Novel pH-Responsive Structural Rearrangement of Myristic Acid-Conjugated Quetiapine Nanosuspension for Enhanced Long-Acting Delivery Performance

Abstract

Quetiapine myristate (QM), an ester-bonded lipophilic prodrug of quetiapine (QTP), is synthesized and converted into an amphiphilic structure in acidic pH to trigger a novel self-assembled QM nanosuspension (QMN). Following injection, this QMN rearranges within physiological pH to form nanoaggregates in structure, resulting in enhanced physicochemical properties and in vivo therapeutic performance without an initial burst release. The 200-nm-sized QMN exhibits less invasive injection, higher drug content, and better storage stability profile than conventional poly(lactide-co-glycolide) (PLGA) nanosuspensions containing QTP or QM. Following a single intramuscular injection to beagle dogs (35 mg kg^-1 QTP), QMN undergoes pH-responsive nanoaggregation to form the lipophilic prodrug, providing esterase-oriented sustained release for five weeks compared with the two-week period of PLGA nanosuspensions. Notably, QMN exhibits improved in vivo pharmacokinetic performance with long-acting delivery while minimizing issues associated with polymeric PLGA formulations, including the initial massive burst release, cellular toxicity, and adverse side effects. These results support the further development of QMN as a novel long-acting injectable to improve patient compliance and dosing frequency.

Keywords: initial burst release; long‐acting injectables; nanoaggregates; pH‐responsive structural rearrangement; quetiapine myristate; self‐assembled nanoparticles.

Scheme 1

Schematic illustration of pH‐responsive myristic acid‐conjugated quetiapine nanosuspension (QMN) for enhanced in vitro and in vivo performance and long‐acting delivery. Quetiapine myristate (QM), a lipophilic prodrug synthesized from quetiapine (QTP) and myristic acid, can be converted to QTP by plasma esterase. In an acidic buffer, QM self‐assembles to form positively charged 200‐nm sized QMN with good injectability, stability, and drug loading efficiency. Following intramuscular injection in beagle dogs, QMN undergoes physiological pH‐responsive structural rearrangement, forming nanoaggregates at the injection site for long‐acting performance with minimized initial burst release compared with conventional poly(lactide‐co‐glycolide) (PLGA) nanosuspensions loaded with QTP or QM.

Figure 1

Physicochemical properties of three nanosuspensions (F1–F3). A) Particle size, polydispersity index (PDI) and B) zeta potential of nanosuspensions. C) Representative TEM images of nanosuspensions. D,E) Physical stability of polymeric nanosuspensions (F1, F2) in the powder (D) and aqueous liquid (E) states at 25 °C. F) Shear viscosities of nanosuspensions as a function of shear rate. G) Drug content and loading efficiency of three nanosuspensions. Data are presented as mean ± standard deviation (n = 3). Significant differences were analyzed using one‐way analysis of variance (ANOVA) followed by the Bonferroni post hoc test: ***p < 0.001, **p < 0.01, and *p < 0.05; ns: no significant difference (p > 0.05).

Figure 2

Physiological responsiveness of three nanosuspensions. A, B) SEM images of nanosuspensions (F1–F3) in pH 4.5 (A) and pH 7.4 (B) buffers. C, D) Stability of three nanosuspensions in different concentrations (w/v) of sodium chloride (NaCl) solutions (C) and fetal bovine serum (10% v/v in PBS 0.01 M) (D) at 37 °C. Data are presented as mean ± standard deviation (n = 3). Significant differences were analyzed using one‐way analysis of variance (ANOVA), followed by the Bonferroni post hoc test: ***p < 0.001, **p < 0.01, and *p < 0.05; ns: no significant difference (p > 0.05).

Figure 3

In vitro drug release profiles of NSPs (F1–F3) in the presence or absence of esterase. A) Release rate (%)–time profile of QTP (red) and QM (blue) in the absence of esterase. B) Release rate (%)–time profile of QTP (red) and QM (blue) in the presence of esterase (5 U mL⁻¹). The sink condition was guaranteed by adding polysorbate 80 (0.5% w/v) to 0.01 M phosphate‐buffered saline (PBS). Data are expressed as mean ± standard deviation (n = 3).

Figure 4

Cytotoxicity of three NSPs (F1–F3). A) Cell viability after treatment with the QTP solution and three NSPs (F1–F3) at different QTP concentrations (100, 1000, 10 000, 50 000, and 100 000 ng mL⁻¹) for 24 h. B) Live/dead images of cell viability after treatment with QTP solution and three NSPs at 100 000 ng mL⁻¹ for 24 h. Data are expressed as mean ± standard deviation (n = 6). Significant differences were analyzed using one‐way analysis of variance (ANOVA), followed by the Bonferroni post hoc test: ***p < 0.001, **p < 0.01, and *p < 0.05; ns: no significant difference (p > 0.05).

Figure 5

Pharmacokinetic profiles following IM injection of three NSPs (F1–F3) to beagle dogs (35 mg kg⁻¹ as QTP). A) Experimental schedule for the in vivo study. B,C) Plasma concentration–time profiles of QTP (B) and QM (C). Data represents mean ± standard deviation (n = 4).