The limited efficacy of current therapeutic approaches for a number of socially relevant human diseases requires the exploration of alternative and more effective therapeutic strategies. In this regard, the researchers have pursued on one hand the identification of novel and more effective therapeutic molecules and on the other the optimization of drug delivery systems. So far, many therapeutic molecules, especially those used as anticancer drugs, are plagued by a low therapeutic index being the efficacious dose very close to the lethal one; moreover, they often lack any specificity of action. This aspect can be improved by the use of drug delivery systems composed of different drug carriers including lipids and polymers. The carriers, often in the shape of nanoparticles , can be loaded by the therapeutic molecule and directed against the target cells via the presence of targeting moieties allocated on the nanoparticle surface. The specificity of the complex carrier/drug can be further improved by the use of therapeutic molecules preferentially/exclusively active on the target diseased cells. Molecules active against diseased-associated target (oncogenes etc) may hit the diseased cells leaving healthy cells substantially unaffected. In this regard, in the last three decades, nucleic acid based drugs (NABDs) have emerged as an attractive and novel alternative with great therapeutic potential. NABDs, which include antisense oligonucleotides, decoys, aptamers, triple helix forming oligonucleotides, DNAzymes, Ribozymes and small interfering RNAs, have been shown to be able to efficiently and specifically counteract pathological gene expression in many different experimental systems. Notably as they can be engineered to hit virtually any cell target, their potential applicability is very broad. Despite NABD broad potential applicability, their use in the clinic is limited by the lack of optimal delivery systems. Due to their hydrophilic nature, NABDs cannot efficiently cross cellular membrane for which appropriate carriers are needed. Moreover, their instability in serum requires a proper protection to prevent a fast degradation which would invariably lead to the abrogation of any significant therapeutic effect. The present special issue will be focused on the critical description of some aspects related to the optimization of drug delivery with a particular emphasis on NABD; despite this, a discussion about the possibility to use/adapt NABD developed delivery systems for more conventional drugs, is also present. The papers of Chan et al., of Marrache et al, of Schaffert et al., Jung et al. and Grassi et al. describe different delivery approaches for NABD and other commonly used therapeutic molecules for several pathological conditions. In the paper of Chan et al. attention is given to liposome and polymeric based delivery systems with regard to DNA enzymes; the described studies offer perspectives on future methodologies for improved DNAzyme delivery and utility as novel drugs. Marrache et al. describe the use of nanoparticles (made by polymer, liposome and other delivery agents), as delivery devices which can be engineered to load multiple drugs with varied physicochemical properties, contrast agents, and cellular or intracellular component targeting moieties. Schaffert et al draw their attention on the description of delivery systems based on the polycation linear polyethylenimine, where peptide based ligands are attached to the polycation via heterobifunctional polyethylene glycol linker molecules. Conjugate synthesis, in vitro testing and in vivo cancer models in rodents are discussed. Jung et al describe the employment of the thermo sensitive pluronic-based core/shell nanoparticles, formed using various strategies such as self-assembly and temperature induced-phase transition. Particular emphasis is given to the use of the nanoparticles for tumor targeting, stimulated release of proteins, and cancer imaging capabilities. Grassi et al, beside discussing the above mentioned delivery systems, for most of the different types of NABDs, draw their attention on the complex situation of NABD delivery to the arteries describing the advantages and dis-advantages of three different administration routes i.e. systemic, perivascular and intravascular. The papers of Lico et al, Pagliari et al and Castronovo et al report the use of “living delivery systems” and describe the influences of nano-systems on NABD. Lico et al. focus their attention on the use of a different approach for NABD delivery based on plant viruses which have a size particularly suitable for nanoscale applications and can offer several advantages being structurally uniform, robust, biodegradable and easy to produce. Pagliari et al. continue the description of “living vector” reporting the possible and very innovative use of stem cells as delivery devices for therapeutic molecules to the injured myocardium. Finally, in the paper of Castronovo et al., a completely innovative point of view about NABD complexation in nano-carriers is provided. The author show that the functionality of NABD in nano-systems is highly dependent upon the local density, molecular flexibility and network of weak interactions between adjacent molecules. The understanding of these properties can enable the development of powerful molecular tools for nano-medicine. In conclusion, whereas the developmental process of many delivery systems is still at the beginning, other delivery strategies are closer to possible applications. Regardless of the fact that the delivery systems are used for NABD or clinically available drugs, we believe the target tissue will mainly determine the nature of the optimal strategy. Despite the delivery issue can and should be further optimized, the encouraging results displayed so far in different experimental models using NABD or clinically used drugs, fully justify further economic and scientific efforts.

Improving drug efficacy and specificity by innovative drug delivery approaches

GRASSI, GABRIELE;GRASSI, Mario
2013

Abstract

The limited efficacy of current therapeutic approaches for a number of socially relevant human diseases requires the exploration of alternative and more effective therapeutic strategies. In this regard, the researchers have pursued on one hand the identification of novel and more effective therapeutic molecules and on the other the optimization of drug delivery systems. So far, many therapeutic molecules, especially those used as anticancer drugs, are plagued by a low therapeutic index being the efficacious dose very close to the lethal one; moreover, they often lack any specificity of action. This aspect can be improved by the use of drug delivery systems composed of different drug carriers including lipids and polymers. The carriers, often in the shape of nanoparticles , can be loaded by the therapeutic molecule and directed against the target cells via the presence of targeting moieties allocated on the nanoparticle surface. The specificity of the complex carrier/drug can be further improved by the use of therapeutic molecules preferentially/exclusively active on the target diseased cells. Molecules active against diseased-associated target (oncogenes etc) may hit the diseased cells leaving healthy cells substantially unaffected. In this regard, in the last three decades, nucleic acid based drugs (NABDs) have emerged as an attractive and novel alternative with great therapeutic potential. NABDs, which include antisense oligonucleotides, decoys, aptamers, triple helix forming oligonucleotides, DNAzymes, Ribozymes and small interfering RNAs, have been shown to be able to efficiently and specifically counteract pathological gene expression in many different experimental systems. Notably as they can be engineered to hit virtually any cell target, their potential applicability is very broad. Despite NABD broad potential applicability, their use in the clinic is limited by the lack of optimal delivery systems. Due to their hydrophilic nature, NABDs cannot efficiently cross cellular membrane for which appropriate carriers are needed. Moreover, their instability in serum requires a proper protection to prevent a fast degradation which would invariably lead to the abrogation of any significant therapeutic effect. The present special issue will be focused on the critical description of some aspects related to the optimization of drug delivery with a particular emphasis on NABD; despite this, a discussion about the possibility to use/adapt NABD developed delivery systems for more conventional drugs, is also present. The papers of Chan et al., of Marrache et al, of Schaffert et al., Jung et al. and Grassi et al. describe different delivery approaches for NABD and other commonly used therapeutic molecules for several pathological conditions. In the paper of Chan et al. attention is given to liposome and polymeric based delivery systems with regard to DNA enzymes; the described studies offer perspectives on future methodologies for improved DNAzyme delivery and utility as novel drugs. Marrache et al. describe the use of nanoparticles (made by polymer, liposome and other delivery agents), as delivery devices which can be engineered to load multiple drugs with varied physicochemical properties, contrast agents, and cellular or intracellular component targeting moieties. Schaffert et al draw their attention on the description of delivery systems based on the polycation linear polyethylenimine, where peptide based ligands are attached to the polycation via heterobifunctional polyethylene glycol linker molecules. Conjugate synthesis, in vitro testing and in vivo cancer models in rodents are discussed. Jung et al describe the employment of the thermo sensitive pluronic-based core/shell nanoparticles, formed using various strategies such as self-assembly and temperature induced-phase transition. Particular emphasis is given to the use of the nanoparticles for tumor targeting, stimulated release of proteins, and cancer imaging capabilities. Grassi et al, beside discussing the above mentioned delivery systems, for most of the different types of NABDs, draw their attention on the complex situation of NABD delivery to the arteries describing the advantages and dis-advantages of three different administration routes i.e. systemic, perivascular and intravascular. The papers of Lico et al, Pagliari et al and Castronovo et al report the use of “living delivery systems” and describe the influences of nano-systems on NABD. Lico et al. focus their attention on the use of a different approach for NABD delivery based on plant viruses which have a size particularly suitable for nanoscale applications and can offer several advantages being structurally uniform, robust, biodegradable and easy to produce. Pagliari et al. continue the description of “living vector” reporting the possible and very innovative use of stem cells as delivery devices for therapeutic molecules to the injured myocardium. Finally, in the paper of Castronovo et al., a completely innovative point of view about NABD complexation in nano-carriers is provided. The author show that the functionality of NABD in nano-systems is highly dependent upon the local density, molecular flexibility and network of weak interactions between adjacent molecules. The understanding of these properties can enable the development of powerful molecular tools for nano-medicine. In conclusion, whereas the developmental process of many delivery systems is still at the beginning, other delivery strategies are closer to possible applications. Regardless of the fact that the delivery systems are used for NABD or clinically available drugs, we believe the target tissue will mainly determine the nature of the optimal strategy. Despite the delivery issue can and should be further optimized, the encouraging results displayed so far in different experimental models using NABD or clinically used drugs, fully justify further economic and scientific efforts.
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