Development of a polymeric nanoparticulate drug delivery system: In vitro characterization of nanoparticles based on sugar-containing conjugates
Introduction
Controlled drug delivery technology represents one of the frontier areas of science, which involves a multidisciplinary scientific approach. These delivery systems offer numerous advantages compared to conventional dosage forms. These include improved efficacy, reduced toxicity, and improved patient compliance and convenience. Such systems often use macromolecules as drug carriers. This field of pharmaceutical technology has grown and has diversified rapidly in recent years.
Among the different dosage forms reported, both nano- and microparticles have gained increasing importance, due to a tendency to accumulate in the inflamed areas of the body (Illum et al., 1989). Nano- and microparticles occupy a unique position in drug delivery technology due to their attractive properties. In particular, nanoparticles have several advantages in pharmaceutical applications. They are easily purified and sterilized. In addition, they offer drug targeting possibilities and a sustained release action (Allemann et al., 1993). Nanoparticles based on a core-shell structure or polymeric micelle present advantages in terms of lengthy circulation in the body, drug solubility, drug stability, and a high level of drug encapsulation (Yokoyama et al., 1991, Gref et al., 1994, Kwon et al., 1995).
For liver disease therapy, there has been growing interest in the area of liver-cell specific drug delivery systems in recent years. This may be due to a failure of other pharmacological approaches to the liver disease site as a result of the non-specific delivery mechanism towards the other organs and several side effects. A great deal of effort has been made to achieve an appropriate liver targeting of chemotherapeutic agents with liposomes (Kim and Han, 1995), microspheres (Kim et al., 1993), and drug-carrier molecule conjugates (Seymour et al., 1991). Among the liver-associated surface receptors, the asialoglycoprotein receptor (ASGP-R: galactose receptor) is well known to be present only on hepatocytes (Ashwell and Harford, 1982). It is also retained on several human hepatoma cell lines (Fallon and Schwartz, 1988). If a ligand binds to a galactose receptor, the ligand–receptor complex is rapidly internalized and the receptor recycles back to the surface (Ciechanover et al., 1983). Accordingly, the receptor shows a high binding capacity and efficient cellular uptake of galactosylated ligands. Therefore, designing a drug delivery system for galactose receptor-mediated endocytosis would be useful for targeting the hepatocyte/liver and hepatoma cells (Nishikawa et al., 1993, Goto et al., 1994).
In this study, core-shell type polymeric nanoparticles composed of cholic acid (CA) and diamine-terminated poly(ethylene glycol) (ATPEG) with a galactose moiety from lactobionic acid (abbreviated as LEC) was synthesized for a liver-specific drug delivery system. CA is a naturally occurring substance and acts as a drug incorporation site with hydrophobic characteristics. ATPEG is a modified PEG which has well defined biocompatibility, is non-toxic, and has non-immunogenic properties. It is known to prevent interactions with cells and proteins due to its hydrophilic nature (Wang et al., 1997). Because of the amphiphilicity of the LEC conjugate, core-shell type nanoparticles with a sugar moiety were prepared by a diafiltration method, and the physico-chemical characteristics were evaluated in vitro.
Section snippets
Materials
ATPEG with an average molecular weight of 2000 was supplied by the Texaco Chem. Co. (Ballaire, TX). CA and N-hydroxysuccinimide (NHS) were purchased from the Sigma Chem. Co. (St. Louis, MO). Lactobionic acid (LA) and N,N′-dicyclohexyl carbodiimide (DCC) were obtained from the Aldrich Chem. Co. (Milwaukee, USA). The dialysis membranes with a molecular weight cutoff (MWCO) of 2000 g/mol were purchased from Spectra/Por™ Membranes. Dimethyl sulfoxide (DMSO) and other chemicals were of reagent grade
Results and discussion
The synthesized LEC conjugate structure is represented schematically in Fig. 1. The FT-IR spectra provided evidence of LE and LEC conjugate synthesis. In the LE spectrum, the amide stretch and amide bend vibration was observed at 3335 and 1627 cm−1, respectively. The LEC conjugate spectrum contained CH stretch absorption bands at 2927 and 2851 cm−1 due to CA, and an amide bend at 1576 cm−1. The LEC conjugate was also characterized by 1H NMR spectroscopy as shown in the previous report (Kim et
Acknowledgements
This work was supported by Korea Research Foundation Grant (KRF-2001-015-FP0127).
References (20)
- et al.
Lactose-carryingpolystyrene as a drug carrier: investigation of body distribution to parenchymal liver cells using 125I-labelled lactose-carrying polystyrene
J. Control. Rel.
(1994) - et al.
Clonazepam release from core-shell type nanoparticles in vitro
J. Control. Rel.
(1998) - et al.
The organ targetability of small and large albumin microspheres containing free and HAS conjugate methotrexate
Int. J. Pharm.
(1993) - et al.
Core-shell type polymeric nanoparticles composed of poly(l-lactic acid) and poly(N-isopropylacrylamide)
Int. J. Pharm.
(2000) - et al.
Self-assembled hydrogel nanoparticles composed of dextran and poly(ethylene glycol) macromer
Int. J. Pharm.
(2000) - et al.
Evaluation of polymeric nanoparticles composed of cholic acid and methoxy poly(ethylene glycol)
Int. J. Pharm.
(2001) - et al.
In vitro and in vivo evaluation of taxol release from poly(lactic-co-glycolic acid) microspheres containing isopropyl myristate and degradation of the microspheres
J. Control. Rel.
(1997) - et al.
Drug-loaded nanoparticles preparation method and drug targeting tissues
Eur. J. Pharm. Biopharm.
(1993) - et al.
Carbohydrate-specific receptors of the liver
Annu. Rev. Biochem.
(1982) - et al.
Sorting and recycling cell surface receptors and endocytosed ligands: the asialoglycoprotein and transferring receptors
J. Cell. Biochem.
(1983)
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