Intravenous delivery of poorly water-soluble anticancer drugs such as
docetaxel (DTX) is challenging due to the low bioavailability and the toxicity related to solubilizing
excipients. Colloidal nanoparticles are used as alternative carriers, but low drug loading capacity and circulation instability limit their clinical translation. To address these challenges, DTX nanocrystals (NCs) were prepared using
Pluronic F127 as an intermediate stabilizer and
albumin as a functional surface modifier, which were previously found to be effective in producing small and stable NCs. We hypothesize that the
albumin-coated DTX NCs (DTX-
F-alb) will remain stable in serum-containing medium so as to effectively leverage the enhanced permeability and retention effect. In addition, the surface-bound
albumin, in its native form, may contribute to cellular transport of NCs through interactions with
albumin-
binding proteins such as secreted
protein acidic and rich in
cysteine (SPARC). DTX-
F-alb NCs showed sheet-like structure with an average length, width, and thickness of 284 ± 96, 173 ± 56, and 40 ± 8 nm and remained stable in 50% serum
solution at a concentration greater than 10 μg/mL. Cytotoxicity and cellular uptake of DTX-
F-alb and unformulated (free) DTX were compared on three cell lines with different levels of SPARC expression and DTX sensitivity. While the uptake of free DTX was highly dependent on DTX sensitivity, DTX-
F-alb treatment resulted in relatively consistent cellular levels of DTX. Free DTX was more efficient in entering drug-sensitive B16F10 and SKOV-3 cells than DTX-
F-alb, with consistent cytotoxic effects. In contrast, multidrug-resistant NCI/ADR-RES cells took up DTX-
F-alb more than free DTX with time and responded better to the former. This difference was reduced by SPARC knockdown. The high SPARC expression level of NCI/ADR-RES cells, the known affinity of
albumin for SPARC, and the opposing effect of SPARC knockdown support that DTX-
F-alb have exploited the surface-bound
albumin-SPARC interaction in entering NCI/ADR-RES cells.
Albumin-coated NC system is a promising formulation for the delivery of hydrophobic anticancer drugs to multidrug-resistant
tumors.