Albumin Corona Overturns Long-Acting Behaviors of Myristic Acid-Conjugated Quetiapine Nanosuspension

Abstract

This work aimed to investigate the interaction of a self-assembled myristic acid-conjugated quetiapine nanosuspension (QMN) with human serum albumin and its overturning effect on QMN's long-acting performance. Albumin corona formation modified the physicochemical properties and pharmacokinetic profile of QMN by overturning its pH-responsiveness and nano-aggregation behavior. The adsorption of albumin on QMN is initially triggered by electrostatic forces and later by hydrophobic-hydrophobic interactions with the conformational change of the albumin structure. While QMN is highly susceptible to ionic strength, pH, and albumin concentration in solution, albumin-precoated QMN (A-QMN) stabilized particle size and reversed the surface charge from ≈+60 to -16 mV, annulling the pH-responsive nanoaggregation behaviors under physiological pH conditions. Consequently, A-QMNs exhibited much faster in vitro release and more rapid in vivo absorption, resulting in a huge initial burst release and shorter duration within one week in plasma concentration-time profiles compared to the extended five-week duration of QMN following intramuscular injection in beagle dogs. These findings indicated the important role of serum proteins in the release kinetics and pharmacokinetics of the nanoparticles. The manipulation of protein corona can be utilized to control the physicochemical properties, biological states, and pharmacokinetics of intended long-acting nanosuspensions.

Keywords: albumin protein corona; fattigated drug nanosuspension; nanoparticle‐protein interaction; pH‐responsive nanoaggregates.

Figure 1

A) Effect of albumin concentration on the particle size and zeta potential of QMN. 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; ns: no significant difference (p > 0.05). Statistical analysis applied to particle size. B) TEM and C) CLSM images of QMN (top) and A‐QMN (bottom). Scale bars = 100 nm (TEM) and 10 µm (CLSM).

Figure 2

A) Particle size and zeta potential of the A‐QMN in different pH; B) TEM images of A‐QMN in pH 4.7 and pH 7.4. Particle size could not be measured at pH 2.7 due to aggregation (#). Scale bars = 0.5 µm. 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; ns: no significant difference (p > 0.05). Statistical analysis applied to particle size. C) Synchronous fluorescence and D) circular dichroism spectra with E) the α‐helix ratios of albumin in the presence of different QMN concentrations. F) FT‐IR spectroscopy of QMN, albumin, and A‐QMN.

Figure 3

Stability of the QMN and A‐QMN in A) PBS buffer at different concentrations of NaCl solutions andB) FBS at 37 °C. Particle size could not be measured at NaCl 0.5 and 5 m due to aggregation (#). 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). C) SDS‐PAGE image with Coomassie staining of serum protein corona of QMN and A‐QMN following the incubation with FBS at 37 °C for 24 h. The molecular weights of the proteins in the standard (Std) ladder are given on the left side. The black arrow indicates the band of albumin (66.5 kDa). The yellow arrows indicate example bands preferentially adsorbed by either QMN (≈25 kDa) or A‐QMN (≈15 kDa).

Figure 4

In vitro drug release profiles of the QMN and A‐QMN. Release rate (%) – time profile of A) QTP and B) QM in PBS buffer with the presence of esterase 5 U mL⁻¹. The sink condition was guaranteed by adding polysorbate 80 (0.5% w v⁻¹) to 0.01 m PBS. Data are expressed as mean ± standard deviation (n = 3).

Figure 5

Pharmacokinetic profiles following IM injection of the QMN and A‐QMN to beagle dogs (35 mg kg⁻¹ as QTP). Plasma concentration‐time profiles of A) QTP and B) QM. Data represents mean ± standard deviation (n = 4). Data of QMN was adapted from “Novel pH‐Responsive Structural Rearrangement of Myristic Acid‐Conjugated Quetiapine Nanosuspension for Enhanced Long‐Acting Delivery Performance”, by Hy D. Nguyen, Hai V. Ngo and Beom‐Jin Lee, 2024, Advanced Science, 11, 2405200. CC BY.