A New Methodology to Create Polymeric Nanocarriers Containing Hydrophilic Low Molecular-Weight Drugs: A Green Strategy Providing a Very High Drug Loading

Abstract

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.

The Critical Role of Aromatic-Aromatic Drug-Polymer Interactions to Provide Nanomedicines Containing Chloroquine: A Simple Proposal to Provide High Encapsulation, High Stability, and Prolonged Drug Release

“…The former are thought to place at the inner part of the NPs, stabilized in hydrophobic domains, and the latter are thought to bind into hydrated segments at the surface of the NPs. As previously reported, formulations with a higher kinetically bound fraction (% KB) are associated with a controlled and prolonged release pro le [21]. The dia ltration parameters for all tested CQ/PSS formulations (CQ/PSS between 0.1 and 1.2) are shown in Table S1 (see supplementary information).…”

“…3C). This ndings are characteristic for the presence of secondary site-speci c aromatic-aromatic interactions since the hydration shell of the components changes, and the magnetic elds produced by electronic currents of aromatic groups strongly affect the neighbor structures [21,41,42]. A decrease on the molecular mobility is responsible for the broadening of the bands and the low signal-to-noise values.…”

“…Based on previous investigations where our group demonstrated the synthesis of NPs comprising imipramine, amitriptyline, or cyclobenzaprine with the hydrophilic and aromatic polymer PSS [21], polymer already approved by the FDA for therapeutic applications [29,30,32,34,35], we postulate in this work a simple strategy to create NPs loaded with CQ.…”

“…Moreover, nanoparticle tracking analysis (NTA) evidenced nanoparticle concentrations in the range of 0.9 × 10 10 to 6.6 × 10 10 NPs/mL for our formulations. Other studies analyzing this parameter for amitriptyline-PSS NPs, doxorubicin loaded in carbomer NPs, and doxorubicin loaded in skim milk derived nanovesicles, reported values in the range of 1.0 × 10 6 − 4.26 × 10 11 NPs/mL [21,43,44]. Interestingly, when comparing formulations with PSS versus PVS, despite CQ/PVS also formed NPs at molar ratio 0.4 (presumably due to ionic bonds between the CQ and PVS), less e cient interactions are evidenced.…”

“…Bearing in mind the physicochemical characteristics of CQ (cationic, hydrophilic, aromatic and low molecular-weight drug, Fig. 1, its entrapment in drug delivery systems such as nanoformulations to provide controlled and prolonged release, represents a main challenge [21][22][23]. The above statement is based on the very low capacity of this kind of molecules to undergo interactions with excipients that surpass their a nity with water, producing low drug association and, consequently, very fast drug release upon exposing the medicines to biological media [21][22][23].…”