hyaluronic acid in drug delivery systems

Journal of Pharmaceutical Investigation

Vol. 40, Special issue, 33-43 (2010)

33

Hyaluronic Acid in Drug Delivery Systems

Yu-Jin Jin, Termsarasab Ubonvan and Dae-Duk Kim†

College of Pharmacy and Research Institute of Pharmaceutical Sciences,

Seoul National University, Seoul 151-742, Korea

(Received August 9, 2010·Revised October 4, 2010·Accepted October 5, 2010)

ABSTRACT − Hyaluronic acid (HA) is a biodegradable, biocompatible, non-toxic, non-immunogenic and non-inflam-

matory linear polysaccharide, which has been used for various medical applications including arthritis treatment, wound

healing, ocular surgery, and tissue augmentation. Because of its mucoadhesive property and safety, HA has received much

attention as a tool for drug delivery system development. It has been used as a drug delivery carrier in both nonparenteral

and parenteral routes. The nonparenteral application includes the ocular and nasal delivery systems. On the other hand, its

use in parenteral systems has been considered important as in the case of sustained release formulation of protein drugs

through subcutaneous injection. Particles and hydrogels by various methods using HA and HA derivatives as well as by con-

jugation with other polymer have been the focus of many studies. Furthermore, the affinity of HA to the CD44 receptor

which is overexpressed in various tumor cells makes HA an important means of cancer targeted drug delivery. Current trends

and development of HA as a tool for drug delivery will be outlined in this review.

Key words − Hyaluronic acid, Biodegradable polymer, Protein delivery, Gene delivery, Sustained delivery

Hyaluronic acid (also called as Hyaluronan and Hyaluronate

(HA) and Sodium Hyaluronate(SA) is sodium salt form of

hyaluronic acid) is a biodegradable, biocompatible, and vis-

coelastic linear polysaccharide of a wide molecular weight

range (1000 to 10,000,000 Da). It is composed of alternating

disaccharide units of d-glucuronic acid and N-acetyl-d-glu-

cosamine with (1→4) inter glycosidic linkage (Laurent, 1998)

and is distributed throughout the extracellular matrix, con-

nective tissues, and organs of all higher animals (Prestwich et

al., 1998). Metabolism of HA occurs through the enzymatic

hydrolysis by hyaluronidase (HAase) which is present in var-

ious mammalian tissues (Price et al., 2007). The HA molecule

is readily soluble in water, producing a gel that behaves like a

lubricant. It also adsorbs water, lending it hygroscopic and

homeostatic properties (Price et al., 2007). The viscosity of the

HA gel is dependent upon a number of factors including the

length of the chain (and by extension and the degree of entan-

glement), cross-linking, pH and chemical modification while

the absolute concentration seems to be much less important

(Varma et al., 1975; Park and Chakrabarti, 1978; Kobayashi et

al., 1994).

HA controls tissue hydration and exists in hydrated networks

with collagen fibers in the extra-cellular matrix. It also con-

stitutes the backbone of cartilage proteoglycan. Because of its

unique physicochemical properties and various biological

functions, HA and modified HA have been extensively inves-

tigated and widely used for pharmaceutical and medical appli-

cations,(Balazs and Denlinger, 1993; Illum et al., 1994; Hahn

et al., 2004; Ohri et al., 2004) such as for arthritis treatment

(Balazs and Denlinger, 1993), ophthalmic surgery (Bothner

and Wik, 1987), drug development (Kim et al., 2005), and tis-

sue engineering (West et al., 1985; Ohri et al., 2004). HA is

known to be involved in wound healing, promoting cell motil-

ity and differentiation during development (Laurent, 1998). A

number of strategies for the chemical modification of HA for

improving its physicochemical properties through carboxyl

and hydroxyl groups have been developed (Balazs and Lesh-

chiner, 1987; Kuo et al., 1991; Illum et al., 1994; Luo et al.,

2000; Hahn et al., 2004; Ohri et al., 2004).

Recently, HA polymers have become the topic of interest for

developing sustained drug delivery devices of peptide and pro-

tein drugs in subcutaneous formulations. Studies also sug-

gested that a number of HA molecules may be used as gel

preparations for ocular and nasal drug delivery (Le Bourlais et

al., 1998). In addition, HA has been used for targeting specific

intracellular delivery of genes or anticancer drugs. Since the

uptake of HA is known to be through the receptor-mediated

endocytosis on specific receptors such as cluster determinant

44 (CD44) and receptor for hyaluronate-mediated motility

(RHAMM), HA is usually conjugated or coated with the

chemical drug or polymer to enhance therapeutic efficiency as

well as to provide sustained release (SR) properties. The appli-

†Corresponding Author :

Tel : +82-2-880-7870 E-mail : [email protected]

DOI : 10.4333/KPS.2010.40.S.033

34 Yu-Jin Jin, Termsarasab Ubonvan and Dae-Duk Kim

J. Pharm. Invest., Vol. 40, Special issue (2010)

cations of HA in the above mentioned drug delivery systems

for both nonparentral and parenteral delivery will be discussed

in the current review.

HA in Nonparenteral Delivery

The water solubility, viscoelasticity and biocompatibility of

HA allow its application in nonparental delivery. Ocular and

nasal delivery are two areas where HA has especially been

widely used.

Ocular delivery

HA has been used in ocular delivery due to its nonirritating

property and high water-binding capacity. Its viscosity and

pseudoplastic behavior providing mucoadhesive property can

increase the ocular residence time. Various studies have been

conducted with HA where an increase in biocompatibility as

well as mucoadhesive property has been observed. For exam-

ple, 1% pilocarpine solution dissolved in HA increased the 2-

fold absorption of drug (Camber et al., 1987), improving the

bioavailability, and miotic response while extending the dura-

tion of action (Bucolo and Mangiafico, 1999). In another

study, HA allowed maintenance of 50 % of the drug activity up

to 20 min after administration (Gurny et al., 1990). Gentamicin

bioavailability was also reported to be increased when for-

mulated with a 0.25 % HA solution (Bernatchez, 1993).

Moreover, films and microspheres have been prepared from

various esters of HA. Methylprednisolone, either physically

incorporated into the polymer matrix or chemically bound to

the polymer backbone through an ester linkage resulted in an

improved corneal bioavailability (Kyyrönen et al., 1992). In

addition, prednisolone using HA benzyl ester films through

ocular delivery provided optimally sustained drug delivery

(Hume et al., 1994) while ocular formulation of poly-ε-capro-

lactone (PCL) nanosphere coated with HA increased bio-

availablity (Barbault-Foucher et al., 2002). Recently, HA

coated PCL/benzalkonium chloride nanospheres were able to

achieve high levels of cyclosporine A (Cy A) in the cornea that

was 10-15-fold higher than that achieved with Cy A solution

in castor oil (Yenice et al., 2008).

Nasal delivery

The nasal route has been explored as an alternative for sys-

temic drug delivery for decades. This is because rapid absorp-

tion is possible in the nasal cavity due to its large surface area

and relatively high blood flow while being able to avoid

hepatic first-pass elimination (Turker et al., 2004; Ugwoke et

al., 2005). However, these nasal formulations still need to

Table I. Advantages of HA in Formulations for Various Administration Routes

Administration route Advantages References

Intravenous • Enhances drug solubility and stability• Promotes tumor targeting via active (CD44 and other cell surface

receptors) and passive (EPR) mechanisms• Can decrease clearance, increase AUC and increase circulating

half-life

(Bourguignon et al., 2000; Dollo et al., 2004)

Dermal • Surface hydration and film formation enhance the permeability of the skin to topical drugs

• Promotes drug retention and localization in the epidermis• Exerts an anti-inflammatory action (medium- and high-

molecular-weight HA)

(Tammi et al., 1988; Brown and Jones, 2005)

Subcutaneous • Sustained/controlled release from site of injection• Maintenance of plasma concentrations and more favorable

pharmacokinetics• Decreases injection frequency

(Prisell et al., 1992; Esposito et al., 2005; Kim et al., 2005)

Intra-articular • Retention of drug within the joint• Beneficial biological activities include the anti-inflammatory,

analgesic and chondroprotective properties of HA

(Rydell and Balazs, 1971; Marshall, 2000)

Ocular • The shear-thinning properties of HA hydrogels mean minimal effects on visual acuity and minimal resistance to blinking

• Mucoadhesion and prolonged retention time increase drug bioavailability to ocular tissues

(Kaur and Smitha, 2002, Wysenbeek et al., 1988,(Sintzel et al., 1996)

Nasal • Mucoadhesion, prolonged retention time, and increased permeability of mucosal epithelium increase bioavailability

(Lim et al., 2000; Turker et al., 2004; Ugwoke et al., 2005)

Oral • Protects the drug from degradation in the GIT• Promotes oral bioavailability

(Necas et al., 2008)

Hyaluronic Acid in Drug Delivery Systems 35


overcome the challenge of poor bioavailability. The mucoad-

hesive properties of HA could enhance the absorption of drugs

and proteins via mucosal tissues (Lim et al., 2000; Cho et al.,

2003; Ludwig, 2005) as reported in the case where SA solution

resulted in enhanced nasal absorption of vasopressin (Morim-

oto et al., 1991).

A study conducted in sheep, HA ester microspheres of insu-

lin for the nasal delivery resulted in a significant increase in

drug absorption (Illum et al., 1994). Moreover, a bioadhesive

delivery system for the intranasal administration of a flu vac-

cine which comprised of esterified hyaluronic acid (HYAFF)

microspheres in combination with a mucosal adjuvant (LTK63)

was also reported to be effective (Singh et al., 2001). Also, a

formulation of microparticles prepared by the spray dry

method using HA-based microspheres containing PEG 6000

and/or sodium taurocholate for the nasal delivery of fex-

ofenadine hydrochloride was able to enhance the AUC and

Cmax values (Huh et al., 2010).

The mucoadhesive property can be increased by conjugating

HA with other bioadhesive polymers. Lim et al. was able to

increase drug absorption by preparing biodegradable micro-

particles of gentamicin using chitosan (CH) and HA by the sol-

vent evaporation method (Lim et al., 2000). On the other hand,

when HA is grafted with poly (ethylene glycol) (PEG-g-HA),

PEG works as a drug reservoir in biodegradable HA. This

matrix could prevent drug leakage and achieve degradation-

controlled insulin release (Moriyama et al., 1999).

A nanocarrier composed of HA and CH was reported to

encapsulate bovine serum albumin (BSA) and cyclosporine A

for the nasal delivery of macromolecules (de la Fuente et al.,

2008a). Combination of absorption enhancer materials and

bioadhesive polymers such as Cremophor RH 40 and SA

could potentially increase the delivery of drugs, including pep-

tide size molecules, into the CNS via the olfactory pathway

(Horvat et al., 2009).

Parenteral Delivery Using HA

HA for sustained release of protein

Therapeutic proteins are becoming an important source of

medicine. Since the establishment of recombinant DNA tech-

nology which made it possible to produce large-scale of

recombinant proteins, several therapeutic proteins have been

approved and marketed for the treatment of various illnesses,

including some diseases which were previously incurable. HA

has been shown to be useful for SR formulations of protein

and peptide drugs (Elbert et al., 2001) after parenteral delivery.

While conventional drug delivery systems using poly-lactic

glycolic acid (PLGA) exhibited inflammation and protein

denaturation associated with the degradation of PLGA (Lau-

rent, 1998), HA appeared to be a protein-friendly drug carrier.

In 1992, Prisell et al. dissolved human insulin like growth

hormone-I (hIGF-I) in HA solution and found that HA can be

used for SR of protein (Prisell et al., 1992). Later, sponge and

hydrogel systems using HA blended with collagen was

reported to be effective for the SR of human growth hormone

(hGH) (Cascone and Sim, 1995). More studies thereafter were

conducted for the SR of insulin through the nasal route for

treatment of diabetes (Moriyama et al., 1999; Surendrakumar

et al., 2003; Ohri et al., 2004).

The first SR formulation of recombinant human growth hor-

mone (Nutropin® Depot) prepared using PLGA was launched

in 1999 in the United States. Unfortunately, patient compliance

was a problem eventually leading to withdrawal of Nutropin®

Depot from the market in 2004 (Johnson et al., 1996; Herbert

et al., 1998; Tracy, 1998). Problems included scale-up dif-

ficulties, pain from injection and denaturation of the human

growth hormone due to the hydrophobic interaction with

PLGA and acidic environment created by disintegrating of

PLGA. Thus, attention has been placed on HA for developing

a SR formulation of human growth hormone using HA.

Microparticle formulation using Hyaff11p50, where 50% of

the carboxyl groups of HA are esterified with benzyl alcohol,

was prepared by the solvent evaporation method and the spray

dry method for a 7-day release of hGH (Esposito et al., 2005).

Figure 1 shows the scheme of the SR-rhGH preparation by the

solvent evaporation method. Growth hormone was dissolved

in water, which was added to mineral oil dropwise that con-

tained Span 85. After stirring the mixture, the oil phase was

washed. However, the solvent evaporation method resulted in

the significant denaturation of hGH by oil phase and produced

too big size particles thereby resulting in low patient com-

pliance. One the other hand, a formulation of hGH/HA/lecithin

by the spray dry method resulted in small particles that could

be injected easily through a 26-gauge needle resulting in

increasing patient compliance (Figure 2). This formulation was

developed and launched exclusively in Korea by LG Life Sci-

ence (Seoul, Korea) in 2007 which is the only SR-rhGH prod-

uct currently available (Kim et al., 2005).

However, there was significant loss in the course of spray

dry process and scale up. Thus, the current research is focused

on making hydrogel of HA for the SR of protein drugs. HA

derivatives, crosslinkers (Hahn et al., 2006) and conjugation

with various polymers (Jeong et al., 2000; Hirakura et al.,

2009; Lee et al., 2009) have been reported.

Hydrogels are physically or chemically crosslinked natural



or synthetic polymers. Due to the hydrophilic nature of HA,

hydrogels can provide an aqueous environment preventing

proteins from denaturation (Hirakura et al., 2009). Once inside

the body, the gel precursors can crosslink physically due to the

change in temperature (Jeong et al., 2000; Jeong et al., 2002)

and pH (Shim et al., 2005) and chemically by Michael type

addition reaction (Lutolf et al., 2003; Shim et al., 2005; Lee et

al., 2006) and disulfide bond formation (Shu et al., 2002). Kim

et al. has reported on a HA/pluronic composite hydrogel which

exhibited temperature-dependent swelling and collapse behav-

iors in aqueous solution. These hydrogels chemically degraded

and eventually eroded as a result of hydrolytic scission of ester

linkage in the structural unit of di-acryloyl pluronic component

releasing the drug (Kim and Park, 2002). Nevertheless, despite

the facile procedure and minimized invasiveness of an inject-

able hydrogel system for the sustained delivery of proteins, a

potential problem still exists. Slow gelation could cause a large

amount of drugs to diffuse away from the injection site and

lead to drug overdose. Thus, an attempt has been made to

decrease gelation time by using HA-tyramine with proper

amount of horseradish peroxidase and H2O2 (Hirakura et al.,

2009). However, because physically crosslinked hydrogel was

very soft and easily disintegrated, an initial burst and rapid pro-

tein release resulted. Additionally, the chemically crosslinked

hydrogel brought about protein denaturation during encap-

sulation (Oh et al., 2010). Thus, hybrid hyaluronan hydrogel

encapsulating nanogel was developed to overcome the above

mentioned problems. The nanogels were physically entrapped

and well dispersed in a three-dimensional network of chem-

ically cross-linked HA (HA gel). Therapeutic peptides and

proteins, such as glucagon-like peptide-1, insulin and eryth-

ropoietin, were spontaneously trapped in the cholesteryl group-

bearing pullulan (CHP) nanogels in the HA gel by immersing

hybrid hydrogels into the drug solutions. The synergy between

the CHP nanogel as a drug reservoir and the HA gel as a nan-

ogel-releasing matrix of the hybrid hydrogel system simul-

taneously achieved both simple drug loading and controlled

release with no denaturation of the protein drugs (Jeong et al.,

2000).

Another type of susbtained formulation using HA is that

Figure 2. Preparation scheme of SR-rhGH formulation by spray dried method.

Figure. 1. Preparation scheme of SR-rhGE formulation by solvent evaporation method.



which makes use of the electrostatic interaction between the

negatively charged carboxylate groups of HA and the positive

surface charge of Fe2O3 nanoparticles forming a corral-like

structure. The A549 and HEK 293 cell cultures were tested

and found to be capable of taking in the HA particles and HA-

Fe2O3 hybrid nanoparticles, delivering the peptides into the

cells and nucleus very efficiently (Kumar et al., 2007). In

another report, HA/N-carboxyethyl CH (CEC)/ BSA ternary

complex by colloid titration with great quantitative precision

had been prepared (Jiang et al., 2005). The advantages of this

ternary complex were facile formulation process, mild pre-

parative conditions, high entrapment efficiency, biodegradable

components, biocompatibility, pH-sensitivity, and extended

release capability. On the other hand, porous microparticles

(PMs) with a low density (<0.4 g/cm3) were prepared by the

water-in-oil-in-water (W1/O/W2) multi-emulsion method using

a cyclodextrin derivative as a porogen (Lee et al., 2007a). The

interaction of Lysine (Lys) and HA not only increased protein

encapsulation efficiency but also stabilized Lys against a dena-

turing organic solvent (dichloromethane). Furthermore, PMs

with Lys/HA complexes increased the Lys release period up to

7 days, as opposed to a 4 h Lys release time from PMs without

Lys/HA complexes.

The high demand for SR formulation of protein is expected

to continue because of the short biological half life of most

protein drugs. The current commercial products make use of

PLGA which is not water soluble. HA is thus still considered

a promising candidate for these formulations due to its bio-

compatibility and water soluble property.

Gene delivery

Human gene therapy involves the insertion of genes, deox-

yribonucleic acid (DNA) or ribonucleic acid (RNA), into cells

and biological tissues to treat gene defective diseases. Pres-

ently, most gene therapy studies are aimed at cancer related

small interfering RNA (siRNA) by inhibition of oncogene

expression. However, poor intracellular uptake, insufficient

endosomal escape of genes and rapid enzymatic degradation of

nucleic acid limit the efficiency of gene therapy (Edelstein et

al., 2004; Schiffelers et al., 2004; Wilson et al., 2005).

The use of synthetic nanocarrier with various cationic poly-

mers, polypeptides and lipid has been recently proposed as a

promising alternative for genes delivery. HA has been intro-

duced as a nanocarrier for gene delivery since 2003 (Kim et

al., 2003). Anionic nucleic acid drug by electrostatic binding or

self assembly with DNA or genes form complex nanoparticles

that are capable of being endocytosed by cells. However, low

level of transfection and expression due to non-specific inter-

action between cationic complex and serum protein in the

body have been barriers for gene therapy (Goldman et al.,

1997). Moreover, the strong positive surface charge, especially

polyethyleneimine (PEI), have caused severe cytotoxicity (Fis-

Figure 3. Illustration of the hydrogel nanoparticle formed by self-aggregation

Figure 4. Illustration of CHP self aggregates and incorporated protein of a reversible reaction



cher et al., 2003). The DNA-HA matrix crosslinking with adi-

pic dihydrazide (ADH) was able to sustain gene release while

protecting the DNA from enzymatic degradation.

HA has also been used as HA-ADH hydrogel conjugated

with an antigen for cell-specific targeting (Yun el al., 2004). In

addition, photocrosslinking pluronic hydrogel where the vinyl

group of PluronicTM was modified with HA (Chun et al.,

2005), crosslinking HA film with DNA incorporated within its

structure (Kim, 2005), photocrosslinking acryl-modified HA

hydrogel (Wieland et al., 2007) and CH –DNA complexes

incorporated into the multilayer via layer-by-layer deposition

with HA (Lin et al., 2009) have been reported. To enhance

gene delivery for tissue engineering, immobilized DNA/PEI

complexes in HA-collagen hydrogel using biotin/neutravidin

was fabricated with the ability to transfect adherent cells (Seg-

ura, 2005).

The biocompatibility of the anionic polysaccharide HA is

achieved by shielding the positive surface of gene/polycation

complexes and by inhibiting non-specific binding to serum

proteins, thereby reducing the cytotoxicity of cationic poly-

mers. HA combined with PEI (Ito et al., 2006; Saraf et al.,

2008; Xu et al., 2009), poly(L-lysine) (PLL) (Takei et al.,

2004), CH (de la Fuente et al., 2008b), poly(L-arginine) (PLR)

(Kim et al., 2009), and liposome (Chono et al., 2008) have

been reported. HA coated to the surface of DNA/PEI com-

plexes and HA-PEI conjugation has especially been widely

studied as showed in Figure 5. Ito et al. (Ito et al., 2006) syn-

thesized conjugated spermine-HA which could mimic HMG

(High Mobility Group) protein which has amphoteric struc-

ture, for loosening interaction between DNA/PEI and higher

releasing free DNA. DNA/PEI/HA small complexes (<70 nm)

for preventing aggregation of the complexes through freeze-

drying was also reported (Ito et al., 2010).

Another use of HA was for target specific intracellular deliv-

ery of gene. CD44 and RHAMM have been identified as

receptors of HA which were over-expressed in tumor or cancer

cells. Figure 6 shows HA binding to the receptor on the cell

surface and being intracellularly up-taken to the cell with

increasing gene transfection efficiency. The comb-type poly-

cation (PLL) having HA side chains has been synthesized for

targeting foreign DNA to sinusoidal endothelial cells in liver

(Takei et al., 2004). In addition, DNA/PEI/HA ternary com-

plex has been formulated for target specific delivery of DNA.

It showed higher transfection and efficiency and lower cyto-

toxicity than DNA/PEI binary complex in malignant breast

cancer cells with high CD44 level (Sun et al., 2009). Fur-

thermore, low molecular weight HA (<10kDa) showed higher

stability and transfection efficacy than high molecular weight

HA (Hornof et al., 2008). PEI-HA conjugate also was devel-

oped for siRNA delivery. The siRNA/PEI-HA complex was

more efficient in LYVE-1 receptors B16F1 cells than in HEK-

293 cells without HA receptor and provided higher levels of

siRNA delivery than did the physical mixture of HA and PEI

(Han et al., 2009). Also, the siRNA/PEI-HA complexes exhib-

ited higher gene silencing efficiency reducing VEGF pro-

duction which resulted in tumor growth inhibition (Jiang et al.,

2009).

In another formulation, HA nanogels with thiol-conjugated

HA has been synthesized where siRNA was encapsulated by

inverse water-in-oil method. The release rate of siRNA was

Figure 5. Schematic illustration of gene/polycation/HA ternarycomplex. The formation of electrostatic complex between negatively-chargedHA and positively-charged polycation is showed.



modulated by the concentration of glutathione (GSH) and the

HA nanogels were transported into the cells mainly by CD44

receptor mediated endocytosis compared with negative cell

lines (Lee et al., 2007b). In addition, the thiol-modified HA

was covalently conjugated to oligodeoxynucleotide (ODN) via

disulfide linkage for increasing the charge density of ODN and

then complexed with protamine, as a cationic polypeptide to

form more stable polyelectrolyte complexes comparing to

naked ODN (Mok et al., 2007). Target specific gene delivery

using HA also include lipoplexes containing HA conjugated to

dioleoylphosphatidylethanolamine (DOPE) to target the CD44

receptor on breast cancer cells (Surace et al., 2009). Therefore,

the advantages of HA for genes delivery not only include SR

properties, enhanced serum stability and reduced cytotoxicity

but also target specific delivery with gene silencing efficiency.

Target specific delivery of antitumor drug

HA is one of the major components of the extracellular

matrix and is the main ligand for CD44 and RHAMM, which

are over-expressed in a variety of tumor cell surfaces (Culty et

al., 1994) including human breast epithelial cells (Bourguignon

et al., 2000), colon cancer (Catterall et al., 1999), lung cancer

(Matsubara et al., 2000) and acute leukemia (Yokota et al.,

1999) cells. Therefore, anticancer drug targeting to tumor cells

and tumor metastases can be accomplished by HA polymer

drug conjugates via the HA receptor-mediated uptake of these

drugs (Akima et al., 1996). Furthermore, anticancer drugs cou-

pled to HA can provide advantages in drug solubilization, sta-

bilization, localization and controlled release (Maeda et al.,

1992).

The HA conjugates containing anticancer drugs include

sodium butyrate (Coradini et al., 1999), cisplatin (Xie et al.,

2010), doxorubicin (Luo et al., 2002) , paclitaxel (Auzenne et

al., 2007) and mitomycin C (Peer and Margalit, 2004).

Depending on the degree of substitution of HA with drugs,

these exhibited enhanced targeting ability to the tumor and

higher therapeutic efficacy compared to free-anticancer drugs.

HA receptor targeted liposomes (HALs) were also developed

which could target drug-containing liposomes to tumor cell

that express CD44 (Eliaz and Szoka Jr, 2001).

Amphiphilic HA derivatives capable of self-assembly to

form nanoparticles as drug carriers were also formulated.

(Choi et al., 2010). It was composed of hydrophobically mod-

ified HA derivatives with 5β-cholanic acid, the hydrophobic

core of nanoparticles for encapsulating various anticancer

drugs. Amphiphilic poly-peptide-block-polysaccharide copol-

ymer based polymersomes loaded with doxorubicin by the

nanoprecipitation method has also been reported (Upadhyay et

al., 2010).

Conclusion and Prospect

HA is a biodegradable, biocompatible, non-toxic, non-

immunogenic and non-inflammatory linear polysaccharide

which is of interest to pharmaceutical scientists for the delivery

of various drugs. HA or HA derivatives are being investigated

for various formulations including those where HA is being

conjugated with other polymers. What is of special interest is

Figure 6. Schematic illustration of HA target-mediated endocytosis delivery.



the SR formulations using HA. Microparticle, hydrogel and

nanogel-releasing matrix of the hybrid hydrogel have been and

are continuously being explored in this aspect. An ideal SR

formulation of protein would need to be able to maintain the

initial burst concentration for more than 7 days while being

small in particle size enough to be injected through a 26-gauge

needle. Also, reducing possible toxicity due to HA is an impor-

tant consideration when developing novel formulations.

The advantage of HA formulations is seen in cancer therapy

since HA specifically binds to the CD44 receptor which is

overexpressed in several cancers. However, target specific

gene therapy as well as controlled drug targeting still needs to

overcome the problem of increasing intracellular uptake for

future in vivo therapy. It is therefore expected that more HA

related formulations will be studied and developed in the

future as target specific drug delivery systems.

Acknowledgements

This study was supported by a grant of the Korean Health

Technology R&D Project, Ministry for Health, Welfare &

Family Affairs (A092018).

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