Combination of cell-penetrating peptides with nanomaterials for the potential therapeutics of central nervous system disorders: a review

Zhang, Ying; Guo, Pan; Ma, Zhe; Lü, Peng; Kebebe, Dereje; Liu, Zhidong

doi:10.1186/s12951-021-01002-3

Cited by 43 publications

(42 citation statements)

References 199 publications

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“…The peptides were primarily selected on the basis of predicted relatively higher blood brain barrier score, lower haemolytic activity and toxicity (Table 1). Among amphipathic peptides, we selected well-characterized and widely used pVEC, ARF, MAP and TP-10 while TAT, R8, IMT-P8, SynB3 and Penetratin were selected from the cationic class (Stalmans et al, 2015; Zhang et al, 2021). Peptides from the hydrophobic class were not selected due to their limited solubility and high propensity to aggregate.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the identification of suitable inhibitors of α-syn fibrillation has primarily been carried out by screening large libraries of small molecules. Attempts have been made to further enhance the efficacy of inhibitors by increasing their ability to cross the blood-brain barrier using approaches based on nanoparticles or cell-penetrating peptides (CPPs) (Zhang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinson’s disease

Gupta

Singh

Mehrotra

et al. 2022

Preprint

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. The presence of lewy bodies, primarily consisting of α-synuclein (α-syn) aggregates is one of the common features seen in the substantia nigra region of the brain in PD patients. The disease remains incurable and only symptomatic relief is available. We screened various cell-penetrating peptides and reveal that penetratin is a potent inhibitor of α-syn aggregation in-vitro, and significantly improved locomotor coordination in mice models of PD in-vivo. The peptide inhibits α-syn aggregation in vitro as well as in yeast, and C.elegans models. We further made a cyclic derivative of penetratin by disulfide coupling of N- and C-terminal cysteine residues. Both penetratin and its cyclized derivative interact with α-syn. NMR studies show that both linear as well as cyclic derivative interact at the acidic C-terminal tail of the protein. Similar to penetratin, its cyclic derivative inhibited α-syn aggregation in the C.elegans model of Parkinson’s disease, and also improved worm motility. Molecular Dynamics studies show that penetratin interacts with α-synuclein and prevents its conformational transition from disordered into β-sheet rich structure. The therapeutic efficacy of penetratin was further confirmed in a transgenic mice model of the disease, wherein penetratin treatment over a period of 90 days improved locomotor coordination, and halted disease progression. Overall, the present work provides a potent therapeutic agent that could be further explored in the management of PD.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinson’s disease

Gupta

Singh

Mehrotra

et al. 2022

Preprint

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show abstract

“…The results are very promising and demonstrate the therapeutic potentials of the CPP-modified nanomaterials on targeting brain diseases effectively. [160] These findings suggested that manipulating CPPs on NP surfaces would be a safe, effective, and promising strategy to improve IN medication transport for therapeutic applications in brain diseases. [161] Among all, the Bom/PEG-PCLTat is more effective to release camptothecin in the brain for GBM therapy via IN delivery, owing to the higher drug encapsulation efficiency (70%) and a more controllable drug release capacity.…”

Section: Cpp-modified Npsmentioning

confidence: 99%

“…The results are very promising and demonstrate the therapeutic potentials of the CPP‐modified nanomaterials on targeting brain diseases effectively. [ 160 ] These findings suggested that manipulating CPPs on NP surfaces would be a safe, effective, and promising strategy to improve IN medication transport for therapeutic applications in brain diseases. [ 161 ]…”

Section: Therapeutic Applications Of Modified Nps For Brain Diseasesmentioning

confidence: 99%

Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain

Zha

Wong

All

2022

Adv Healthcare Materials

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Intravenous delivery of nanomaterials containing therapeutic agents and various cargos for treating neurological disorders is often constrained by low delivery efficacy due to difficulties in passing the blood-brain barrier (BBB). Nanoparticles (NPs) administered intranasally can move along olfactory and trigeminal nerves so that they do not need to pass through the BBB, allowing non-invasive, direct access to selective neural pathways within the brain. Hence, intranasal (IN) administration of NPs can effectively deliver drugs and genes into targeted regions of the brain, holding potential for efficacious disease treatment in the central nervous system (CNS). In this review, current methods for delivering conjugated NPs to the brain are primarily discussed. Distinctive potential mechanisms of therapeutic nanocomposites delivered via IN pathways to the brain are then discussed. Recent progress in developing functional NPs for applications in multimodal bioimaging, drug delivery, diagnostics, and therapeutics is also reviewed. This review is then concluded by discussing existing challenges, new directions, and future perspectives in IN delivery of nanomaterials.

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“…That study supported further development of therapeutic delivery platforms that enable compounds to more readily cross the BBB. Along these lines, cell‐penetrating peptides or peptides loaded onto nanoparticles have been in development to deliver therapeutic agents and proteins into the CNS (Zhang et al, 2021). Although this strategy is promising, the nanomaterials show signs of toxicity, and the delivery system itself lacks cell specificity.…”

Section: Therapeutic Interventions In Neurodegenerative Disease Progr...mentioning

confidence: 99%

Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease

Keifer

2022

J of Neuroscience Research

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Research demonstrates that the neural mechanisms underlying synaptic plasticity and learning and memory involve mobilization of AMPA‐type neurotransmitter receptors at glutamatergic synaptic contacts, and that these mechanisms are targeted during neurodegenerative disease. Strengthening neural transmission occurs with insertion of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPARs) into synapses while weakening results from receptor withdrawal. A key player in the trafficking of AMPARs during plasticity and learning is the brain‐derived neurotrophic factor (BDNF) signaling system. BDNF is a neurotrophic factor that supports neuronal growth and is required for learning and memory. Significantly, a primary feature of many neurodegenerative diseases is a reduction in BDNF protein as well as disrupted neuronal surface expression of synaptic AMPARs. The resulting weakening of synaptic contacts leads to synapse loss and neuronal degeneration that underlies the cognitive impairment and dementia observed in patients with progressive neurodegenerative disease such as Alzheimer’s. In the face of these data, one therapeutic approach is to increase BDNF bioavailability in brain. While this has been met with significant challenges, the results of the research have been promising. In spite of this, there are currently no clinical trials to test many of these findings on patients. Here, research showing that BDNF drives AMPARs to synapses, AMPAR trafficking is essential for synaptic plasticity and learning, and that neurodegenerative disease results in a significant decline in BDNF will be reviewed. The aim is to draw attention to the need for increasing patient‐directed clinical studies to test the possible benefits of increasing levels of neurotrophins, specifically BDNF, to treat brain disorders. Much is known about the cellular mechanisms that underlie learning and memory in brain. It can be concluded that signaling by neurotrophins like BDNF and AMPA‐type glutamate receptor synaptic trafficking are fundamental to these processes. Data from animal models and patients reveal that these mechanisms are adversely targeted during neurodegenerative disease and results in memory loss and cognitive decline. A brief summary of our understanding of these mechanisms indicates that it is time to apply this knowledge base directly to development of therapeutic treatments that enhance neurotrophins for brain disorders in patient populations.

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Combination of cell-penetrating peptides with nanomaterials for the potential therapeutics of central nervous system disorders: a review

Cited by 43 publications

References 199 publications

Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinson’s disease

Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinson’s disease

Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain

Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease

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