Application of sialic acid/polysialic acid in the drug delivery systems

School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China

Application of sialic acid/polysialic acid in the drug delivery systems

Ting Zhang,Zhennan She,Zhenjun Huang,Jing Li,Xiang Luo,Yihui Deng*

School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China

A R T I C L E I N F O

Article history:

Received 18 December 2013

Received in revised form

11 March 2014

Accepted 12 March 2014

Available online 19 March 2014

Sialic acid

Polysialic acid

Drug delivery system

Active targeting

Circulation time

The properties of modif i ed biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances, which are non-immunogenic and biodegradable.At the same time,SA modif i cation of the drugs/carriers can enhance the uptake of tumor cell and retention in brain;PSA modif ication can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modif i ed drugs/carriers in the blood,thus achieving active targeting effect.These properties offer a variety of opportunities for applications in drug delivery systems.This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modif i ed small molecule drugs,proteins and carriers in drug delivery systems.

© 2014 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.All rights reserved.

1. Introduction

Nature sialic acid(SA)is constituted structurally by ninecarbons3-deoxy-ulosonicacids.Thissaccharidemoiety attached to carbohydrate chains of glycolipids and glycoproteins plays a crucial role in many important biological events [1].Interestingly,it has been found that SA is a well-known ligand for selectin,which is known to have a close relationship with tumor metastases.Owing to its modulation of cell-cell interactions among leukocytes,platelets,endothelial cells and tumor cells,selectin is responsible for tumor metastasis[2-5].SA serves as endogenous substances that can specif i cally bind to selectin[6-8].Hence,the application of SA-modif i ed carriers in cancer targeted therapy has a certain signif i cance[9].

Polysialic acid(PSA)is a homopolymer of sialic acid in α-2,8 or α-2,9 linkages or a mixture of α-2,8 and α-2,9.PSA constituted of α-2,8 bond is non-immunogenic and biodegradableand then reduces the immunogenicity of the protein polypeptide.Likewise PSA shows the properties of escaping from phagocytes andpresentinglong circulation time in vivo[10,11]. This review summarizes the applications of SA/PSA in targeting carriers construction and brief l y discusses their prospects in drug delivery systems.

2. Sialic acid,polysialic acid and derivatives

2.1. Sialic acid

In 1957,Blix[1]isolated a substance from the submandibular gland mucin via a hydrolysis method,which produced a purple color reaction with Bial’s reagent.He named the substance as sialic acid(SA).Afterward,people got perfect crystalline SA from colostrumand bird’s nest.Withthe progressof biological evolution,the amount of SA in vivo also increased, such as f i sh,amphibians,reptiles,birds and other vertebrates. In mammals,SA mainly distributed over the cerebrospinal fluid and mucus.

SA belongs to a family of neuraminic acid(5-amido-3,5-dideoxy-D-glycero-D-galacto-nonulosonic acid).In this family,there are three main SA derivatives,which are N-acetyl neuraminic acid(Neu5Ac),N-acetyl neuraminic acid hydroxyalkyl(Neu5Gc)and 3-deoxy-D-glycero-D-galacto-nonyl ketose (KDN)(Fig.1).The other SA derivatives are further derived from these.

Each SA carries a unit negative charge,which generates repulsion or attraction between SA and plasma protein. Furthermore,the charge will modulate membrane surface charge density,while the carboxyl groups of SA can regulate its own pH.The surface charge density and pH coordinately regulate the transmembrane transport capacity of cell membrane[12].

SA spreads widely over mammalian cell surface,wherein the surfaces of red blood cells and endothelial cells are highly sialylated[13].It has been found that after treated by sialidase, the lifetime of erythrocytes dropped from the initial 120 days to just a few hours[14].In addition,many pathogens employ SA to camouf l age themselves and mask their epitopes,which inhibits complement activation pathway to reduce immunogenicity and thus protect the pathogens from the attacks of host immune system[15-17].

2.2. Polysialic acid

Polysialic acid(PSA)was f i rst found in E.coli(Escherichia coli)K-1 and K-235 by Barry[18].Subsequent studies have discovered that PSA was one of the ingredients of bacterial capsular materials,such as Neisseria miningitidis B,Salmonella toucra 048 and Citrobacter freundii 05,etc.The structure of PSA was shown in Fig.2.

In vertebrates,PSA can attach to the neural adhesion molecule(NCAM),with its fragments connecting to the asparagine at Ig5 of NCAM[19].PSA can attenuate NCAM-NCAM interaction and facilitate cell migration and nerve regeneration.Accordingly,Polysialylated NCAM exists abundantly in the embryo brain.But for the brain tissue of adults, PSA only appears in the hippocampus and olfactory bulb with continuous growth ability[20].

Polycondensation of SA occurs between hydroxyl groups at its 2 and 8 positions and makes the constructed PSA more stable[21].The study also found that PSA showed excellent water solubility,low viscosity,good biocompatibility and degradation in vivo[22].

PSA has been found in various tumors including small cell and non-small cell lung carcinomas,rhabdomyosarcoma, multiple myeloma,neuroblastoma,and Wilms tumor etc[20]. Study[23]found patients with extensive rhabdomyosarcoma showed a high level of PSA-NCAM,while patients had a lesser amount after chemotherapy.They concluded that the presence of PSA on the tumor cells reduced adhesion of NCAM, and enhanced cell motility,thus allowing the tumor cells that expressed PSA to deviate from the primary tumor and format metastases.In another study[24],small cell lung carcinoma cells expressing different amounts of PSA were isolated from H69 cell line.After subcutaneous inoculation with nude mice, tumor cells that express PSA produced more intracutaneous metastasisthantumorcells poorlyexpressingPSA.Suzuki[20] et al.reported among 44 patients with astrocytoma examined, 30 cases were NCAM-positive,of which nine cases PSA were detected,interestingly the nine cases had strong diffusion ability,revealing that PSA closely correlated with tumor invasion.Therefore,PSA plays an important role in tumor invasion and recurrence.

2.3. Ganglioside

Ganglioside is widely used as a SA derivative,which is quite rich in the brain.It cannot only promotes nerve cell differentiation,growth and synaptic formation,but also takes part in regulation of neural plasticity and functional recovery after brain injury.Amonggangliosides,monosialylganglioside (GM1)have drawn the most interest by far.

GM1 is mainly distributed over the central nervous system, which promotes the neuronal proliferation,neurotrophy, anti-excitatory nerve repair and other multiple effects.GM1 can be used clinically for the treatment of central nervous system injury diseases,such as stroke,traumatic brain injury,Parkinson’s disease,neonatal hypoxic-ischemic encephalopathy,and peripheral nerve disease.

Fig.1-The structure of sialic acid.

Fig.2-The structure of polysialic acid, α-2,8-(A), α-2,9-(B).

In addition,other current common gangliosides are GM2, GM3,GD1,GD2 and GD3,wherein GM contains mono sialic acid group,GD representsdouble,GT representstriple and,GQ means quadruple.All glycolipid contain two parts:a common nucleus-ceramide(Cer)that constitutes a hydrophobic “tail”, inserts in the membrane lipid bilayer;oligosaccharide sugar chain as a hydrophilic “head”,mainly includes theD-glucose (Glc),D-galactose(Gal),N-acetylgalactosamine(GalNAc),N-acetyl neuraminic acid(NeuNAc)and N-hydroxy-acetylneuraminic acid[25].

3. Sialic acid/polysialic acid in the drug delivery systems

In the history of drug delivery systems(DDS),carrier and drug molecules PEGylated(PEGylation)technology is regarded as a milestone.PEGylation nanoparticles can effectively reduce the macrophage uptake in vitro,prolong the circulation halflife in vivo and decrease the accumulation of nanoparticles in liver and spleen.PEGylation can also improve the accumulation of nanoparticles in tumor tissue by exerting the enhanced permeability and retention(EPR)effect that is the basis for delivering the macromolecular drugs to the site of solidtumorsselectively[26].However,the PEG layerbrings the following three problems.1)Cellular uptake blocked phenomenon.The “cloud” of hydrophilic steric barrier plays a crucial role in prolonging the residence time but it can dramatically suppress their interaction with cells[27].2) Accelerated blood clearance phenomenon.When repeated injection,PEGylatedcarriersabundantlyproduceanti-PEGIgM and consequently enhance blood clearance because of anti-PEG IgM mediating complement activation under certain conditions.The phenomenon is called “accelerated blood clearance(ABC)” [28].3)Security.PEG is diff i cult to degrade in the body and accumulates in lysosomes,which can induce toxicity and even a small amount of PEG oxidation products in vivo is also harmful[29].So ABC phenomenon and the accumulation of PEG may bring fairly serious consequences to the body.

SA/PSA may successfully solve the above problems[30].As an endogenous substances,SA can specif i cally bind to selectin,which is highly expressed on tumor and endothelial cell surface[4,6,12,31-34].SA can transport the drug into the cell by receptor-mediated endocytosis,which proves to be of high specif i city and strong aff i nity and increases the eff i ciency of drug transportation and thus solves the problem of cellular uptake blocked[35].At the same time,PSA on the surfaces of drugs/carriers will provide a “water cloudy” barrier,mainly owing to its high hydrophilicity and chain f l exibility.The“cloud”protects modif i ed drugs/carriers from interacting with plasma proteins or macrophages,which causes less RES uptake and prolongs the circulation half-life[10,11].What is more,antibodyinduced by 2-8linked,showsa lowlevelinthe blood,which indicates weak aff i nity and would not enhance modif i ed drugs/carriers clearance from the blood circulation. Meanwhile,degradation products of SA/PSA are CO2and water that is non-toxic.Therefore,using SA/PSA as a nonimmunogenic and biodegradable new material,has the potential of reducing or eliminating PEGylation preparation inducing ABC phenomenon.

3.1. The modif i cation of drug/carrier

3.1.1. The modif i cation of small molecule drug

When modif i ed by SA/PSA many excellent properties of SA/ PSA can be transferred to the coupling small molecules and endow the conjugates with targeting,biocompatible and nontoxic characteristics.

SA was covalently conjugated with PEG and DOX through a criticacid spacer.Stability,spontaneousand esterasestimulated drug release was evaluated.More than 40%of DOX was released from the conjugate in the presence of esterase enzyme,whereas it was stable at pH 7.4.SA-PEG-modif i ed doxorubicin(DOX),PEG-DOX and free DOX were incubated with A2780 ovarian cancer cells,respectively.It is found that SA-conjugated DOX enhanced cytotoxicity when compared with non-targeted prodrugs and free DOX[6].

The potential of polysialic acid(PSA)for low molecular weight anti-cancer drugs also has been explored.A PSA-epirubic(PSA-Epi)conjugate was synthesized and it was compared against three other Epi conjugates,named:N-(2-hydroxypropyl)methacrylamide copolymers(HPMA),poly(-ethylene glycol)(PEG)and polyglutamic acid(PGA).In vitro biological evaluation,which was conducted in the breast cancer cell line MCF-7 and in the anthracycline resistant MCF-7/DX,both showed that the PSA-Epi conjugate possessed the highest activity.In vivo evaluation showed that all conjugates had a signif i cantly longer retention than free Epi[12].

This is the f i rst study that PSA was used as a carrier to conjugate with a low molecular drug.In this case,the studyillustrated the synthesis,characterization and biological evaluation of the PSA-Epi.Meanwhile,the authors also carried out a systematic comparison with those of the most common drug carriers,aiming at obtaining some insight into the impact of the polymeric carrier on the activity of an anticancer drug conjugate.

3.1.2. The modif i cation of protein

PSA is non-immunogenic,biodegradable,and can maintain activity of the modif i ers.Studies have pointed out that PSA-asparaginase was non-immunogenic[11],and the activity of the asparaginase almost remained,while after PEG modif i cation,its activity declined seriously[10].Moreover,the PSA modif i ed protein/peptide eliminated immunogenicity and antigenicity.At the same time,it also did not seem to inf l uencetheirconnectionwith therespective receptors[11].PSAis a human endogenous substance,which can be completely degraded non-toxic SA by neuraminidase.However PEG is a synthetic polymer,which generates ketone and aldehyde groups by cytochrome P450 enzymes at a very low rate,and its high/low molecular weight forms tend to accumulate in the tissues[36].When PEG was long-term injected,it would cause accumulated toxicity.In this point of view,Gregoriadis claimed that PSA is the best alternative to PEG[37].PSA can improve the pharmacokinetic properties of the drug and reduce toxicity[38,39].Currently a PSA modif i cation industrialization technology platform named PolyXen®Technology (Lipoxen PLC,London,UK)is commercially available,which has been applied to insulin(SuliXen®,clinical stage II),alfa2βinterferon(InferoXen®),granulocyte colony-stimulating factor(StimuXen™)and erythropoietin(ErepoXen®).

3.1.3. The modif i cation of nanocarrier

To date,there are few reports on PSA-modif i ed nanocarrier, Bader et al.synthesized its derivatives in the preparation of drug-loaded micelles.Carboxyl group of PSA reacted with ndecylamine to produce PSA-decylamine derivative which mayself-assemble intomicelles thusload insolubledrugs[40]. The schematic was shown in Fig.3.3 years later,the same laboratory alternated the hydrophobic end ODA with polycaprolactone(PCL).They found that the new derivative presented more stability and less cytotoxicity in vitro[41].

The f i rst work applying GM1 modif i cation to nanocarriers was introduced by Gabizon and Papahadjopoulos[42].After intravenous injection in mice,it demonstrated that GM1-modif i ed liposomes reduced a 3.4-fold decrease in reticuloendothelial system(RES)uptake compared with conventional liposomes(PC:Chol=10:5,w/w).Afterward,Liu et al.[43] provedthatGM1-modif i edliposomescouldescapeRES uptake.After GM1 liposomes intravenously administered in Balb/c mice,these liposomes were rapid uptake by the spleen instead of liver Kupffer cells.The reason may be due to the GM1 on the liposomes,which prolonged liposomes residence time and then offered more chances to reach the spleen area.

Fig.4-The structure of Neu5Ac-PA.

To make a comparison of the long circulating effects promoted by PEG and GM1,Maruyama et al.took DOX as a model drug and prepared GM1 and PEG-modif i ed liposomes.After 6 h,intravenously injection in DBA/2 mice,the drug concentrations in the bloodstream was 2.3-fold and 2.9-fold when loaded with GM1 and PEG compared with conventional liposomes,respectively.Meanwhile,GM1 and PEG-modif i ed liposome Blood/ERS uptake ratios were increased by 4.6-fold and 7.3-fold,respectively[44].

Neu5Ac-PA(Fig.4)is a sialic acid derivative.The effects of Neu5Ac-PA modif i ed liposomes on the blood circulation and tissue distribution was investigated compared with liposomes composed of GM1.When liposomes were intravenously administered in rats,the liver and spleen uptakes of liposomes containing Neu5Ac-PA were signif i cantly reduced compared with those ones of liposomes containing GM1.The plasma concentration of liposomes containing Neu5Ac-PA was signif i cantly greater than that of GM1 at all times and was about as 10.3-fold as liposomes containing GM1 at 24 h [45].

GM1 and Neu5Ac-PA are both sialic acid derivatives and they have beenusedto modify nanocarrier.Studiesfoundthat the modif i ed nanocarrier presented a longer residence time and reduced uptake of RES.PSA modif i ed nanocarriers have been study little,but we believed that PSA can offer more chances to receive the ideal residence time.

3.2. Targeting applications

3.2.1. Tumor targeting

Fig.3-The preparation of polysialic acid decylamine derivatives and their micelles.

Fig.5-The structure of sialyl Lewis X.

SA can be served as a targeting ligand for selectin.Selectin is highly expressed on tumorvascularendothelialcells [6,12,31-33,46].There are a lot of selectin ligands,such as E-selectin ligand-1(ESL-1),P-selectin glycoprotein ligand-1 (PSGL-1),glycosylation-dependent cell adhesion molecule-1 (GlyCAM-1),the surrounding lymph nodes addressin(PNAd), CD24,CD34 and CD44 and so on.Nevertheless,sialyl Lewis A (sLea)and sialyl Lewis X(sLex)are the smallest unit of the known selectin ligands.At the same time,carboxyl group of sialic acid on sLea/xis a functional group to identify selectin indispensable[47].The structure of sialyl Lewis X presented in Fig.5.

SA can be applied for cancer treatment mainly in two aspects.On the one hand,selectin serves as a target receptor. People can make use of SA binding to selectin,which is overexpressed on the surfaces of tumor cells.Afterward,SA modif i ed drugs/carriers are delivered to tumor cells,thus achieving targeted therapeutic effects.Zheng et al.prepared the selenium nanoparticles modif i ed by SA to investigate the targeting effects on human cervical carcinoma cells(HeLa). In vitro showed that,compared with the general selenium nanoparticles,SA modif i cation could enhance cancer cell uptake and induced apoptosis[48].

On the other hand,SA can be applied to inhibit tumor metastasis.As is known to all,several cytokines produced by tumor cells induce endothelial cells to express adhesion molecules,such as selectin which mediates the adhesion of malignant tumor cells to endothelium[49].Selectin targeting can inhibit cancer cell adhesion by competing with ligandbearing,and deliver anti-cancer drugs to tumor cells via activated endothelial cells.Therefore,this kind of receptor could prevent the adhesion and thereby inhibit metastasis. sLexhas been applied for inhibiting tumor cells adhesion with endothelial cells.It is known[8]that E-selectin overexpressed on tumor cells mediated tumor cells adhesion.Authors found sLex-modif i ed liposomes can inhibit tumor cells adhesion with endothelial cells by competing with E-selectin.

SA seems to be an useful model in vitro for studies on sitespecif i c interactions and acts as an inhibitor in cancer therapy.

3.2.2. Brain targeting

Studies have shown that the SA receptors exist in the brain parenchymal,so brain targeting applications of SA were explored.Bondioli and colleagues[50]synthesized SA-PLGA and prepared the double covered(SA and glycopeptides) nanoparticles,after intravenous injection in rats.They found that therapeutical eff i cacy of loaded loperamide persisted for more than 24 h,which presented a signif i cant difference comparedwithunmodif i ednanoparticles.Thestudysuggested thatthemodif i ednanoparticlespassedthroughthebloodbrain barrierwiththehelpoftheglycopeptidesonthesurfaces.Then owing to SA on the nanoparticle’surfaces,the modif i ed nanoparticles could interact with brain SA-specif i c receptors in the brain parenchymal,thus brain residence time was extended and loperamide gained an increased activity.

3.2.3. Lymphocyte targeting

Sunamoto et al.[51]demonstrated that SA involved in the activation of lymphocytes,especially T cells.Meanwhile the SA has been applied to the preparation of liposome vaccine. Modif i ed tumor surface antigen(TSAP)was incorporated in liposome.After BALB mice were intravenously administrated by liposomal vaccine,T lymphocytes were effectively activated and tumor growth was largely inhibited.

In the following research[52],TSAP was substituted with ganglioside(GT1b or GQ1b)in liposome preparation,which presented a more effective stimulation of T lymphocytes.The authors suggested that the concentration of ganglioside on the liposome surface was also crucial,demonstrating both the number of SA groups and the position of the linkage on the liposome play an important role in the activation of the T lymphocytes.But the pathway that activated lymphocytes mechanisms needs to be further explored.

4. Conclusions

SA/PSA has shown specif i c advantages of tumor targeting, cancer inhibition and stealth properties in the drug delivery systems.At the same time,SA/PSA is non-immunogenic, biocompatible and biodegradable,which can reduce or eliminate ABC phenomenon of PEGylation preparation to some extent.However,SA receptors lie in other normal cells,tissues and organs that will bring undesired problems.Hence,it is of great signif i cance to f i nd SA/PSA appropriate modif i cation sites,change drugs/carriers linkage and optimize SA/PSA modif i ed density in the drug delivery systems.

Acknowledgments

This review was supported by the National Natural Science Foundation of China(Grant No.81373334).

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*Corresponding author.Shenyang Pharmaceutical University,No.103,Wenhua Road,Shenyang 110016,China.Tel./fax:+86 24 23986316.

E-mail address:dds-666@163.com(Y.Deng).

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