STIMULI-SENSITIVE PARTICLES FOR DRUG DELIVERY - Biologically-Responsive Hybrid Biomaterials - page 171

The PEG chains were conjugated to cationic PLL chains for condensation of
nucleic acids via electrostatic interactions forming stable complexes. In the
endosome, the acetal linkage will be hydrolyzed in response to the acidic
environment thus unmasking the hydrophobic polymer backbone, which ruptures
the endosomal membrane and releases the condensed nucleic acid into the
cytoplasm. These encrypted polymers proved 9 times more effective at
endosomal disruption compared to PPAA homopolymers and were effective in
delivery of model ASODN into macrophage-like cells in vitro. [17, 81]
3.2. Role of “smart” particles in delivery of peptides and proteins
The route of administration of peptide and protein drugs dictates the formulation
parameters required to achieve efficient drug delivery. Oral and parenteral
delivery routes have distinctive sets of challenges. Orally-administered peptide
and protein drugs have to survive the acidity of the stomach, withstand the
hydrolytic activity of the metabolizing enzymes in the small intestine, permeate
across the intestinal epithelium and reach the systemic circulation to become
therapeutically effective. [82, 83] However, the enzymatic susceptibility of
peptide and protein drugs coupled with their large size and hydrophilicity result
in poor oral bioavailability and diminished therapeutic activity. [82-84] “Smart”
cationic and anionic polymers have been used as carriers to enhance oral
absorption of peptide and protein drugs across the gastrointestinal tract (GIT).
[85-87] These pH-sensitive carriers shield the encapsulated drug from the
metabolizing enzymes and harsh environment of the GIT while providing a
mechanism to tune the site and rate of drug release in response to changes in the
environment pH (Figure 10).
Several anionic polymers such as methyl acrylic acid (Eudragit L-100; MW
135 KDa), methyl methacrylate (S-100; MW 135 KDa), and hydroxypropyl
methylcellulose phthalate (HP-55) have been commercially used as enteric
coatings for oral delivery of peptide and protein drugs, where they release the
encapsulated drug molecules into the small intestine in response to the alkaline
pH. [88-91] Earlier research focused on optimizing the polymer composition
and consequently its pKa to tune the site of release of the encapsulated
peptide/protein drug in the small intestine. For example, Serres et al. loaded
calcitonin hydrogel particles prepared using NIPAM, BMA, and AA monomers
where the molar ratio of the hydrophilic AA monomer varied from 0-10%.
Results showed that the particles prepared using a higher AA content had a
higher drug loading capacity, were more stable, and released the encapsulated