Endocytosis Pathways for Nucleic Acid Therapeutics

Malefyt, Amanda P.; Walton, S. Patrick; Chan, Christina

doi:10.1142/s179398441241005x

Cited by 9 publications

(6 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this mode of trafficking, it was thought that when cells were exposed to nanoparticles carrying siRNA that following endosomal acidification the result was lysosomal osmotic swelling and rupture, leading to the release of its contents into the cytosol (protonsponge effect). 5,41 Several studies have reported this mode of internalization and trafficking to be an efficient route for nanoparticles to release siRNA into the cytoplasm. 40−42 However, recent studies have suggested that siRNA release from nanoparticles may be more complex and involve multiple internalization and trafficking processes.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The physicochemical properties of nanoparticles including, size, shape, and surface charge can have a major influence on the mode of internalization and intracellular trafficking. , Accumulating evidence shows that different modes of endocytosis can lead to different intracellular trafficking of nanoparticles within the cell, which can impact transfection efficiency. , Intracellular trafficking is a dynamic process and is responsible for transporting internalized molecules to different subcellular locations. , For example, nanoparticles that are internalized via a clathrin-dependent endocytic pathway can be transported from early endosomes to lysosomes. For this mode of trafficking, it was thought that when cells were exposed to nanoparticles carrying siRNA that following endosomal acidification the result was lysosomal osmotic swelling and rupture, leading to the release of its contents into the cytosol (proton-sponge effect). , Several studies have reported this mode of internalization and trafficking to be an efficient route for nanoparticles to release siRNA into the cytoplasm. − However, recent studies have suggested that siRNA release from nanoparticles may be more complex and involve multiple internalization and trafficking processes. Gilleron et al demonstrated that the internalization and trafficking of lipid nanoparticles is cell-type dependent and can use both clathrin-mediated endocytosis and micropinocytosis.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo

et al. 2016

View full text Add to dashboard Cite

Pancreatic cancer is a devastating disease with a dismal prognosis. Short-interfering RNA (siRNA)-based therapeutics hold promise for the treatment of cancer. However, development of efficient and safe delivery vehicles for siRNA remains a challenge. Here, we describe the synthesis and physicochemical characterization of star polymers (star 1, star 2, star 3) using reversible addition-fragmentation chain transfer polymerization (RAFT) for the delivery of siRNA to pancreatic cancer cells. These star polymers were designed to contain different lengths of cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA) side-arms and varied amounts of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA). We showed that star-POEGMA polymers could readily self-assemble with siRNA to form nanoparticles. The star-POEGMA polymers were nontoxic to normal cells and delivered siRNA with high efficiency to pancreatic cancer cells to silence a gene (TUBB3/βIII-tubulin) which is currently undruggable using chemical agents, and is involved in regulating tumor growth and metastases. Notably, systemic administration of star-POEGMA-siRNA resulted in high accumulation of siRNA to orthotopic pancreatic tumors in mice and silenced βIII-tubulin expression by 80% at the gene and protein levels in pancreatic tumors. Together, these novel findings provide strong rationale for the use of star-POEGMA polymers as delivery vehicles for siRNA to pancreatic tumors.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Efficient transfection and release of Bcl-2 AONs in MCF-7 cells was effective for all systems except for the K-PA assembly, presumably due to poor AON binding with only a single lysine available for complementary pairing. Transport assays conducted in the presence of uptake inhibitors 655 demonstrated that AON delivery with the K-PA/AON and the R 4 -PA/AON complexes were not inhibited by any of the assessed inhibitors, suggesting a non-endocytotic pathway for internalization. Delivery with the R 8 -PA and KRSR-PA/AON complexes were found to be dynamin-mediated and interestingly, coassembled R 8 -PA/KRSR-PA/AON complexes were found to be mediated by dynamin, clathrin-mediated endocytosis, and caveolae-mediated endocytosis internalization pathways, indicating the complex effects of PA formulation on transport mechanism.…”

Section: Peptide/biopolymer Hybridsmentioning

confidence: 95%

Multicomponent peptide assemblies

2018

View full text Add to dashboard Cite

Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and β-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.

show abstract

“…Uptake inhibitors were used to study the mechanisms involved in the internalization of PAs decorated with CPPs and heparin binding sequences (Figure ). Amiloride, dynasore, chlorpromazine, and nystatin were used to inhibit macropinocytosis, dynamin-dependent pathway, clathrin-mediated endocytosis, and caveolae-mediated endocytosis, respectively . The internalization of K-PA and R 4 -PA was not inhibited with any of the chemical inhibitors used, which strongly indicates that the internalization was via a nonendocytotic pathway and probably through direct translocation.…”

Section: Resultsmentioning

confidence: 99%

Oligonucleotide Delivery with Cell Surface Binding and Cell Penetrating Peptide Amphiphile Nanospheres

et al. 2015

View full text Add to dashboard Cite

A drug delivery system designed specifically for oligonucleotide therapeutics can ameliorate the problems associated with the in vivo delivery of these molecules. The internalization of free oligonucleotides is challenging, and cytotoxicity is the main obstacle for current transfection vehicles. To develop nontoxic delivery vehicles for efficient transfection of oligonucleotides, we designed a self-assembling peptide amphiphile (PA) nanosphere delivery system decorated with cell penetrating peptides (CPPs) containing multiple arginine residues (R 4 and R 8 ), and a cell surface binding peptide (KRSR), and report the efficiency of this system in delivering G-3129, a Bcl-2 antisense oligonucleotide (AON). PA/AON (peptide amphiphile/antisense oligonucleotide) complexes were characterized with regards to their size and secondary structure, and their cellular internalization efficiencies were evaluated. The effect of the number of arginine residues on the cellular internalization was investigated by both flow cytometry and confocal imaging, and the results revealed that uptake efficiency improved as the number of arginines in the sequence increased. The combined effect of cell penetration and surface binding property on the cellular internalization and its uptake mechanism was also evaluated by mixing R 8 -PA and KRSR-PA. R 8 and R 8 / KRSR decorated PAs were found to drastically increase the internalization of AONs compared to nonbioactive PA control. Overall, the KRSR-decorated self-assembled PA nanospheres were demonstrated to be noncytotoxic delivery vectors with high transfection rates and may serve as a promising delivery system for AONs.

show abstract

Endocytosis Pathways for Nucleic Acid Therapeutics

Cited by 9 publications

References 78 publications

A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo

A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo

Multicomponent peptide assemblies

Oligonucleotide Delivery with Cell Surface Binding and Cell Penetrating Peptide Amphiphile Nanospheres

Contact Info

Product

Resources

About