Hydrophobic oleic acid-coated vaterite core shell particles as a platform for encapsulation of hydrophobic drugs

Hydrophobic small-molecule drugs remain challenging to formulate due to their poor aqueous solubility, limited loading and the need for controllable release profiles. We report oleic acid (OA)-coated vaterite based core-shell particles with polymeric and lipid shells as a platform for hydrophobic drug delivery, using temozolomide (TMZ) as a model compound. A porous vaterite CaCO₃ core was first coated with OA to create a hydrophobic layer and then with PEG-PLKC/PEG-PLE or a cholesterol/PC/DSPE-PEG shell to form polymeric and lipid capsules, respectively. Water contact angle measurements confirmed the hydrophobization: unmodified vaterite was completely wetted and did not support a sessile drop, whereas the OA-modified vaterite gave a well-defined droplet. OA-coated polymeric capsules showed low TMZ entrapment efficiency (EE < 5%) and sizes of ~800 nm. To further increase the EE of the drug and prevent leakage through the shell, TMZ was additionally conjugated with OA and palmitic acid (PA); however, the synthetized polymeric particles showed no improvement in EE. Whereas OA-based lipid capsules achieved higher loading (EE ≈ 25%) with an average diameter of ~400 nm and retained low polydispersity index (PDI) during the first 6 days at 4⁰C. The TMZ release demonstrated two-phase behavior where the extent of both phases was pH-dependent: the cumulative release reached approximately 60% at pH 7.4, whereas at pH 5.5 it exceeded 90% within 24 h. Both carrier types were exposed to focused ultrasound (FUS, 5.03 and 8.03 MPa); OA-based lipid capsules exhibited pronounced FUS-induced destabilization, while OA-coated polymeric capsules retained higher mechanical integrity. TMZ-loaded OA-based lipid capsules preserved the intrinsic cytotoxic activity of TMZ against GL261 glioma cells, and empty OA-containing formulations were non-toxic. These results identify OA-modified vaterite core-shell particles, particularly lipid formulations, as a promising and tunable platform for hydrophobic drug delivery with potential for stimuli-responsive release.