Novel peptide-conjugated nanomedicines for brain targeting: In vivo evidence

Duskey, Jason Thomas; Ottonelli, Ilaria; Ros, Federica Da; Vilella, Antonietta; Zoli, Michèle; Kovachka, Sandra; Spyrakis, Francesca; Vandelli, Maria Angela; Tosi, Giovanni; Ruozi, Barbara

doi:10.1016/j.nano.2020.102226

Cited by 21 publications

(21 citation statements)

References 28 publications

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“…PLGA-g7 was synthesized via amide formation in the Nanotech Laboratory of the University of Modena and Reggio Emilia, following a previously described protocol [8,29]. PLGA is a synthetic polymer approved by the US Food and Drug Administration (FDA) and European Medicine Agency (EMA) for biomedical devices.…”

Section: Production and Characterization Of Hybrid-g7-nps-cholmentioning

confidence: 99%

Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington's disease

Birolini

Valenza

Ottonelli

et al. 2021

Journal of Controlled Release

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Supplementing brain cholesterol is emerging as a potential treatment for Huntington's disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the blood-brain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

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Section: Production and Characterization Of Hybrid-g7-nps-cholmentioning

confidence: 99%

Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington's disease

Birolini

Valenza

Ottonelli

et al. 2021

Journal of Controlled Release

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“…The PLGA-b-PEG copolymer was previously obtained through the modification of PLGA with mPEG-NH 2 (MW: 5000 Da) [22]. The PLGA (Resomer 503 H) derivatized with the fluorophore Cy5 was obtained by the Laboratory of Nanomedicine and Pharmaceutical Technology of the University of Modena and Reggio Emilia (Modena, Italy) as previously reported [25]. The PLGA-Mal (MW: 20 kDa) was purchased from Nanosoft Biotechnology (Lewisville, TX, USA).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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The treatment of diseases that affect the central nervous system (CNS) represents a great research challenge due to the restriction imposed by the blood–brain barrier (BBB) to allow the passage of drugs into the brain. However, the use of modified nanomedicines engineered with different ligands that can be recognized by receptors expressed in the BBB offers a favorable alternative for this purpose. In this work, a BBB-penetrating peptide, angiopep-2 (Ang–2), was conjugated to poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles through pre- and post-formulation strategies. Then, their ability to cross the BBB was qualitatively assessed on an animal model. Proof-of-concept studies with fluorescent and confocal microscopy studies highlighted that the brain-targeted PLGA nanoparticles were able to cross the BBB and accumulated in neuronal cells, thus showing a promising brain drug delivery system.

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“…Fluorescently labelled MIX NPs were produced with the same protocol described in 1.1.1, adding 2% in weight of Cy5 derived PLGA and 2% in weight of Bodipy-Cholesterol (Avanti, Alabama, USA). Cy5-PLGA was synthesized in the Nanotech Laboratory of the University of Modena and Reggio Emilia using a protocol published in [27]. The total composition was a mixture of Chol:Chol-Bodipy:PLGA:PLGA-Cy5:PLGA-g7 in weight ratio of 0.96:0.04:0.76:0.04:0.2 (24 mg Chol, 1 mg Chol-Bodipy, 19 mg PLGA, 1 mg PLGA-Cy5, 5 mg PLGA-g7).…”

Section: Methods Sectionmentioning

confidence: 99%

“…Emilia using a protocol published in [27]. The total composition was a mixture of Chol:Chol-Bodipy:PLGA:PLGA-Cy5:PLGA-g7 in weight ratio of 0.96:0.04:0.76:0.04:0.2 (24 mg Chol, 1 mg Chol-Bodipy, 19 mg PLGA, 1 mg PLGA-Cy5, 5 mg PLGA-g7).…”

Section: Cy5-plga Was Synthesized In the Nanotech Laboratory Of The Umentioning

confidence: 99%

Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

Birolini

Valenza

Ottonelli

et al. 2020

Preprint

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Supplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

show abstract

Novel peptide-conjugated nanomedicines for brain targeting: In vivo evidence

Cited by 21 publications

References 28 publications

Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington's disease

Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington's disease

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

Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

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