Pharmacokinetic and pharmacodynamic profiles of recombinant human erythropoietin-loaded poly(lactic-co-glycolic acid) microspheres in rats.

AIM: To characterize the pharmacokinetic and pharmacodynamic profiles of the recombinant human erythropoietin (rhEPO)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres in rats. METHODS: The rhEPO-loaded microspheres were prepared using a solid-in-oil-in-water emulsion method. Pharmacokinetics and pharmacodynamics of the rhEPO-loaded microspheres were evaluated in male Sprague-Dawley rats. The serum rhEPO level was determined with ELISA. The level of anti-rhEPO antibody in the serum was measured to assess the immunogenicity of rhEPO released from the microspheres. RESULTS: rhEPO was almost completely released from the PLGA microspheres in vitro, following zero-order release kinetics over approximately 30 d. After intramuscular injection (10,000 or 30,000 IU rhEPO/kg) in the rats, the serum rhEPO concentration reached maximum levels on d 1, then decreased gradually and was maintained at nearly steady levels for approximately 4 weeks. Furthermore, the release of rhEPO from the PLGA microspheres was found to be controlled mainly by a dissolution/diffusion mechanism. A good linear correlation (R(2)=0.98) was obtained between the in vitro and in vivo release data. A single intramuscular injection of the rhEPO-loaded PLGA microspheres (10,000 or 30,000 IU rhEPO/kg) in the rats resulted in elevated hemoglobin and red blood cell concentrations for more than 28 d. Moreover, the immunogenicity of rhEPO released from the PLGA microspheres was comparable with that of the unencapsulated rhEPO. CONCLUSION: The results prove the feasibility of using the PLGA-based microspheres to deliver rhEPO for approximately 1 month.

Magnetic polycarbonate microspheres for tumor-targeted delivery of tumor necrosis factor.

OBJECTIVE: The specific expression of transferrin receptor can represent a diagnostic tool or therapeutic target in solid tumors expressing this antigen. Herein, the human transferrin receptor monoclonal antibody (T9) was investigated as a tumor-targeting group for active targeted-drug delivery systems. MATERIALS AND METHODS: A tumor-targeted conjugate T9-TNF was synthesized by the attachment of both human transferrin receptor monoclonal antibody (T9) as a tumor-targeting group and human tumor necrosis factor-α (TNF) as an anti-cancer drug to two terminated hydroxyl groups of poly(ethylene glycol). Subsequently, a solvent evaporation technique was adopted to produce anti-cancer magnetic polymer microspheres T9-TNF-PC-M containing T9-TNF and Fe3O4 magnetic ultrafine powders (M) using poly(trimethylene carbonate-co-5,5-dimethyl trimethylene carbonate) (PC, P(TMC-co-DTC)) as a polymeric carrier. RESULTS AND DISCUSSION: These magnetic polycarbonate microspheres possessed a steady TNF release rate in phosphate buffer saline solution, strong magnetic responsiveness and high T9-TNF loading capacity. In vitro cytotoxicity assays demonstrated the microspheres T9-TNF-PC-M and conjugate T9-TNF were strongly inhibitory to the human hepatic carcinoma (Bel-7204) cells. In vivo site-specific therapy in nude mice with human hepatic carcinoma indicated that the microspheres T9-TNF-PC-M and conjugate T9-TNF possessed markedly higher anti-tumor activity against Bel-7204 in mice than that of TNF. CONCLUSIONS: These results indicated that the magnetic polycarbonate microspheres were suitable as the potential-targeted treatment for hepatic carcinoma therapeutics.