The lysosome/endosome membrane: A barrier to polymer-based drug delivery?

Drug delivery by means of polymer conjugates that are internalized into cel ls by endocytosis is now a viable therapeutic approach. Successful deployme nt of this model depends upon release of the free drug within the endosome/ lysosome compartments and its efflux into the cytoplasm. The latter process involves the drug crossing the endosome/lysosome membrane, which is known to be impermeable to all large and many small molecules and which is equipp ed with numerous substrate-specific transporters that allow metabolites acr oss. Passive diffusion is the only viable mechanism for most xenobiotics to cross the endosome/lysosome membrane. Studies are reported on the permeabi lity of the rat liver lysosome membrane. These demonstrate that permeance o f molecules correlates inversely with their hydrogen-bonding capacity, a fu nction that can be calculated from inspection of structural formulae. It is deduced that drug molecules containing cationic and/or anionic functional groups, or numerous hydrogen-bonding moieties such as hydroxy, ether or car bonyl, will cross the lysosome membrane unacceptably slowly, but that many drugs will cross at a satisfactory rate. This conclusion is supported by th e rather meagre data available on membrane permeability of lysosomes in sit u within cells. Systematic experimental studies on the endosome membrane ar e lacking, but there is every reason to suppose that its permeability is si milar to that of the lysosome membrane.