5 research outputs found
Polyglycerol-based amphiphilic dendrons as potential siRNA carriers for in vivo applications
The development of nonviral synthetic vectors for clinical application of gene
therapy using siRNA transfection technology is of particular importance for
treatment of human diseases, which is yet an unsolved challenge. By employing
a rational design approach, we have synthesized a set of well-defined, low-
molecular-weight dendritic polyglycerol-based amphiphiles, which are decorated
peripherally with the DAPMA (N,N-di-(3-aminopropyl)-N-(methyl)amine) moiety.
The main differences that were introduced in the structural motif relate to
dendron generation and the type of linker between the hydrophilic and
hydrophobic segment. The synthesized amphiphiles were then characterized for
their aggregation behaviour and further evaluated with respect to their siRNA
transfection potential by comparing their physico-chemical and biological
features. Our findings demonstrated that all four synthesized amphiphiles
yielded high gene binding affinities. Furthermore, the ester-linked compounds
(G1-Ester-DAPMA, G2-Ester-DAPMA) revealed noticeable gene silencing in vitro
without affecting the cell viability in the tumor cell line 786-O. Remarkably,
neither G1-Ester-DAPMA nor G2-Ester-DAPMA induced inflammatory side effects
after systemic administration in vivo, which is noteworthy because such highly
positively charged compounds are typically associated with toxicity concerns
which in turn supports their prospective application for in vivo purposes.
Therefore, we believe that these structures may serve as new promising
alternatives for nonviral siRNA delivery systems and have great potential for
further synthetic modifications
Polyglycerol-based amphiphilic dendrons as potential siRNA carriers for in vivo applications
The development of nonviral synthetic vectors for clinical application of gene
therapy using siRNA transfection technology is of particular importance for
treatment of human diseases, which is yet an unsolved challenge. By employing
a rational design approach, we have synthesized a set of well-defined, low-
molecular-weight dendritic polyglycerol-based amphiphiles, which are decorated
peripherally with the DAPMA (N,N-di-(3-aminopropyl)-N-(methyl)amine) moiety.
The main differences that were introduced in the structural motif relate to
dendron generation and the type of linker between the hydrophilic and
hydrophobic segment. The synthesized amphiphiles were then characterized for
their aggregation behaviour and further evaluated with respect to their siRNA
transfection potential by comparing their physico-chemical and biological
features. Our findings demonstrated that all four synthesized amphiphiles
yielded high gene binding affinities. Furthermore, the ester-linked compounds
(G1-Ester-DAPMA, G2-Ester-DAPMA) revealed noticeable gene silencing in vitro
without affecting the cell viability in the tumor cell line 786-O. Remarkably,
neither G1-Ester-DAPMA nor G2-Ester-DAPMA induced inflammatory side effects
after systemic administration in vivo, which is noteworthy because such highly
positively charged compounds are typically associated with toxicity concerns
which in turn supports their prospective application for in vivo purposes.
Therefore, we believe that these structures may serve as new promising
alternatives for nonviral siRNA delivery systems and have great potential for
further synthetic modifications
Double-degradable responsive self-assembled multivalent arrays-temporary nanoscale recognition between dendrons and DNA
This article reports self-assembling dendrons which bind DNA in a multivalent manner. The molecular design directly impacts on self-assembly which subsequently controls the way these multivalent nanostructures bind DNA-this can be simulated by multiscale modelling. Incorporation of an S-S linkage between the multivalent hydrophilic dendron and the hydrophobic units responsible for self-assembly allows these structures to undergo triggered reductive cleavage, with dithiothreitol (DTT) inducing controlled breakdown, enabling the release of bound DNA. As such, the high-affinity self-assembled multivalent binding is temporary. Furthermore, because the multivalent dendrons are constructed from esters, a second slow degradation step causes further breakdown of these structures. This two-step double-degradation mechanism converts a large self-assembling unit with high affinity for DNA into small units with no measurable binding affinity-demonstrating the advantage of self-assembled multivalency (SAMul) in achieving highly responsive nanoscale binding of biological targets
Glycine-Terminated Dendritic Amphiphiles for Nonviral Gene Delivery
Development of nonviral vectors for the successful application
of gene therapy through siRNA/DNA transfection of cells is still a
great challenge in current research., In the present
study, we have developed multivalent polyglycerol dendron based amphiphiles
with well-defined molecular structures that express controlled glycine
arrays on their surfaces. The structure–activity relationships
with respect to the siRNA complexation, toxicity, and transfection
profiles were studied with synthesized amphiphilic polycations. Our
findings revealed that a second-generation amphiphilic dendrimer (G2-octaamine, <b>4</b>) that has eight amine groups on its surface and a hydrophobic
C-18 alkyl chain at the core of the dendron, acts as an efficient
vector to deliver siRNA and achieve potent gene silencing by investigating
the knockdown of luciferase and GAPDH gene activity in HeLa cells.
Interestingly, the amphiphilic vector is nontoxic even at higher ratio
of N/P 100. To the best of our knowledge this is the first example
of successful in vitro siRNA transfection using dendritic amphiphiles.
We believe that this supramolecular complex may serve as a new promising
alternative for nonviral siRNA delivery systems and will be investigated
for in vivo siRNA delivery in the future