Euro Biotechnology 2018: Next step in drug delivery: getting inside cells and to individual organelles- Vladimir P Torchilin- Northeastern University

Many pharmaceutical agents need to be delivered intracellularly to exert their therapeutic action onto specific cell organelles for maximum therapeutic outcome. It is true for preparations for gene and antisense therapy (target cell nuclei), proapoptotic drugs, (target mitochondria or lysosomes); or enzymes for therapy of storage diseases (target lysosomes). Intracellular delivery of different biologically-active molecules is one of the key problems in drug delivery in general. In some cases, intracellular drug delivery allows to overcome serious problems, such as multifrug resistance in cancer. The problem however is that the lipophilic cell membranes restrict the direct intracellular penetration of various extracellular compounds. Under certain circumstances, these molecules or even small particles can be taken from the extracellular space into cells by the receptor-mediated endocytosis, but any molecule/particle entering the cell via the endocytic pathway becomes entrapped in endosome and eventually ends in the lysosome, where active degradation takes place. As a result, only a small fraction of intact therapeutic substance appears in the cell cytoplasm and performs its function. So far, multiple and only partially successful attempts have been made to bring various drugs and drug-loaded pharmaceutical carriers directly into the cell cytoplasm, bypassing the endocytic pathway, to protect drugs and DNA-related substances from the lysosomal degradation. Various noninvasive methods, such as the use of pH-sensitive carriers, including pH-sensitive liposomes (which under the low pH inside endosomes destabilize endosomal membrane, liberating the entrapped drug into the cytoplasm) and cell-penetrating molecules are currently applied to solve the problem. In many cases, to increase the stability of administered drugs, improve their efficacy, and decrease side effects, various pharmaceutical nanocarriers are used. Among the most popular and well-investigated nanocarriers are liposomes, polymeric micelles, solid lipid or polymeric nanoparticles, dendrimers and some others. Pharmaceutical nanocarriers have already a great history with quite a few of them being approved for clinical use and even more being under clinical trials. Currently, multiple attempts are under way to make pharmaceutical nanocarriers multifunctional, i.e. capable of simultaneous or sequential performing of several functions, such as for example, a specific recognition of a target cell and endosomal escape. Clearly, the ability to target individual cell organelles would be a highly