1,721,208 research outputs found
Improving drug efficacy and specificity by innovative drug delivery approaches
No full textThe 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
Application of mathematical modelling in sustained release delivery systems
No full textIntroduction: This review, presenting as starting point the concept of the mathematical modelling, is aimed at the physical and mathematical description of the most important mechanisms regulating drug delivery from matrix systems. The precise knowledge of the delivery mechanisms allows to set up powerful mathematical models which, in turn, are essential for the design and optimization of appropriate drug delivery systems.
Areas covered: The fundamental mechanisms for drug delivery from matrices are represented by drug diffusion, matrix swelling, matrix erosion, drug dissolution with possible re-crystallisation (as in the case of amorphous and nano-crystalline drugs, for example), initial drug distribution inside the matrix, matrix geometry, matrix size distribution (in the case of spherical matrices of different diameter) and osmotic pressure. Depending on matrix characteristics, the above reported variables may play a different role in drug delivery; thus the mathematical model needs to be built solely on the most relevant mechanisms of the particular matrix considered.
Expert opinion: Despite the somewhat diffident behaviour of the industrial world, in the light of the most recent findings, we believe that mathematical modelling may have a tremendous potential impact in the pharmaceutical field. We do believe that mathematical modelling will be more and more important in the future especially in the light of the rapid advent of personalised medicine, a novel therapeutic approach intended to treat each single patient instead of the “average” patient
GT75 oligonucleotide as therapeutically new antitumoral agent and new aptamer for diagnostic u
No full textIn vitro allele-specific cleavage of collagen mRNA from patients affected by Osteogenesis Imperfecta by hammerhead ribozymes: qualitative and quantitative analysis.
No full textComment on: “First-in-human trial of Dz13 for nodular basal-cell carcinoma”.
No full textNucleic-acid-based drugs1 are a novel class of drugs with great therapeutic potential. Among these are DNAzymes, which contain short stretches of single-stranded DNA molecules synthesised in vitro. A DNAzyme can recognize through Watson-Crick basepairing a specific messenger RNA (mRNA) sequence and induce cleavage between a purine and a pyrimidine residue. Upon cleavage, the target mRNA undergoes accelerated degradation, which leads to a reduction in the concentration of the encoded protein and its related biological functions. Thus, DNAzymes can potentially be used to target specific mRNA in diseases dependent on individual genes. Nevertheless, although the great therapeutic potential of these drugs has been noted in preclinical studies, data about their use in human beings are missing.
In The Lancet, Eun-Ae Cho and colleagues report a first-in-human study of the DNAzyme Dz13 in patients with nodular basal-cell carcinoma. The therapeutic promise of Dz13 is strongly supported by previous animal studies. The drug targets the mRNA of the JUN proto-oncogene: this target is particularly well suited for the purpose of the study, as c-Jun protein is minimally expressed in normal skin tissue but concentrations are notably increased in skin cancer tumours. Additionally, the model tumour pathology chosen is well suited for clinical investigation because basal-cell carcinomas are easily accessible, monitoring is straightforward, the risk of systemic tumour spread is low, and the therapeutic drug can be injected locally
Mathematical modelling of nanocrystalline and amorphous drugs release and gastro-intestinal absorption from polymeric particles
No full textQuantitative ananlysis of hepatitis C virus RNA in liver biopsies by competitive reverse transcription and polymerase chain reaction
No full textDrug mechanochemical activation
No full textThe aim of this review is to describe the theoretical background lyin
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