Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier

In this study, we formulated polyplexes with different compositions for co-delivery of DNA and small-interfering RNA (siRNA). Since DNA and siRNA have distinctive and complementary morphological characteristics (DNA is long and winding and siRNA is short and rigid), we hypothesized that their co-delivery using polyplex would enhance each other's transfection. To test this hypothesis, cationic polymer branched polyethylenimine (bPEI) as a standard transfecting agent and its derivative arginine-rich oligopeptide-grafted bPEI modified with polyethylene glycol (P(SiDAAr)5P3), synthesized in our laboratory, were used as carriers for transfection. Polyplexes at different nucleic acid to polymer weight ratios were characterized for transfection in breast cancer sensitive (MCF-7) and resistant (MCF-7/Adr) cell lines. Gene silencing effect of polyplexes was determined in MDA-MB-231-luc-D3H2LN cell line. The results demonstrated that the polyplexes formed with derivative P(SiDAAr)5P3 show significantly lower toxicity compared to polyplexes formed using bPEI. Further, co-delivery resulted in 20-fold higher DNA transfection and 2-fold higher siRNA transfection as compared to the respective single nucleotide delivery. DNA transfection was ∼100 fold lower in resistant MCF-7/Adr cells than in sensitive MCF-7 cells. Confocal imaging and flow cytometry data demonstrated that enhanced transfection does not solely depend on DNA's cellular uptake, suggesting that other mechanisms contribute to increased transfection. DNA-co-siRNA delivery could be a promising therapeutic approach to achieve synergistic effects, because it can simultaneously target and interfere with multiple regulatory levels in a cell to halt and reverse disease progression.

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“…14 Therefore, chemical modifications are usually made to mitigate the effect of high cationic charge of PEI. 15 …”

Section: Introductionmentioning

confidence: 99%

Codelivery of DNA and siRNA via Arginine-Rich PEI-Based Polyplexes

Morris

Labhasetwar

2015

Mol. Pharmaceutics

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“…Multiple intravenous administrations improved the recovery of rotenone induced parkinsonian rats. Recently, polyethylene imine grafted chitosan nanocarriers for GDNF gene delivery were assayed [52] demonstrating a high in vitro GDNF gene expression and confirming the biocompatibility of this approach. Therefore this application should be borne in mind to design future in vivo evaluations.…”

Section: Dds For Gene Therapymentioning

confidence: 82%

Brain aging and Parkinson’s disease: New therapeutic approaches using drug delivery systems

et al. 2016

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The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed.

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“…Despite the versatility of chitosan, nanoparticles have been the preferred candidates to counter different neurological disorders. Among these disorders are glioblastoma (Malmo et al, 2013;Danhier et al, 2015;Xu et al, 2015;Van Woensel et al, 2016, medulloblastoma (Kievit et al, 2015), Parkinson's disease (Peng et al, 2014), Alzheimer's disease Rassu et al, 2017), and multiple sclerosis (Youssef et al, 2019). Even viral infections, like HIV-infected brain, have been a target for this therapeutic strategy (Gu et al, 2017).…”

Section: Gene Therapymentioning

confidence: 99%

Potential of Chitosan and Its Derivatives for Biomedical Applications in the Central Nervous System

Ojeda-Hernández

Canales-Aguirre

Matías‐Guiu

et al. 2020

Front. Bioeng. Biotechnol.

117

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It is well known that the central nervous system (CNS) has a limited regenerative capacity and that many therapeutic molecules cannot cross the blood brain barrier (BBB). The use of biomaterials has emerged as an alternative to overcome these limitations. For many years, biomedical applications of chitosan have been studied due to its remarkable biological properties, biocompatibility, and high versatility. Moreover, the interest in this biomaterial for CNS biomedical implementation has increased because of its ability to cross the BBB, mucoadhesiveness, and hydrogel formation capacity. Several chitosanbased biomaterials have been applied with promising results as drug, cell and gene delivery vehicles. Moreover, their capacity to form porous scaffolds and to bear cells and biomolecules has offered a way to achieve neural regeneration. Therefore, this review aims to bring together recent works that highlight the potential of chitosan and its derivatives as adequate biomaterials for applications directed toward the CNS. First, an overview of chitosan and its derivatives is provided with an emphasis on the properties that favor different applications. Second, a compilation of works that employ chitosan-based biomaterials for drug delivery, gene therapy, tissue engineering, and regenerative medicine in the CNS is presented. Finally, the most interesting trends and future perspectives of chitosan and its derivatives applications in the CNS are shown.

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Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier

Cited by 15 publications

References 38 publications

Codelivery of DNA and siRNA via Arginine-Rich PEI-Based Polyplexes

Codelivery of DNA and siRNA via Arginine-Rich PEI-Based Polyplexes

Brain aging and Parkinson’s disease: New therapeutic approaches using drug delivery systems

Potential of Chitosan and Its Derivatives for Biomedical Applications in the Central Nervous System

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