Limiting the level of tertiary amines on polyamines leads to biocompatible nucleic acid vectors

Carlos, Margarida Isabel Simão; Zheng, Kai; Garrett, Natalie; Arifin, Natrah; Workman, David G.; Kubajewska, Ilona; Halwani, Abdulrahman A.; Moger, Julian; Zhang, Qi; Schätzlein, Andreas; Uchegbu, Ijeoma F.

doi:10.1016/j.ijpharm.2017.04.059

Cited by 17 publications

(15 citation statements)

References 72 publications

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“…For instance, chitosan-tripolyphosphate siRNA nanoparticles silenced galectin-1, a gene that drives chemoresistance and immune-therapy resistance on intranasal administration, resulting in increased survival in a mouse tumor model [181]. Chitosan nanoparticles prepared with a chitosan-mangafodipir (mangafodipir is a manganese dipyridoxyl diphosphate chelator) electrostatic complex showed effective delivery of siRNA to the olfactory bulb for gene silencing [196,197].…”

Section: Nanoparticles Composed Of Chitosan and Chitosan Derivativesmentioning

confidence: 99%

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

et al. 2020

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Although the global prevalence of neurological disorders such as Parkinson's disease, Alzheimer's disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs' entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices. Figure 1. Schematic demonstrating various transport systems that shuttle molecules across the BBB. Very small amount of water-soluble compounds cross through the tight junctions (paracellular), whereas lipid-soluble agents traverse via the transcellular lipophilic pathway. Selective transport systems exist for glucose, amino acids, nucleosides, and other substances, in addition to specific receptor-mediated endocytosis for certain proteins such as insulin and transferrin. (AZT = azathioprine). List of CNS Diseases Parkinson's Disease (PD)PD, occurring primarily in the substantia nigra, is the second-most common neurodegenerative disease, leading to the development of bradykinesia and tremors of cardinal motor functions ( Figure 2) [3]. PD models specifically show a decrease in dopamine transporters, which are responsible for dopamine uptake by dopaminergic neurons and progression of neuronal communications. Reduced Figure 1. Schematic demonstrating various transport systems that shuttle molecules across the BBB. Very small amount of water-soluble compounds cross through the tight junctions (paracellular), whereas lipid-soluble agents traverse via the transcellular lipophilic pathway. Selective transport systems exist for glucose, amino acids, nucleosides, and other substances, in addition to specific receptor-mediated endocytosis for certain proteins such as insulin and transferrin. (AZT = azathioprine). List of CNS Diseases Parkinson's Disease (PD)PD, occurring primarily in the substantia nigra, is the second-most common neuro...

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Section: Nanoparticles Composed Of Chitosan and Chitosan Derivativesmentioning

confidence: 99%

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

et al. 2020

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“…Ijeoma Uchegbu (University College London, School of Pharmacy, UK; Chief Scientific Officer of Nanomerics, London, UK) reported on recent work [9] where her group developed nanoparticles (50–450 nm) made from N -(2-ethylamino)-6-O-glycolchitosan (EAGC) for the delivery of siRNA or DNA which, by limiting the level of tertiary amines on the polyamine, was 10 to 50-fold less toxic than Lipofectamine 2000 a common liposomal transfection reagent. The higher biocompatibility allowed 10-fold higher doses of DNA and siRNA to be applied to cells in vitro and intra-nasal dosing to rats resulted in siRNA transfer to the olfactory bulb.…”

Section: Discussionmentioning

confidence: 99%

Nanomedicines for the Delivery of Biologics

et al. 2019

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A special symposium of the Academy of Pharmaceutical Sciences Nanomedicines Focus Group reviewed the current status of the use of nanomedicines for the delivery of biologics drugs. This meeting was particularly timely with the recent approval of the first siRNA-containing product Onpattro™ (patisiran), which is formulated as a lipid nanoparticle for intravenous infusion, and the increasing interest in the use of nanomedicines for the oral delivery of biologics. The challenges in delivering such molecules were discussed with specific emphasis on the delivery both across and into cells. The latest developments in Molecular Envelope Technology® (Nanomerics Ltd, London, UK), liposomal drug delivery (both from an academic and industrial perspective), opportunities offered by the endocytic pathway, delivery using genetically engineered viral vectors (PsiOxus Technologies Ltd, Abingdon, UK), Transint™ technology (Applied Molecular Transport Inc., South San Francisco, CA, USA), which has the potential to deliver a wide range of macromolecules, and AstraZeneca’s initiatives in mRNA delivery were covered with a focus on their uses in difficult to treat diseases, including cancers. Preclinical data were presented for each of the technologies and where sufficiently advanced, plans for clinical studies as well as early clinical data. The meeting covered the work in progress in this exciting area and highlighted some key technologies to look out for in the future.

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“…Fluorescence associated with the olfactory bulb 5 min after intranasal delivery of a fluorescent molecule‐incorporated nanomedicine. This figure was published in Simão Carlos et al (2017), Copyright Elsevier, 2017…”

Section: Demonstration Of Brain Parenchyma Nanomedicine Deliverymentioning

confidence: 97%

“…Olfactory bulb siRNA fluorescence was 12‐fold higher 5 min after i.n. siRNA‐ and fluorescent molecule‐incorporated glycolchitosan polymer 255 nm particles than siRNA alone (Simão Carlos et al, 2017). Rat olfactory bulb and cerebrum LENK concentration was greater 15 and 30 min after i.n.…”

Section: Pharmacokinetic Benefitmentioning

confidence: 99%

Direct nose to the brain nanomedicine delivery presents a formidable challenge

Yokel

2021

WIREs Nanomed Nanobiotechnol

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This advanced review describes the anatomical and physiological barriers and mechanisms impacting nanomedicine translocation from the nasal cavity directly to the brain. There are significant physiological and anatomical differences in the nasal cavity, olfactory area, and airflow reaching the olfactory epithelium between humans and experimentally studied species that should be considered when extrapolating experimental results to humans. Mucus, transporters, and tight junction proteins present barriers to material translocation across the olfactory epithelium. Uptake of nanoparticles through the olfactory mucosa and translocation to the brain can be intracellular via cranial nerves (intraneuronal) or other cells of the olfactory epithelium, or extracellular along cranial nerve pathways (perineural) and surrounding blood vessels (perivascular, the glymphatic system). Transport rates vary greatly among the nose to brain pathways. Nanomedicine physicochemical properties (size, surface charge, surface coating, and particle stability) can affect uptake efficiency, which is usually less than 5%. Incorporation of therapeutic agents in nanoparticles has been shown to produce pharmacokinetic and pharmacodynamic benefits. Assessment of adverse effects has included olfactory mucosa toxicity, ciliotoxicity, and olfactory bulb and brain neurotoxicity. The results have generally suggested the investigated nanomedicines do not present significant toxicity. Research needs to advance the understanding of nanomedicine translocation and its drug cargo after intranasal administration is presented. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

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Limiting the level of tertiary amines on polyamines leads to biocompatible nucleic acid vectors

Cited by 17 publications

References 72 publications

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Nanomedicines for the Delivery of Biologics

Direct nose to the brain nanomedicine delivery presents a formidable challenge

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