Targeting of Synthetic Gene Delivery Systems

Abstract

Safe, efficient, and specific delivery of therapeutic genes remains an important bottleneck for the development of gene therapy. Synthetic, nonviral systems have a unique pharmaceutical profile with potential advantages for certain applications. Targeting of the synthetic vector improves the specificity of gene medicines through a modulation of the carriers' biodistribution, thus creating a dose differential between healthy tissue and the target site. The biodistribution of current carrier systems is being influenced to a large extent by intrinsic physicochemical characteristics, such as charge and size. Consequently, such nonspecific interactions can interfere with specific targeting, for example, by ligands. Therefore, a carrier complex should ideally be inert, that is, free from intrinsic properties that would bias its distribution away from the target site. Strategies such as coating of DNA carrier complexes with hydrophilic polymers have been used to mask some of these intrinsic targeting effects and avoid nonspecific interactions. Preexisting endogenous ligand-receptor interactions have frequently been used for targeting to certain cell types or tumours. Recently exogenous ligands have been derived from microorganisms or, like antibodies or phage-derived peptides, developed de novo. In animal models, such synthetic vectors have targeted remote sites such as a tumour. Furthermore, the therapeutic proof of the concept has been demonstrated for fitting combinations of synthetic vectors and therapeutic gene.

Peptide-guided gene delivery

“…96 Many peptides can function as ligands to target nonviral gene delivery systems to specifi c cell and/or tissue types within the body and enhance the delivery of nonviral vectors. These peptides can be used to condense the DNA if they contain enough positively charged basic residues, but in general they are covalently attached to another condensing agent and function only for targeting purposes.…”

Reversible Covalent Chemistry in Drug Delivery

“…The importance of drug delivery as a tool in contemporary medicine can hardly be overstated (for reviews, see: [1,2,3,4]). The ultimate aim in drug delivery is the total control over the biodistribution of drugs, generating therapeutically useful drug concentrations near the target, while the concentrations in other tissues are kept at safe levels.…”

Enhanced in vivo gene transfer into the placenta using RGD fiber-mutant adenovirus vector

“…In animal models, such improved vectors have targeted specific tissues such as the kidney [27e29]. Furthermore, therapeutic proof of concept has been demonstrated for fitting combinations of these improved vectors and therapeutic genes [30].…”