Folic acid-conjugated long circulating co-encapsulated atorvastatin and quercetin solid lipid nanoparticles: pharmacokinetics and biodistribution in rats

Background: Solid lipid nanoparticles (SLNs) have emerged as effective carriers for the simultaneous delivery of two drugs. Moreover, the surface modification of SLNs enhances their targetability and minimizes side effects, rendering them a promising and dynamic strategy for addressing various life-threatening diseases. The assessment of pharmacokinetic parameters is a critical aspect of this approach. In the present study, we report the development and validation of an LC-MS/MS-based bioanalytical method for the quantification of Atorvastatin (ATR) and Quercetin (QUER) encapsulated in folic acid-modified SLNs as a drug delivery system to estimate their pharmacokinetics and tissue distribution. Method: FA-SLNs were synthesized by amide linkage formation (carbodiimide reaction) and tested for their haemocompatibility. Further, an LC-MS/MS method was developed on a C18 (3 × 100 mm, 2.7 μm) column using 0.1% v/v formic acid in water and acetonitrile as the mobile phase with a 0.3 mL min⁻¹ flow rate. For detection, analytes were ionized using an electron spray ionization (ESI) source in multiple reaction monitoring (MRM) mode. MRM for the ATR (559.0 → 440.2) m/z and IS (482.1 → 257.8) m/z in positive polarity, and QUER (301.9 → 151.0) m/z in negative polarity were optimized. Results: Pharmacokinetics studies demonstrated an increase in the half-lives of ATR and QUER of about 6.4-fold and 5.7-fold, respectively, from FA-SLN compared to pure drugs. Further, the active targeting facilitated by FA conjugation showed increased mean residence time (MRT) and decreased clearance time, resulting in long circulation time without the enhanced retention of drugs in the tissues of rats. These findings underscore the potential of FA-modified ATR and QUER-loaded SLNs as an advanced drug delivery strategy in improving the therapeutic outcomes.