Rational Design of Thermosensitive Hydrogel to Deliver Nanocrystals with Intranasal Administration for Brain Targeting in Parkinson’s Disease

Abstract

Mitochondrial dysfunction is commonly detected in individuals suffering from Parkinson’s disease (PD), presenting within the form of excessive reactive oxygen species (ROS) generation as well as energy metabolism. Overcoming this dysfunction within brain tissues is an effective approach to treat PD, while unluckily, the blood-brain barrier (BBB) substantially impedes intracerebral drug delivery. In an effort to improve the delivery of efficacious therapeutic drugs to the brain, a drug delivery platform hydrogel (MAG-NCs@Gel) was designed by complexing magnolol (MAG)-nanocrystals (MAG-NCs) into the noninvasive thermosensitive poly(N-isopropylacrylamide) (PNIPAM) with self-gelation. The as-prepared MAG-NCs@Gel exhibited obvious improvements in drug solubility, the duration of residence with the nasal cavity, and the efficiency of brain targeting, respectively. Above all, continuous intranasal MAG-NCs@Gel delivery enabled MAG to cross the BBB and enter dopaminergic neurons, thereby effectively alleviating the symptoms of MPTP-induced PD. Taking advantage of the lower critical solution temperature (LCST) behavior of this delivery platform increases its viscoelasticity in nasal cavity, thus improving the efficiency of MAG-NCs transit across the BBB. As such, MAG-NCs@Gel represented an effective delivery platform capable of normalizing ROS and adenosine triphosphate (ATP) in the mitochondria of dopaminergic neurons, consequently reversing the mitochondrial dysfunction and enhancing the behavioral skills of PD mice without adversely affecting normal tissues.

Brain-Targeted Biomimetic Nanodecoys with Neuroprotective Effects for Precise Therapy of Parkinson’s Disease

“…Finally, the depolarization of the mitochondrial membrane in SH-SY5Y cells was studied using JC-1 staining. 29 In normal SH-SY5Y cells, a strong red fluorescence was observed, indicating a high mitochondrial membrane potential. In contrast, MPP + -treated cells showed a green fluorescence signal, indicating a reduced mitochondrial membrane poten-tial�a sign of early apoptosis (Figure 4F).…”

“…Finally, the depolarization of the mitochondrial membrane in SH-SY5Y cells was studied using JC-1 staining . In normal SH-SY5Y cells, a strong red fluorescence was observed, indicating a high mitochondrial membrane potential.…”

Research progress on intranasal treatment for Parkinson's disease

“…However, it remains unclear how different types of intranasally injected stem cells enter the body, their influence, and how their effects differ from one another. Before being OE-MSCs [28] HEDSCs [29] DPSCs [30] NSCs Fasudil-treated bone marrow-derived NSCs [31] Nanotechnology NPs Selegiline-loaded chitosan nanoparticles [32] Lf-BNPs [33] Lf-modified rosiglitazone nanoparticles [34] CONPs [35] Nanoemulsions Selegiline nanoemulsion [36] CS-modified ropinirole nanoemulsion [37] CS-coated ropinirole nanoemulsion [38] Ibuprofen-loaded multi-carbon-based adhesive MMEI [39] Resveratrol-vitamin E capsule nanoemulsion [40] Levodopa-loaded nanoemulsion [41] Lipid-based NPs SLNs: SLNs loaded with ropinirole hydrochloride, rotigotine, astaxanthin, dopamine, GSE, dopamine, and mesylate rasagiline [42][43][44][45][46] NLCs: selegiline hydrochloride NLCs, ropinirole encapsulated in NLCs with N,N,N-trimethyl CS surface modification, and a combination of four levodopa drugs in NLCs [47][48][49] Hybrid nanosystems ROT-PM-TSG delivery system (improving the solubility of ropinirole) [50] Pluronic PF127-prepared thermo-reversible gel incorporating chitosan nanoparticles for levodopa [51] Drug delivery platform hydrogel (MAG-NCs@Gel) [52] RIN thermosensitive gel [53] Others Polymer-lipid hybrid NPs [54] Nanocomplexes [55] NC [56,57] Liposomes modified drugs [58,59] GDNF-loaded CS-coated NLCs [60] Resagraline-loaded deformable vesicles [61] Plasmid transfection encoding GDNF DNA NPs [62] OESCs loaded with SPIONs…”

“…To directly transport levodopa to the brain via the nasal route, thus improving its brain uptake rates, researchers created levodopa (CNL)‐loaded CS nanoparticles and added them to a Pluronic PF127 thermoreversible gel (CNLPgel), enhancing the bioavailability and brain uptake of levodopa while avoiding drug interactions and side effects 51 . Tan et al 52 combined magnolol nanocrystals (MAG‐NCs) with noninvasive poly(N‐isopropylacrylamide) (PNIPAM) in a thermosensitive hydrogel to create a drug delivery platform, hydrogel (MAG‐NCs@Gel). Through this platform, drug solubility, nasal cavity retention time, and targeting efficacy to the brain were improved.…”

Elastic Macroporous Matrix‐Supported In Situ Formation of Injectable Extracellular Matrix‐Like Hydrogel for Carrying Growth Factors and Living Cells

“…202300475 of biomedical applications such as regenerative medicine, tissue engineering, drug delivery, and biosensing, among others. [5][6][7][8][9][10] Numerous methods have been established to synthesize hydrogels. [11][12][13][14][15] These methods can be simply classified into two categories.…”