Molecular modeling of polynucleotide complexes.
Biomaterials
; 35(25): 7068-76, 2014 Aug.
Article
em En
| MEDLINE
| ID: mdl-24856107
ABSTRACT
Delivery of polynucleotides into patient cells is a promising strategy for treatment of genetic disorders. Gene therapy aims to either synthesize desired proteins (DNA delivery) or suppress expression of endogenous genes (siRNA delivery). Carriers constitute an important part of gene therapeutics due to limitations arising from the pharmacokinetics of polynucleotides. Non-viral carriers such as polymers and lipids protect polynucleotides from intra and extracellular threats and facilitate formation of cell-permeable nanoparticles through shielding and/or bridging multiple polynucleotide molecules. Formation of nanoparticulate systems with optimal features, their cellular uptake and intracellular trafficking are crucial steps for an effective gene therapy. Despite the great amount of experimental work pursued, critical features of the nanoparticles as well as their processing mechanisms are still under debate due to the lack of instrumentation at atomic resolution. Molecular modeling based computational approaches can shed light onto the atomic level details of gene delivery systems, thus provide valuable input that cannot be readily obtained with experimental techniques. Here, we review the molecular modeling research pursued on critical gene therapy steps, highlight the knowledge gaps in the field and providing future perspectives. Existing modeling studies revealed several important aspects of gene delivery, such as nanoparticle formation dynamics with various carriers, effect of carrier properties on complexation, carrier conformations in endosomal stages, and release of polynucleotides from carriers. Rate-limiting steps related to cellular events (i.e. internalization, endosomal escape, and nuclear uptake) are now beginning to be addressed by computational approaches. Limitations arising from current computational power and accuracy of modeling have been hindering the development of more realistic models. With the help of rapidly-growing computational power, the critical aspects of gene therapy are expected to be better investigated and direct comparison between more realistic molecular modeling and experiments may open the path for design of next generation gene therapeutics.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Polinucleotídeos
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Modelos Moleculares
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Técnicas de Transferência de Genes
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article