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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.

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This study was undertaken to develop a sustained-release formulation of tiaramide (TAM), a non-steroidal anti-inflammatory drug with a short half-life, using alginate of different chemical compositions. Alginate gel beads containing TAM were prepared using a gelation of alginate with calcium cations. Bead performance was evaluated in vitro for different dissolution media and beads were also subjected to coating. TAM release was dependent both on its solubility in dissolution medium and the guluronate residue content of the alginate used. The release rate was in the following order: in pH 1.2 > pH 6.8 > water. The fast release rate in pH 1.2 is the result of the high solubility of TAM in acidic medium. Beads based on alginate rich in guluronate residue had the lowest release rate, which can be attributed to the compact structure formed by guluronate residues through cooperative interaction with calcium ions. Alginate beads were administered to beagle dogs, and pharmacokinetic parameters (mean residence time [MRT], tmax, Cmax, and AUC) were calculated. In vivo results were in good agreement with in vitro dissolution characteristics. Beads with high guluronate content gave the best controlled results. In addition, coated beads showed a more satisfactory sustained-release pattern. Calcium alginate appears to be a potential carrier for controlling drug release rate, even for water-soluble drugs such as TAM.