Anti-Aβ1-42…”

“…It was demonstrated that these NPs promote the delivery of schisantherin A into the brain, improve the oral bioavailability, increase the brain uptake, and enhance the bioactivity of this drug. Huang et al synthesized PLGA NPs with a BBB-penetrating peptide for the co-delivery of Aβ generation inhibitor and curcumin in AD mice [119]. Overall, they found that these NPs were associated with a reduced level of Ab, ROS, TNF-a, and IL-6, and increased activity of superoxide dismutase (SOD) and synapse numbers in AD mouse brains, leading to their potential therapeutic use in AD.…”