Development and evaluation of transferrin-stabilized paclitaxel nanocrystal formulation

Abstract

The aim of the present study was to prepare and evaluate a paclitaxel nanocrystal-based formulation stabilized by serum protein transferrin in a non-covalent manner. The pure paclitaxel nanocrystals were first prepared using an antisolvent precipitation method augmented by sonication. The serum protein transferrin was selected for use after evaluating the stabilizing effect of several serum proteins including albumin and immunoglobulin G. The formulation contained approximately 55~60% drug and was stable for at least 3 months at 4 °C. In vivo antitumor efficacy studies using mice inoculated with KB cells demonstrate significantly higher tumor inhibition rate of 45.1% for paclitaxel-transferrin formulation compared to 28.8% for paclitaxel nanosuspension treatment alone. Interestingly, the Taxol® formulation showed higher antitumor activity than the paclitaxel-transferrin formulation, achieving a 93.3% tumor inhibition rate 12 days post initial dosing. However, the paclitaxel-transferrin formulation showed a lower level of toxicity, which is indicated by steady increase in body weight of mice over the treatment period. In comparison, treatment with Taxol® resulted in toxicity issues as body weight decreased. These results suggest the potential benefit of using a serum protein in a non-covalent manner in conjunction with paclitaxel nanocrystals as a promising drug delivery model for anticancer therapy.

Developing Nanocrystals for Cancer Treatment

“…As such, precipitation-ultrasonication (PU) has become the mostly used bottom-up method ( Table 2). The process starts with drug substances dissolved in a solvent and subsequently injected into a miscible antisolvent (usually water) under vigorous stirring and intense sonication [41,42,47]. Production factors affecting the particle size and distribution by PU were investigated in one study of preparation of paclitaxel (PTX) nanocrystals [47].…”

“…The process starts with drug substances dissolved in a solvent and subsequently injected into a miscible antisolvent (usually water) under vigorous stirring and intense sonication [41,42,47]. Production factors affecting the particle size and distribution by PU were investigated in one study of preparation of paclitaxel (PTX) nanocrystals [47]. Good solvents including methylene chloride, ethyl acetate and dimethyl sulfoxide produced significantly larger nanocrystals compared with methanol and ethanol; the difference was attributed to the diffusion rates of the solutions dissipating in the antisolvent, water.…”

“…Because of the advantages of using nanocrystals over conventional delivery systems, an increasing number of anticancer drugs have been formulated into nanocrystals for intravenous delivery (Table 2) [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. As expected for the array of agents examined, various types of cancers, including pancreatic, stomach, lung and prostate, have being studied with the treatment of nanocrystals.…”

Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

“…31 Briefly, organic feeds were prepared by dissolving 80 mg of ATR and Labrasol ® (0.5% w/w) in methanol. Then the organic feeds were injected instanta neously into polymer solution containing chitosan and were prehomogenized at 12,000 rpm for 2 minutes (Ultra-turrax T-25 1KA, Germany).…”

“…At elevated temperature like 40°C, the nanocrystal system becomes more thermodynamically unfavorable and unstable resulting in aggregation of particles within ATR-L and ATR-CS L formulations. 31 However, a more detailed assessment of stability is required for determining accurate shelf-life of ATR-CS L nanocrystal formulations (Table 2).…”