Development of polymeric nanoparticulate drug delivery systems: evaluation of nanoparticles based on biotinylated poly(ethylene glycol) with sugar moiety
Introduction
Nanoparticles are colloidal particles of a size below 1 μm, and widely employed in various fields of life sciences, such as separation technologies, histological studies, clinical diagnostic assays, and drug delivery system (DDS). In the DDS applications, nanoparticles have several merits, like ease purification and sterilization, drug targeting possibility, and a sustained release action (Allemann et al., 1993). We synthesized various core-shell structure nanoparticles in our previous studies (Kim et al., 2000, Kim and Kim, 2001, Kim and Kim, 2002). Core-shell structure nanoparticles present advantages in regard of a long circulation in the body, drug solubility, drug stability, and relatively high level of hydrophobic drug encapsulation into the hydrophobic core (Gref et al., 1994, Peracchia et al., 1997, Yokoyama et al., 1990, Yokoyama et al., 1991, Kwon et al., 1995).
Tissue-specific molecular delivery has been a valuable technique for biological medical research and for the diagnosis and cancer therapy. To achieve this goal, there needs to be an approach that can enable the chemical modification of carriers to allow the attachment of targeting ligands. The recognition of ligands on the surface of delivery systems by organ-specific or cell-specific receptors may result in the organ-targeted drug delivery (Takakura and Hashida, 1996, Daemen et al., 1988), or in improved drug uptake through ligand-induced endocytosis (Sato et al., 1996, Brown and Goldstein, 1986). In recent years, there has been growing interest in the area of liver cell-specific DDS. 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 on hepatocytes (Ashwell and Harford, 1982). It is also retained on several human hepatoma cell lines (Ciechanover et al., 1983). If a ligand binds to a galactose receptor, the ligand-receptor complex is rapidly internalized and the receptor recycles back to the surface (Nishikawa et al., 1993). Therefore, designing a DDS for galactose receptor-mediated endocytosis would be useful for targeting the hepatocyte/liver and hepatoma cells (Goto et al., 1994). The biotin content of cancerous tumors is higher than that of normal tissue. So, we expected that the biotin and the galactose moiety of the lactobionic acid could target together to the tumor cells in the liver. Biotin is a 244 Da, water-soluble vitamin (Vitamin H) composed of a ‘head’, represented by a complex aliphatic heterocycle, and an aliphatic ‘tail’, ending with a carboxyl group. The ‘head’ provides the most important contribution to the binding of biotin to avidin, while the carboxyl group can be rendered capable of reacting with several different functional groups (Elo and Korpela, 1984). To this carboxyl group, we conjugated the one terminal amino group of diamine-terminated poly(ethylene glycol) (PEG). And, subsequently the other amino group was coupled with the carboxyl group of lactobionic acid with galactose moiety. With this galactose moiety, it can be expected that the BEL nanoparticles are endocytosed by liver cells within several minutes, suggesting its preferential uptake mediated by asialoglycoprotein (ASGP) receptor as previous report (Hashida et al., 1995).
Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. All-trans-retinoic acid (ATRA), an active metabolite of retinol (Vitamin A) was chosen as a model anti-cancer drug. ATRA plays essential roles in the regulation of differentiation and proliferation of various cell types. It has been proved that ATRA is effective in the treatments of epithelial and hematologic malignancies such as head and neck cancer, lung cancer, breast cancer, ovarian adenocarcinoma, and acute promyelocytic leukemia (Han and Choi, 1996, Sccks et al., 1995, Trump et al., 1997).
In the present study, we prepared polymeric conjugate nanoparticles composed of biotin and diamine-terminated poly(ethylene glycol) with a galactose moiety from lactobionic acid. The polymeric conjugate (abbreviated as BEL) was physico-chemically characterized by FT-IR spectroscopy, fluorescence spectroscopy, PCS, and TEM. Anti-cancer agent ATRA loading was confirmed by XRD, and the release was studied in vitro to evaluate the possibility for DDS.
Section snippets
Materials
Biotin, lactobionic acid (LA) and N,N′-dicyclohexyl carbodiimide (DCC) were purchased from the Aldrich Chemical Company (Milwaukee, WI). Diamine-terminated poly(ethylene glycol) (ATPEG) with a number-average molecular weight of 2000 was supplied by Texaco Chem. Co. (Ballaire, TX). N-Hydroxysuccinimide (NHS) was purchased from Sigma Chemical Co. (St. Louis, MO). Dialysis membrane with a molecular weight cutoff (MWCO) of 2000 g/mol was obtained from Spectra/Por™ membranes. Dimethylsulfoxide (DMSO)
Results and discussion
The BEL conjugate was synthesized by two-step coupling with biotin, ATPEG, and LA. Synthesized BEL conjugate was confirmed by FT-IR and -NMR spectroscopy as shown in Fig. 1, Fig. 2. The characteristic peaks of FT-IR were listed in Table 1. Especially, two characteristic peaks on this spectrum, i.e. amide stretch absorption at 3330 cm−1, and amide bending at 1570 cm−1, may be used to verify the BEL conjugate. In Fig. 2, the proton signal of biotin appeared at approximately 3.3 ppm, the proton
Acknowledgements
This work was supported by Korea Research Foundation Grant (KRF-2001-015-FP0127).
References (27)
- et al.
Pharmacokinetic consideration in target-organ directed drug delivery
Trends Pharm. Sci.
(1988) - et al.
The occurrence and production of avidin: a new conception of the high-affinity biotin-binding protein (review)
Comp. Biochem. Physiol. B
(1984) - et al.
Lactose-carrying polystyrene as a drug carrier: investigation of body distribution to parenchymal liver cells using -labelled lactose-carrying polystyrene
J. Control. Release
(1994) - et al.
Hepatic targeting of drugs and proteins by chemical modification
J. Control. Release
(1995) - et al.
Clonazepam release from core-shell type nanoparticles in vitro
J. Control. Release
(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.
Evaluation of polymeric nanoparticles composed of cholic acid and methoxy poly(ethylene glycol)
Int. J. Pharm.
(2001) - et al.
Development of a polymeric nanoparticulate drug delivery system. In vitro characterization of nanoparticles based on sugar-containing conjugates
Int. J. Pharm.
(2002) - et al.
PEG-coated nanospheres from amphiphilic diblock and multiblock copolymers: investigation of their drug encapsulation and release characteristics
J. Control. Release
(1997)
Drug-loaded nanoparticles preparation method and drug targeting tissues
Eur. J. Pharm. Biopharm.
Carbohydrate-specific receptors of the liver
Annu. Rev. Biochem.
A receptor-mediated pathway for cholesterol homeostasis
Science
Cited by (40)
Supramolecular design of hydrophobic and hydrophilic polymeric nanoparticles
2018, Design and Development of New NanocarriersFormulation of functionalized PLGA polymeric nanoparticles for targeted drug delivery
2015, PolymerCitation Excerpt :Galactosylated carriers have been developed for liver-specific drug delivery [14]. More recently, Song et al. showed that disaccharide-modified liposomes enhanced cellular uptake into various cancer cell lines via lectins-mediated endocytosis [15]. Our previous work focused on the preparation of surfactant-free PEG-based PNPs by nanoprecipitation [16].
Asialoglycoprotein receptor mediated hepatocyte targeting - Strategies and applications
2015, Journal of Controlled ReleaseNanoparticle and targeted systems for cancer therapy
2012, Advanced Drug Delivery ReviewsCitation Excerpt :A promising receptor for liver targeting is the asialoglycoprotein receptor (ASGP-R, galactose receptor). Work by Kim et al. [40] describes nanoparticles that use the galactose moiety from lactobionic acid, biotin and diamine-terminated poly(ethylene glycol) which exhibit in vitro release of A11-trans-retinoic acid (a model cancer drug) at a fairly constant rate over 1 month. The cell surface receptor for folic acid (folate receptor) is inaccessible from the circulation to healthy cells but is expressed on the surface of cancer cells making it a possible target for a number of types of cancer [41].
A review of glycosylated carriers for drug delivery
2012, BiomaterialsCitation Excerpt :In drug release studies these nanoparticles displayed the pseudo zero-order release pattern during a period of one month. From all these studies the author postulated that the glycosylation of drug delivery system may result in a promising drug carrier to provide sustained release of drugs [73]. Malignant transformation occurs as a result of many molecular changes, and glycosylation of glycoproteins and glycolipids is one of them [74].
Targeting tissue oxidative damage by means of cell signaling modulators: The antioxidant concept revisited
2010, Pharmacology and TherapeuticsCitation Excerpt :Polymeric nanospheres improve not only the release of RA but also its angio-suppressive effects, thus avoiding problems due to high RA concentrations (Hammady et al., 2009). Liver targeting of all-trans-RA can be obtained by mean of polymeric nanoparticles (Cho et al., 2001; Kim & Kim, 2003) or cationic liposomes (Díaz et al., 2006) carrying a galactose moiety that can be specifically recognized by hepatocyte receptors. In mice, cationic nanosized liposomes, which selectively accumulate in angiogenic ECs in tumors, were found to specifically target intravenously injected all-trans-RA to the lung, where the drug accumulated and efficiently reduced colon cancer metastasis (Suzuki et al., 2006).