Despite the advances in anticancer therapies, their effectiveness for many human tumors is still far from being optimal. Significant improvements in treatment efficacy can come from the enhancement ...of drug specificity. This goal may be achieved by combining the use of therapeutic molecules with tumor specific effects and delivery carriers with tumor targeting ability. In this regard, nucleic acid-based drug (NABD) and particularly small interfering RNAs (siRNAs), are attractive molecules due to the possibility to be engineered to target specific tumor genes. On the other hand, polymeric-based delivery systems are emerging as versatile carriers to generate tumor-targeted delivery systems. Here we will focus on the most recent findings in the selection of siRNA/polymeric targeted delivery systems for hepatocellular carcinoma (HCC), a human tumor for which currently available therapeutic approaches are poorly effective. In addition, we will discuss the most attracting and, in our opinion, promising siRNA-polymer combinations for HCC in relation to the biological features of HCC tissue. Attention will be also put on the mathematical description of the mechanisms ruling siRNA-carrier delivery, this being an important aspect to improve effectiveness reducing the experimental work.
The recently proposed Biopharmaceutics Classification System can be used to classify drugs and set standards for scale-up and post-approval changes as well as standards for in vitro/in vivo ...correlation for immediate and controlled release products. This classification scheme is based on determining the underlying process that is controlling the drug absorption rate and extent, namely, drug solubility and intestinal membrane permeability. Theoretical analysis and experimental results suggest that a permeability/solubility classification scheme can be used to set more rationale drug standards. In particular, high solubility/high permeability, rapidly dissolving drugs may be regulated on the basis of a single point rapid dissolution test while low solubility dissolution rate limited drugs can be regulated based on an in vitro dissolution test that reflects the in vivo dissolution process. This dissolution test may include multiple time points, media change, as well as surfactants in order to reflect the in vivo dissolution process and would be used by the manufacturer for requesting a waiver from a bioequivalence (BE) trial. For controlled release products, the regulation of bioequivalence standards is more complex due to the potential differences in position-dependent permeability/solubility and metabolism of drugs along the gastrointestinal tract. These differences may result in drug absorption rates that are highly transit time dependent. This paper will present the current status of the biopharmaceutic drug classification scheme, the underlying developed data base and its application to optimizing IR and CR products.
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