Advances in cytosolic drug delivery

Nanoparticles (particles smaller than 100 nm where materials display different properties than at the bulk state) are frequently used in nanomedicine for drug delivery and other purposes. The sophistication and specificity of nanoparticle use is growing, particularly for delivering drugs past the lipid bilayer barrier of the cell wall to the inside of cells (cytosolic drug delivery) where they can target biophysical processes more easily. Two advances focus on cytosolic drug delivery, using light and peptides to break the endosomes (carrying vehicles) to release drugs directly into the cytosol.

1) Light-mediated endosomal breakage
One advance is in the development of nanoparticles (size-tunable (30-200 nm) highly monodispersed mesoporous silica nanoparticles) that can be loaded with a variety of compounds and released into the cytosol via light-mediated endosomal breakage, as illustrated in Figure 1 (Febvay et al, Nano Lett, 2010).

Figure 1: Nanoparticle cargo discharge through light-activation.

2) GALA peptide endosomal breakage
A second advance is in cytosolic drug delivery with nanoparticles using a peptide, GALA, to encourage endosomal breakage. GALA (comprised of repeating sequences of Glu-Ala-Leu-Ala) mimics the function of viral fusion protein sequences that mediate escape of virus genes from endosomes (Nakase et al, Methods Mol Biol, 2011).

New class of drugs: stapled peptides

Stapled peptides refers to a computational drug design technique that may create a whole new class of drugs by being able to more effectively target substances within cells and increase the number of proteins which can be targeted. Stapled peptides are generated through the synthetic enhancement of a 3-D alpha-helix protein segment with hydrocarbon bonds to make proteins more rigid and able to penetrate cell walls. The more rigid structure also gives stapled peptides longer lives through greater protease degradation resistance.

The two current classes of drugs, small molecules and biologics, are limited in that they can only target 20% of all proteins. Stapled peptides could allow a wider range of proteins to be used in drug-targeting. They are currently in clinical trials for the inhibition of a BCL-2 family protein, oncogene MCL-1, using an exclusive inhibitor, the MCL-1 BH3 helix, which could unblock caspase-dependent apoptosis in cancer cells (paper).