Non-Viral Targeted Nucleic Acid Delivery: Apply Sequences for Optimization

Wang, Yanfang; Wagner, Ernst

doi:10.3390/pharmaceutics12090888

Cited by 13 publications

(11 citation statements)

References 202 publications

(281 reference statements)

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“…Endosomal escape, for instance, can be improved by the incorporation of endosomolytic motifs like saturated carbon chains of middle length , or pH-dependent lytic influenza peptide INF-7 . Moreover, endosomal buffering units could be beneficial such as the pH-responsive diisopropylaminoethy (DPA) motif. ,, For more efficient nuclear pDNA delivery, for example, nuclear localization signals (NLSs), chromatin-targeting peptides, or microtubule-targeting peptides could be included in the polymers . All in all, many options are available for modifying the triblock copolymers to improve the currently rather weak in vitro performance.…”

Section: Resultsmentioning

confidence: 99%

“…16,44,45 For more efficient nuclear pDNA delivery, for example, nuclear localization signals (NLSs), chromatintargeting peptides, or microtubule-targeting peptides could be included in the polymers. 46 All in all, many options are available for modifying the triblock copolymers to improve the currently rather weak in vitro performance. The high flexibility makes this pDNA delivery system much attractive and promising.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Versatile, Multifunctional Block Copolymers for the Self-Assembly of Well-Defined, Nontoxic pDNA Polyplexes

Ritt

Berger

Wagner

et al. 2020

ACS Appl. Polym. Mater.

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In the field of systemically applied, nucleic acid-based drugs, polyplexes are interesting candidates for therapeutic systems. In this study, we synthesized a multifunctional triblock copolymer via reversible addition−fragmentation chain transfer (RAFT) block copolymerization. Due to three orthogonal reactive functionalities (an azide end group, a reactive disulfide block (P(PDSM)), and a reactive ester block (P(PFPMA))), the synthesized polymer system is highly adaptable and can be modified in a tailor-made fashion. After modification with N,N-dimethyl ethylendiamine (DMEDA), the synthesized cationic triblock copolymers form polyplexes with pDNA, even at low N/P ratios. The polyplexes can be stabilized further by crosslinking, having a size range of 113−151 nm in 10 mM NaCl, with high uniformity and low size distribution. ζ measurements indicate a good shielding of the charged polyplex core. Additionally, no significant cytotoxicity of the polyplexes is found. First transfection experiments are positive, but the gene transfer efficiency needs to be improved further. Because of its high modifiability, the presented triblock copolymer system is a good candidate for an adjustable pDNA transport system.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Versatile, Multifunctional Block Copolymers for the Self-Assembly of Well-Defined, Nontoxic pDNA Polyplexes

Ritt

Berger

Wagner

et al. 2020

ACS Appl. Polym. Mater.

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show abstract

“…It showed that higher TAT concentrations significantly increased peptide uptake ( 51 ). In addition to TAT, penetratin, GALA, transportan, and its derivatives such as PepFect and NickFect have also received attention for their cell penetration abilities ( 52 ). Some other peptides can target specific cells by recognizing receptors at the cell surface, resulting in enhanced efficiency and reduced toxicity.…”

Section: Methodsmentioning

confidence: 99%

Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects

Gao

2021

AAPS J

206

116

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Gene therapy has been experiencing a breakthrough in recent years, targeting various specific cell groups in numerous therapeutic areas. However, most recent clinical studies maintain the use of traditional viral vector systems, which are challenging to manufacture cost-effectively at a commercial scale. Non-viral vectors have been a fast-paced research topic in gene delivery, such as polymers, lipids, inorganic particles, and combinations of different types. Although non-viral vectors are low in their cytotoxicity, immunogenicity, and mutagenesis, attracting more and more researchers to explore the promising delivery system, they do not carry ideal characteristics and have faced critical challenges, including gene transfer efficiency, specificity, gene expression duration, and safety. This review covers the recent advancement in non-viral vectors research and formulation aspects, the challenges, and future perspectives.

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“…Chemically programmed vectors have been considered as a turning point in the development of non-viral gene delivery systems [ 200 , 201 ]. The goal is to supply enhanced intercellular penetration followed by sufficient endosomal escape and specific nuclear or cytosolic localization of the cargo to bypass biological barriers [ 202 ].…”

Section: Car Transfer Methodology Into Nk Cellsmentioning

confidence: 99%

NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development

Dezfouli

Yazdi

Pockley

et al. 2021

Cells

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In recent years, cell-based immunotherapies have demonstrated promising results in the treatment of cancer. Chimeric antigen receptors (CARs) arm effector cells with a weapon for targeting tumor antigens, licensing engineered cells to recognize and kill cancer cells. The quality of the CAR-antigen interaction strongly depends on the selected tumor antigen and its expression density on cancer cells. CD19 CAR-engineered T cells approved by the Food and Drug Administration have been most frequently applied in the treatment of hematological malignancies. Clinical challenges in their application primarily include cytokine release syndrome, neurological symptoms, severe inflammatory responses, and/or other off-target effects most likely mediated by cytotoxic T cells. As a consequence, there remains a significant medical need for more potent technology platforms leveraging cell-based approaches with enhanced safety profiles. A promising population that has been advanced is the natural killer (NK) cell, which can also be engineered with CARs. NK cells which belong to the innate arm of the immune system recognize and kill virally infected cells as well as (stressed) cancer cells in a major histocompatibility complex I independent manner. NK cells play an important role in the host’s immune defense against cancer due to their specialized lytic mechanisms which include death receptor (i.e., Fas)/death receptor ligand (i.e., Fas ligand) and granzyme B/perforin-mediated apoptosis, and antibody-dependent cellular cytotoxicity, as well as their immunoregulatory potential via cytokine/chemokine release. To develop and implement a highly effective CAR NK cell-based therapy with low side effects, the following three principles which are specifically addressed in this review have to be considered: unique target selection, well-designed CAR, and optimized gene delivery.

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Non-Viral Targeted Nucleic Acid Delivery: Apply Sequences for Optimization

Cited by 13 publications

References 202 publications

Versatile, Multifunctional Block Copolymers for the Self-Assembly of Well-Defined, Nontoxic pDNA Polyplexes

Versatile, Multifunctional Block Copolymers for the Self-Assembly of Well-Defined, Nontoxic pDNA Polyplexes

Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects

NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development

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