Metoclopramide-loaded poly(alkylcyanoacrylate) (PACA) nanospheres were prepared by emulsifier-free polymerization in aqueous media at ambient conditions. The optimum polymerization conditions for metoclopramide sorption on PACA nanospheres in the presence of dextran (DEX) or hydroxypropyl-beta -cyclodextran (HPCD) in the polymerization medium were studied and the feasibility of either poly(isobutylcyanoacrylate) (PIBCA) or poly(ethylcyanoacrylate) (PECA) nanospheres as parenteral prolonged release drug delivery system of metaclopramide in rats was also investigated. The optimum time for the addition of metaclopramide after initiating the polymerization was 1 h, which results in 14.8 +/- 0.4 and 9.2 +/- 0.5% of drug loading for PIBCA and PECA, respectively. The HPCD in the polymerization medium of PECA nanospheres improved the drug adsorption compared to DEX at all times, but the difference was only significant (p < 0.05) when metoclopramide was added at 0 and 30 min. Wistar rats were given subcutaneous (sc) injections of metoclopramide solution (5 mg/kg) and three different metoclopramide nanospheres suspensions (10 mg/kg) on two phases. The drug solution is rapidly absorbed, distributed, and eliminated. The maximum drug concentration was observed after 30 min of sc administration of all the tested nanosphere formulations. PECA-HPCD showed the highest concentration (3.16 0.66 mg/L) followed by PIBCA-DEX (1.95 +/- 0.37 mg/L) and PECA-DEX (168 +/- 028 mg/L). The AUCs of PECA-DEX, PECA-HPCD and PIBCA-DEX were 4.8, 1.88 and 2.43 times higher than that of the solution form, respectively. Following PECA-DEX the maximum drug concentration, 1.68 +/- 0.28 mg/L, rapidly decreased to 0.54 +/- 0.05 mg/L. The drug was successfully maintained around this serum drug concentration up to 12 h in rats and the mean drug concentration was reduced to 0.2 +/- 0.02 mg/L, 63% reduction, after 24 h of nanosphere administration. The developed aqueous parenteral prolonged release preparation (PECA-DEX) could be used as a promising intermittent formula for metoclopramide or other drugs when the oral route is not accessible, especially during managing chronic nausea in patients with advanced cancer.