Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin
Introduction
Solid lipid nanoparticles (SLN) offer an attractive means of drug delivery, particularly for poorly water-soluble drugs. They combine the advantages of polymeric nanoparticles, fat emulsions and liposomes (Schwarz et al., 1994). SLN consist of drug trapped in biocompatible lipid core and surfactant at the outer shell, offering a good alternative to polymeric systems in terms of lower toxicity (Dingler et al., 1996, Müller et al., 2000). Moreover, the production process can be modulated for desired drug release, protection of drug degradation and avoidance of organic solvents. This flexibility in large scale may have a paramount importance in commercialization of new products (Wissing et al., 2004). Aforementioned characteristics make SLN an interesting carrier system for optimized delivery of drugs.
Doxorubicin, an anthracycline antibiotic, is a widely used antineoplastic agent. Despite good efficacy of doxorubicin, cardiotoxicity is the serious side effect that follows the treatment. Additionally, anthracyclines are likely to cause alopecia and myelosuppression and oral ulcerations (Zara et al., 1999). These toxicity and non-specific distribution of the drug often results in chemotherapeutic failure (Mehnert and Mäder, 2001). Focus should be made on efforts to kill cancer cells by more specific targeting while sparing normal cells. Several nanoparticulate delivery strategies of doxorubicin have been developed to minimize the exposure of drug to the normal tissues (Pereverzeva et al., 2007). Nanoparticles function as a carrier for entry through fenestrations in tumor vasculature allowing direct cell access. This, enhanced permeability and retention following intravenous injection, shows a great potential to overcome drug resistance (Barraud et al., 2005, Brigger et al., 2002). Therapeutic efficacy of doxorubicin could be improved by using nanoparticles as drug carriers. Doxorubicin has been formulated in different colloidal carriers, for example, poly (butyl cyanoacrylate), poly (isohexyl cyanoacrylate), poly (lactic-coglycolic acid) and gelatin (Dreis et al., 2007). Doxorubicin loaded polymer lipid hybrid nanoparticles demonstrated significant in vivo cytotoxic activity against solid tumors with minimal systemic toxicity (Wong et al., 2007). Despite vast research in the field of nanoparticle based antitumor drug delivery, a need for simple, safe and stable formulation persists.
In a previous study, preparation method of SLN based on the curdlan/cacao butter system was developed (Kim et al., 2005). Verapamil was used as model drug and incorporated in the melted solid core. EE is largely determined by the solubility of drug in the lipid. Low solubility of doxorubicin in cacao butter limited the use of previous method. In the present work, Capmul®MCM C10 and Solutol®HS15 were selected as lipid material and surfactant, respectively. These excipients are reported to have better biocompatibility and low in vivo toxicity. Recent reports suggested that Capmul®MCM can be employed for parenteral delivery of anticancer agents (Nornoo et al., 2008). The Capmul®MCM based parenteral micro emulsions were well tolerated in vivo. Also, Solutol®HS15 exhibits good parenteral acceptability and is used in current parenteral formulations (Strickley, 2004). Curdlan, a water insoluble polysaccharide that dissolves at higher pH due to conformational change, was used as shell forming material.
The aim of this study was to prepare solid lipid nanoparticles containing doxorubicin to overcome drug resistance and to reduce side effects. This investigation reports the preparation method of SLN loaded with doxorubicin. Drug release from the SLN was studied using dialysis bag method. Stability and cell viability studies were also conducted for the development of SLN based drug delivery system.
Section snippets
Materials
Capmul®MCM C10 was a generous gift from ABITEC (Columbus, Ohio, USA). Curdlan was obtained from Takeda Chemical Industry Ltd. (Osaka, Japan). Solutol® HS15 was obtained from BASF (Ludwigshafen, Germany). Doxorubicin hydrochloride was obtained from Dong-A Pharmaceuticals (Seoul, Korea). The MCF-7 breast cancer cell line, and its adriamycin-resistant variant, MCF-7/ADR was kindly provided by Professor H.J. Lee (Ewha Womans University, Seoul, Korea). All other chemicals were of analytical grade
Screening of lipid phase
In order to optimize preparation of doxorubicin loaded SLN by solvent emulsification–diffusion method, several formulation variables were studied. For the selection of lipid core, solubility of doxorubicin in lipids was evaluated by measuring DSC thermogram of doxorubicin/lipid (1/5) mixture and is shown in Fig. 1. The melting peak of doxorubicin base at 218 °C completely disappeared when pentadecanoic acid or Capmul®MCM C10 was used as a lipid core. Although the physical state of the drug was
Conclusions
In this study, SLN using doxorubicin as model drug were successfully prepared using Capmul®MCM C10 as lipid core and curdlan as the shell material, by solvent emulsification–diffusion method. Different formulation parameters, found to influence fabrication of drug into nanoparticles, were optimized for high EE and DL. The most important parameters were drug:lipid ratio, Solutol®HS15:curdlan ratio, and DMSO:lipid ratio. Higher in vitro drug release was observed in pH 5 than in pH 7.4.
Acknowledgements
This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) through the Research Center for Resistant Cells (R13-2003-009).
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