Memantine loaded PLGA PEGylated nanoparticles for Alzheimer’s disease: in vitro and in vivo characterization

Abstract

BackgroundMemantine, drug approved for moderate to severe Alzheimer’s disease, has not shown to be fully effective. In order to solve this issue, polylactic-co-glycolic (PLGA) nanoparticles could be a suitable solution to increase drug’s action on the target site as well as decrease adverse effects. For these reason, Memantine was loaded in biodegradable PLGA nanoparticles, produced by double emulsion method and surface-coated with polyethylene glycol. MEM–PEG–PLGA nanoparticles (NPs) were aimed to target the blood–brain barrier (BBB) upon oral administration for the treatment of Alzheimer’s disease.ResultsThe production parameters were optimized by design of experiments. MEM–PEG–PLGA NPs showed a mean particle size below 200 nm (152.6 ± 0.5 nm), monomodal size distribution (polydispersity index, PI < 0.1) and negative surface charge (− 22.4 mV). Physicochemical characterization of NPs confirmed that the crystalline drug was dispersed inside the PLGA matrix. MEM–PEG–PLGA NPs were found to be non-cytotoxic on brain cell lines (bEnd.3 and astrocytes). Memantine followed a slower release profile from the NPs against the free drug solution, allowing to reduce drug administration frequency in vivo. Nanoparticles were able to cross BBB both in vitro and in vivo. Behavioral tests carried out on transgenic APPswe/PS1dE9 mice demonstrated to enhance the benefit of decreasing memory impairment when using MEM–PEG–PLGA NPs in comparison to the free drug solution. Histological studies confirmed that MEM–PEG–PLGA NPs reduced β-amyloid plaques and the associated inflammation characteristic of Alzheimer’s disease.ConclusionsMemantine NPs were suitable for Alzheimer’s disease and more effective than the free drug.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0356-z) contains supplementary material, which is available to authorized users.

Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms

“…Poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-b-PGLA) seems to be a promising DDS [120][121][122], capable of passing the blood brain barrier [123,124]. Liu et al [125] investigated PEG 2000 / 5000 -b-PLGA (different ratio's) micelles on their biocompatibility and indicated that all micelles presented very low cytotoxicity.…”

Nanopharmaceutics: Part II—Production Scales and Clinically Compliant Production Methods

“…Polymeric nanoparticles can be obtained from natural, semi-synthetic or synthetic polymers (e.g., chitosan [37][38][39], polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) [40][41][42][43]), which will then govern the way the drugs are encapsulated inside the matrix (dissolved or dispersed) or attached onto the nanoparticle' surface (chemically bound or adsorbed), and how the drug is released [44]. Polymeric nanoparticles can be produced with a variety of sizes and shapes, with high drug payload for both hydrophilic and lipophilic molecules, can be surface-modified to increase the plasma half-life (e.g., PEGylation [45,46]) to have site-specific targeted delivery [47], and release the drug in a controlled fashion [48][49][50].…”

Multifunctional Polymeric Nanoplatforms for Brain Diseases Diagnosis, Therapy and Theranostics

“…Decreased amyloid-beta (Aβ) plaques and related inflammation characteristics [117] mPEG-PLGA Schisantherin A Improved oral bioavailability, increased brain uptake, and enhanced the bioactivity of this drug [118] Rabies virus glycoprotein 29-modified deferoxamine-loaded PLGA…”

“…These polymeric NPs can target brain cancer and other diseases [195,196]. Sanchez-Lopez et al developed PLGA PEGylated NPs for the delivery of memantine in AD [117]. MTT tests showed that these NPs are safe for brain cell lines (bEnd.3 and astrocytes) and PLGA PEGylated NPs could penetrate the BBB.…”