STIMULI-SENSITIVE PARTICLES FOR DRUG DELIVERY - Biologically-Responsive Hybrid Biomaterials - page 168

3. “Smart” Particles
3.1. Role of “smart” particles in delivery of therapeutic nucleic acids
Several nucleic acid molecules including plasmid DNA (pDNA), antisense
oligodeoxynucleotides (ASODN), and silencing RNA (siRNA) show potential
therapeutic activity against cancer, inflammation, and neurodegenerative
diseases. Activity of these molecules depends on their ability to reach their
intracellular targets commonly present in the cytoplasm of the diseased cell.
However, the systemic administration of therapeutic nucleic acids results in their
degradation by nuclease enzymes, non-specific distribution throughout the body,
rapid elimination into the urine, and limited cellular uptake via endocytosis,
which collectively result in degradation of the administered dose and loss of
therapeutic activity. [50-53]
Cationic polymers proved to be efficient carriers for delivery of nucleic acids
into targeted cells. [26] They complex negatively-charged DNA molecules
through electrostatic interactions forming polyplexes/particles that encapsulate
the nucleic acids in their cores “shielding it” from serum proteins, nucleases, and
other denaturing factors present in the systemic circulation. These particles
typically carry a net positive charge which allows them to interact with the
negatively-charged cell surface, trigger adsorptive-mediated endocytosis, and
gain access into the cell. However, for these particles to be therapeutically
effective, they have to escape the endosomal-lysosomal trafficking pathway,
enter the cytoplasm, and release the encapsulated therapeutic cargo to interact
with its desired intracellular target(s). [50, 54-57]
The endosomal compartment has a membrane-bound ATP-dependent proton
pump that acidifies the endosome down to pH 5.0. Certain cationic
polyamidoamine polymers such as poly(ethyleneimine) (PEI) have primary and
secondary amine groups with a pKa of 5.5-7.2 distributed on the polymer's
backbone. Endocytosis of PEI-based particles results in buffering of the
endosomal pH, which triggers further transport of hydronium ions into the
endosome and the influx of counter ions such as chloride, which increases the
endosomal osmotic pressure. The osmotic gradient causes water influx into the
endosome, which eventually ruptures the endosomal membrane and releases its
contents into the cytoplasm in a process known as the “proton sponge” effect.
[58] Boussif and Richardson tested the transfection efficiency of PEI (9 - 13.5
PEI nitrogen groups per single phosphate group of the DNA), which produced a
10 4 -fold higher transfection efficiency compared to the control. [59, 60]