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Enclocytic pathways: gateways for intracellular drug delivery [Abstract]

Jones, Arwyn Tomos 2007. Enclocytic pathways: gateways for intracellular drug delivery [Abstract]. Journal of Pharmacy and Pharmacology 59 (S1) , A72. 10.1211/002235707781850023

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The unravelling of the human genome together with proteomic and genomic databases of specific diseases identifies a wealth of new therapeutic targets. The target is often intracellular, the therapeutic a macromolecule or nanomedicine and therefore breaching barriers posed by the plasma membrane and intracellular membranes presents a major challenge to drug delivery research. Cells internalise macromolecules using endocytic pathways; these are efficient multifarious and dynamic tubular and vesicular networks originating from the plasma membrane. They also represent vital avenues for intracellular delivery of therapeutic macromolecules. The effectiveness of using endocytosis for drug delivery may be constrained by the fact that the fate of the therapeutic within one of these pathways is predetermined by the dynamics of that pathway and the barriers posed by the plasma and endolysosomal membranes. Thus, more fragile molecules such as proteins and genes may be rapidly delivered to biologically hostile environments such as lysosomes and inactivated before they reach their intended targets. Improved intracellular delivery of nanomedicines is therefore dependent on attaining an equal high level of understanding of specific endocytic pathways that are inherent in the target cell, the traffic and fate of the therapeutic within endocytic organelles, the effect of the macromolecule on the dynamics of endocytic pathways and finally the downstream effects of these on the integrity of the cell (Jones et al 2003; Watson et al 2005). Drug delivery researchers therefore search for molecules that promote endocytosis and the escape of therapeutics from early stages of the endocytic pathway. Described systems include bioresponsive polymers to domains of proteins that have been shown to interact with and promote their own internalisation and escape of associated cargo across membrane bilayers. These include the hundereds of defined sequences classified as cell penetrating peptides (CPP) or protein transduction domains.The most intensely studied include those derived from proteins such as the HIV TAT protein and the Drosophila melanogaster homeobox protein Antennapedia (penetratin), to simpler arginine repeats such as octaarginine. Extensive research has focused on attempting to understand how and where they traverse biological membranes; information vital to furthering their promise as effective drug delivery vectors. Here, focus will be given to techniques that have allowed us to better understand endocytic pathways of a number of different cell types and how these were then used study endocytosis and intracellular dynamics of candidate drug delivery vectors such as CPPs (Watson et al 2005; Fretz et al 2007; Jones 2007). Fretz, M. M., et al (2007) Biochem. J. 403: 335–342 Jones, A. T. (2007) J. Cell Molec. Med. In press Jones, A. T., et al (2003) Adv. Drug Deliv. Rev. 1254: 1353–1357 Watson, P., et al (2005) Adv. Drug Deliv. Rev. 57: 43–61

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Additional Information: Special Issue: BPC Science Abstracts
Publisher: Royal Pharmaceutical Society of Great Britain
ISSN: 0022-3573
Last Modified: 04 Jun 2017 01:57

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