To
date, a large number of active molecules are hydrophilic and
aromatic low molecular-weight drugs (HALMD). Unfortunately, the
low capacity of these molecules to interact with excipients and the
fast release when a formulation containing them is exposed to biological
media jeopardize the elaboration of drug delivery systems by using
noncovalent interactions. In this work, a new, green, and highly efficient
methodology to noncovalently attach HALMD to hydrophilic aromatic
polymers to create nanocarriers is presented. The proposed method
is simple and consists in mixing an aqueous solution containing HALMD
(model drugs: imipramine, amitriptyline, or cyclobenzaprine) with
another aqueous solution containing the aromatic polymer [model polymer:
poly(sodium 4-styrenesulfonate) (PSS)]. NMR experiments demonstrate
strong chemical shifting of HALMD aromatic rings when interacting
with PSS, evidencing aromatic–aromatic interactions. Ion pair
formation and aggregation produce the collapse of the system in the
form of nanoparticles. The obtained nanocarriers are spheroidal, their
size ranging between 120 and 170 nm, and possess low polydispersity
(≤0.2) and negative zeta potential (from −60 to −80
mV); conversely, the absence of the aromatic group in the polymer
does not allow the formation of nanostructures. Importantly, in addition
to high drug association efficiencies (≥90%), the formed nanocarriers
show drug loading values never evidenced for other systems comprising
HALMD, reaching ≈50%. Diafiltration and stopped flow experiments
evidenced kinetic drug entrapment governed by molecular rearrangements.
Importantly, the nanocarriers are stable in suspension for at least
18 days and are also stable when exposed to different high ionic strength,
pH, and temperature values. Finally, they are transformable to a reconstitutable
dry powder without losing their original characteristics. Considering
the large quantity of HALMD with importance in therapeutics and the
simplicity of the presented strategy, we envisage these results as
the basis to elaborate a number of drug delivery systems with applications
in different pathologies.
