Pharmaceutical NanotechnologyCore-shell type of nanoparticles composed of poly[(n-butyl cyanoacrylate)-co-(2-octyl cyanoacrylate)] copolymers for drug delivery application: Synthesis, characterization and in vitro degradation
Introduction
Biodegradable polymeric nanoparticles (NPs) have become important carriers for various drugs, peptides and gene delivery. The active agent encapsulated in the NPs tends to have higher biological stability, thereby, increasing the therapeutic efficiency and reducing the associated side effects. With appropriate design of carrier material (e.g. composition and surface properties), these NPs may possess higher capacity of active agent protecting from degradation and reduce premature elimination so as to reach the target in a controlled manner (Davis and Illum, 1983, Kreuter, 1991, Soppimath et al., 2001). Biodegradable polymers based on poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactide-co-glycolide) (PLGA) (Brannon-Peppas, 1995), poly(ɛ-caprolactone) (PCL) (Shenoy and Amiji, 2005) and poly(alkyl cyanoacrylate) (PACA) (Vauthier et al., 2003b) have been studied extensively as the carrier and have succeeded in development of the nanoparticulate formulations for intravenous administration.
PACA has been used as drug carrier for parenteral administation and tissue glue in surgery. The NPs composed of PACA (Couvreur et al., 1979b) were first prepared as the drug carrier by anion initiated emulsion polymerization in acidic water solution containing stabilizer (Couvreur et al., 1979a). Thus prepared NPs had advantages as easy preparation, high utility size ranges, stable and non-solvent residues. Moreover, PACA NPs have the ability to absorb or encapsulate a wide range of drugs, such as insulin (Damge et al., 1990, Behan and Birkinshaw, 2001b), pilocarpine (Wood et al., 1985), vaccines (Kreuter, 1988), oligonucleotide delivery (Nakada et al., 1996) and anti-tumor drugs (Vauthier et al., 2003a). Researches prove that PACA NPs are quite satisfied to be the drug delivery carriers and have already entered the developing stage of human body's clinical experiment for cancer therapy (Kattan et al., 1992, Vauthier et al., 2003b). The more stimulated and particular finding was that the drug-loaded PACA NPs coated with polysorbates with more than 20 polyoxyethylene units have overcome the barrier of blood–brain barrier to transport drug into the brain (Kreuter, 2001). However, the utility of PACA NPs is still limited because the controls of compatibility and release rate for various drugs are difficult with the structure of a homopolymer.
Degradation is the process of chain scission, whereas erosion is the process of material loss and bioerodiable means a biological system is involved in the kinetic of the process. In the initial study of chemical degradation of PACA indicated that formaldehyde and cyanoacetate were produced from disconnecting the polymer chain during hydrolysis (Leonard et al., 1966, Vezin and Florence, 1980). Since the mechanism of producing formaldehyde in the degradation was hard to explain some results of the studies, more complicated mechanisms were proposed. For example, by analyzing the concentration of isobutanol and formaldehyde in the degradation of poly(isobutyl cyanoacrylate) NPs under alkaline medium or enzyme, Lenaerts et al. proved that the main degradation route consisted of hydrolyzing the ester groups and only few formaldehyde produced (Lenaerts et al., 1984).
The degradation rate of PACA NPs is fast in comparison with other biodegradable polymers such as PLA, PLGA, etc. In general, the degradation rate depends on several factors: such as particle size (Vezin and Florence, 1980), the ester chain length (Leonard et al., 1966, Müller et al., 1992), molecular weight of polymer (Vezin and Florence, 1980), pH of medium (Vezin and Florence, 1980, Lenaerts et al., 1984) and enzyme used (Lenaerts et al., 1984, Scherer et al., 1994, O'Sullivan and Birkinshaw, 2002). While the major mechanism of drug release from the PACA NPs is bioerosion, its drug release rate depends on the PACA hydrolytic rate (Lenaerts et al., 1984, Page-Clisson et al., 1998, O'Sullivan and Birkinshaw, 2004) as well.
Although different PACA NPs synthesized by anion emulsion polymerization have been studied, the degradation rate of PACA homopolymer still cannot be controlled in a wide range. Further, the kinds of drugs encapsulated and the loading/encapsulation efficiency may also be limited. In the present study, monomers of BCA and OCA were used for the synthesis of copolymers of poly(BCA-co-OCA) as the matrix materials for NPs. Such NPs tend to have the modulability for degradation rate while their controllable hydrophilic/hydrophobic properties may provide various compatibilities with different kinds of hydrophobic drugs. The NPs with different BCA/OCA ratios were prepared as shown in Scheme 1.
Section snippets
Materials
The monomers of n-butyl cyanoacrylate and 2-octyl cyanoacrylate of 99.5% purity were obtained from Tongshen Enterprise Co., Ltd., Kaohsiung, Taiwan and were used as received. Pluronic F127 [poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) triblock copolymer; MW 12,600 Da], 2-octanol, fetal bovine serum (FBS), penicillin, streptomycin, Dulbecco's modified Eagle medium (DMEM) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma (USA). N
Nanoparticle properties
In order to prepare the poly(BCA-co-OCA) NPs, respective monomers were mixed well and dispersed into polymerization media. During polymerization process, monomers reacted with each other to form copolymer as shown in Scheme 1. Feed compositions and characterization data of NPs are shown in Table 1. The weight ratio of BCA/OCA in the feed was varied from 100/0 to 0/100. The emulsion polymerization appeared stable and the levels of coagulation and precipitation were consistently very low with the
Conclusion
This study has shown the feasibility of preparing the core-shell type of NPs for drug carrier. All the sizes of particles were less than 100 nm with narrow size distribution. The copolymers were taper-like structure as evidenced by DSC study. The hydrophobicity of NPs can be increased by increasing OCA content in the copolymer. Since the degradation rate may be manipulated in an extremely wide range through varying the monomer composition, the drug release rate may be controlled with some
Acknowledgements
The authors thank Dr. Fwu-Long Mi and Dr. Anandrao R. Kulkarni for stimulating discussions during the preparing this manuscript. They also thank Tongshen Enterprise Co., Ltd. for gift samples of high purity BCA and OCA monomers.
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