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Journal of Controlled Release 70 (2001) 120

www.elsevier.com/locate/jconrel

Review

Biodegradable polymeric nanoparticles as drug delivery devicesa a , a*Kumaresh S. Soppimath , Tejraj M. Aminabhavi , Anandrao R. Kulkarni ,

bWalter E. Rudzinski

aDepartment of Chemistry, Polymer Research Group, Karnatak University, Dharwad 580 003, India

bDepartment of Chemistry, Southwest Texas State University, San Marcos, TX 78666, USA

Received 12 June 2000; accepted 28 September 2000

Abstract

This review presents the most outstanding contributions in the field of biodegradable polymeric nanoparticles used as drug

delivery systems. Methods of preparation, drug loading and drug release are covered. The most important findings on surface

modification methods as well as surface characterization are covered from 1990 through mid-2000. 2001 Elsevier

Science B.V. All rights reserved.

Keywords: Nanoparticle; Method of preparation; Surface modification; Drug delivery; Drug targeting

1. Introduction and reduce the toxicity or side effects [2]. However,

developmental work on liposomes has been limited

Over the past few decades, there has been consid- due to inherent problems such as low encapsulation

erable interest in developing biodegradable efficiency, rapid leakage of water-soluble drug in the

nanoparticles (NPs) as effective drug delivery de- presence of blood components and poor storage

vices. Various polymers have been used in drug stability. On the other hand, polymeric NPs offer

delivery research as they can effectively deliver the some specific advantages over liposomes. For in-

drug to a target site and thus increase the therapeutic stance, NPs help to increase the stability of drugs /

benefit, while minimizing side effects [1]. The proteins and possess useful CR properties.

controlled release (CR) of pharmacologically active Nanoparticles generally vary in size from 10 to

agents to the specific site of action at the therapeu- 1000 nm. The drug is dissolved, entrapped, encapsu-tically optimal rate and dose regimen has been a lated or attached to a NP matrix and depending upon

major goal in designing such devices. Liposomes the method of preparation, nanoparticles, nanos-

have been used as potential drug carriers instead of pheres or nanocapsules can be obtained. Nanocap-

conventional dosage forms because of their unique sules are vesicular systems in which the drug is

advantages which include ability to protect drugs confined to a cavity surrounded by a unique polymer

from degradation, target the drug to the site of action membrane, while nanospheres are matrix systems in

which the drug is physically and uniformly dis-

persed. In recent years, biodegradable polymeric NPs*Corresponding author. Fax: 191-836-747-884.E-mail address: [email protected] (T.M. Aminabhavi). have attracted considerable attention as potential

0168-3659/ 01/ $ see front matter 2001 Elsevier Science B.V. All rights reserved.

P I I : S 0 1 6 8 - 3 65 9 ( 0 0 ) 0 0 3 3 9 - 4

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2 K.S. Soppimath et al. / Journal of Controlled Release 70 (2001) 1 20

drug delivery devices in view of their applications in 2.1.1. Solvent evaporation method

the CR of drugs, their ability to target particular In this method, the polymer is dissolved in an

organs/ tissues, as carriers of DNA in gene therapy, organic solvent like dichloromethane, chloroform or

and in their ability to deliver proteins, peptides and ethyl acetate. The drug is dissolved or dispersed into

genes through a peroral route of administration [3,4]. the preformed polymer solution, and this mixture isSome general aspects on micro- and nanoparticles then emulsified into an aqueous solution to make an

have been reviewed earlier [1,511]. A majority of oil (O) in water (W) i.e., O/ W emulsion by using a

these reviews have dealt with the NPs of poly(D,L- surfactant/ emulsifying agent like gelatin, poly(vinyl

lactide), poly(lactic acid) PLA, poly(D,L-glycolide) alcohol), polysorbate-80, poloxamer-188, etc. After

PLG, poly(lactide-co-glycolide), PLGA, and poly- the formation of a stable emulsion, the organic

(cyanoacrylate) PCA. The present review details the solvent is evaporated either by increasing the tem-

latest developments on the above mentioned poly- perature/ under pressure or by continuous stirring.

mers as well as NPs based on chitosan, gelatin, The effect of process variables on the properties of

sodium alginate and other hydrophilic / biodegradable NPs was discussed earlier [26]. The W/O / W method

polymers. Surface modification aspects are also has also been used to prepare the water-soluble

covered in more detail. The PLA, PLG and PLGA drug-loaded NPs [27]. Both the above methods use apolymers being tissue-compatible have been used high-speed homogenization or sonication. However,

earlier as CR formulations in parentral and implanta- these procedures are good for a laboratory-scale

tion drug delivery applications [1214]. In addition, operation, but for a large-scale pilot production,

poly(e-caprolactone), PCL, which was first reported alternative methods using low-energy emulsification

by Pitt et al. [15,16] for the CR of steroids and are required. In this pursuit, following approaches

narcotic antagonists as well as to deliver opthalmic have been attempted.

drugs [17], and poly(alkylcyanoacrylate), PACA, are

now being developed as NPs. In addition, less 2.1.2. Spontaneous emulsification/solvent diffusion

frequently used polymers like poly(methylidene method

malonate) [18], gelatin [19], chitosan [20] and so- In a modified version of the solvent evaporation

dium alginate [21] will also be included in this method [2830] the water-soluble solvent like ace-

review. The important published literature within the tone or methanol along with the water insolubleperiod 19902000 is critically reviewed. The review organic solvent like dichloromethane or chloroform

does not cover the entire literature within this period, were used as an oil phase. Due to the spontaneous

but the reader is advised to go to the original diffusion of water-soluble solvent (acetone or metha-

literature in order to get more details. nol), an interfacial turbulence is created between two

phases leading to the formation of smaller particles.

As the concentration of water-soluble solvent (ace-

tone) increases, a considerable decrease in particle

2. Preparation of nanoparticles size can be achieved.

Conventionally, NPs have been prepared mainly 2.1.3. Salting out/emulsificationdiffusion method

by two methods: (i) dispersion of the preformed The methods discussed above require the use ofpolymers; and (ii) polymerization of monomers. organic solvents, which are hazardous to the environ-

ment as well as to the physiological system [31]. The

US FDA has specified the residual amount of organic2.1. Dispersion of preformed polymers solvents in injectable colloidal systems [32,33]. In

order to meet these requirements, Allemann and

Several methods have been suggested to prepare co-workers have developed two methods of prepar-

biodegradable NPs from PLA, PLG, PLGA and ing NPs. The first one is a salting-out method [34,35]

poly(e-caprolactone) by dispersing the preformed while the second one is the emulsificationsolvent

polymers [2225]. diffusion technique [36,37].

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K.S. Soppimath et al. / Journal of Controlled Release 70 (2001) 1 20 3

2.1.4. Production of NPs using supercritical fluid [44], the solution is charged with the supercritical

technology fluid in the precipitation vessel containing solute of

Production of NPs with the desired physicochemi- interest in an organic solvent. At high pressures,

cal properties to facilitate the targeted drug delivery enough anti-solvent will enter into the liquid phase

has been a topic of renewed interest in pharma- so that the solvent power will be lowered and theceutical industries. Conventional methods like sol- solute precipitates. After precipitation, when the final

vent evaporation, coacervation and in situ polymeri- operating pressure is reached, the anti-solvent flows

zation often require the use of toxic solvents and / or through the vessel so as to strip the residual solvent.

surfactants. Therefore, research efforts have been When the solvent content has been reduced to the

directed to develop the environmentally safer en- desired level, the vessel is depressurized and the

capsulation methods to produce the drug-loaded solid product is collected. A schematic of the SAS

micron and submicron size particles. If solvent method is shown in Fig. 1. In a modified version of

impurities remain in the drug-loaded NPs, then these the SAS technique [39], the solid of interest is first

become toxic and may degrade the pharmaceuticals dissolved in a suitable solvent and then this solution

within the polymer matrix. Supercritical fluids have is rapidly introduced into the supercritical fluid

now became the attractive alternatives because these through a narrow nozzle. The supercritical fluidare environmentally friendly solvents and the method completely extracts the solvent, causing the super-

can be profitably used to process particles in high critical fluid insoluble solid to precipitate as fine

purity and without any trace amount of the organic particles. This method, also called as gas anti-solvent

solvent. Literature on the production of drug-loaded (GAS) technique, has been successfully used to

microparticles using supercritical fluids is enormous produce microparticles as well as NPs.

[3844]. However, comparatively much less have

been investigated to produce NPs [39,40]. It is 2.1.5. Polymerization methods

beyond the scope of the present review to give an Nanoparticles can also be prepared by polymeri-

entire coverage on supercritical fluid technology; we zation of monomers. Poly(alkylcyanoacrylate)s,

will discuss only two of the most commonly used PACA, being biodegradable, have been used as tissue

methods of producing micro- or nanoparticles. adhesives in surgery since these are well tolerated in

In the rapid expansion of supercritical solution vivo [45,46]. This has prompted intense research(RESS) method the solute of interest is solubilized in activity to study polymerization reactions. Couvreur

a supercritical fluid and the solution is expanded et al. [47,48] reported the production of NPs (|200

through a nozzle. Thus, the solvent power of super- nm diameter) by polymerizing mechanically the

critical fluid dramatically decreases and the solute

eventually precipitates. This technique is clean be-

cause the precipitated solute is completely solvent-

free. Unfortunately, most polymers exhibit little or

no solubility in supercritical fluids, thus making the

technique less of practical interest. RESS was very

popular in the late 80s and early 90s for particle

production of bioerodible drug-loaded polymers likePLA. A uniform distribution of drug inside the

polymer matrix can be achieved by this method for

low molecular mass (,10 000) polymers. However,

the RESS method cannot be used for high molecular

mass polymers due to their limited solubility in

supercritical fluids. For these reasons, much less

information is found in the literature over the pastFig. 1. Schematic diagram of the SAS method: PV1 and PV2 are

67 years on this technique [41,43]. two volumetric pumps, N is nozzle, P is precipitation vessel, MVIn the supercritical anti-solvent (SAS) method is micrometric valve and EV is expansion vessel.

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dispersed methyl or ethyl cyanoacrylate in aqueous

acidic medium in the presence of polysorbate-20 as a

surfactant without irradiation or an initiator. Here,

the cyanoacrylic monomer is added to an aqueous

solution of a surface-active agent (polymerizationmedium) under vigorous mechanical stirring to poly-

merize alkylcyanoacrylate at ambient temperature.

Drug is dissolved in the polymerization medium

either before the addition of the monomer or at the

end of the polymerization reaction. The NP suspen-

sion is then purified by ultracentrifugation or by

resuspending the particles in an isotonic surfactant-

free medium. The mechanism of polymerization of

PACA monomer is given below.

Polymerization follows the anionic mechanism, Fig. 2. Schematic representation for the production of poly-(alkylcyanoacrylate) nanoparticles by anion polymerization.since it is initiated in the presence of nucleophilic

2 2 2initiators like OH , CH O and CH COO leading3 3to the formation of NPs of low molecular mass due [49], but NP production is not possible above a pH

to rapid polymerization. Such NPs are degraded very of 3.0, probably due to the aggregation and stepwise

fast. In order to circumvent this problem and to molecular mass increase at lower pH. Other factors

produce higher molecular mass as well as stable that influence the formation of NPs include the

NPs, polymerization must be carried out in an acidic concentration of monomer and the speed of stirring.

medium (pH 1.03.5). After dispersing the monomer The NPs of PACA have gained wide popularity in

in an aqueous acidic medium containing surfactant recent years despite some major drawbacks such as

and stabilizer, polymerization is continued for 34 h use of low pH (around 2) and cytotoxicity [50]. This

by increasing the pH of the medium to obtain the has lead to the synthesis of new dialkyl-methylidene

desired products. malonic acid ester monomers [51] and the NPs of

During polymerization, various stabilizers like poly(methylidenemalonate), PDEMM were prepared,dextran-70, dextran-40, dextran-10, poloxamer-188, and these were found to be non-biodegradable both

-184, -237, etc are added. In addition, some surfac- in vitro and in vivo [52,53]. To overcome this

tants like polysorbate-20, -40 or -80 are also used. problem, new derivatives of PDEMM were prepared

Particle size and molecular mass of NPs depend i.e., ethyl-2-ethoxycarbonylmethylenoxycarbonyl

upon the type and concentration of the stabilizer acrylate. NPs from these monomers were prepared

and/ or surfactant used. A schematic representation by the same methods as those adopted for the

for the production of poly(alkylcyanoacrylate) NPs is preparation of PACA NPs by anionic polymerization

shown in Fig. 2. The size and molecular mass of NPs [54]. The pH of the polymerization medium critically

depend upon the pH of the polymerization medium influenced the physicochemical properties of NPs,

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3. Drug loading when compared to chromatographic methods, which

require ultracentrifugation.

A successful NP system may be the one, which In addition to adsorption and incorporation, a new

has a high loading capacity to reduce the quantity of method of drug loading for the water-soluble drugs

the carrier required for administration. Drug loading was proposed by Yoo et al. [85]. In this method, druginto the NPs is achieved by two methods: one, by was chemically conjugated into NPs. The conjugated

incorporating the drug at the time of NP production doxorubicinPLGA and doxorubicin-loaded PLGA

or secondly, by adsorbing the drug after the forma- NPs were prepared by the spontaneous emulsion

tion of NPs by incubating them in the drug solution. solvent diffusion method. The encapsulation ef-

It is thus evident that a large amount of drug can be ficiency of 96.6% and 3.5% loading of doxorubicin

entrapped by the incorporation method when com- PLGA conjugate have been achieved. For the un-

pared to the adsorption [76,77]. Adsorption iso- conjugated doxorubicin, these values were, respec-

therms for the NP/ drug delivery system give vital tively 6.7% and 0.3% (w/ w).

information on the best possible formulation, the

drug binding capacity onto the surface of NPs and

the amount of drug adsorbed. For instance, Couvreur 4. Drug release

et al. [78] reported the adsorption of two antineoplas-

tic drugs viz, dactinimycin and methotrexate onto Drug release from NPs and subsequent biodegra-

poly(methylcyanoacrylate) and poly- dation are important for developing the successful

(ethylcyanoacrylate). It was observed that methotrex- formulations. The release rates of NPs depend upon:

ate was bound to the NPs to a lesser extent than (i) desorption of the surface-bound/ adsorbed drug;

dactinimycin. Generally, in the case of PACA, it is (ii) diffusion through the NP matrix; (iii) diffusion

observed that longer the alkyl chain length higher the (in case of nanocapsules) through the polymer wall;

affinity for the drugs. The capacity of adsorption is (iv) NP matrix erosion; and (v) a combined erosion/

thus related to the hydrophobicity of the polymer and diffusion process. Thus, diffusion and biodegradation

the specific area of the NPs. In case of entrapment govern the process of drug release.

method, an increase in concentration of the mono- Methods to study the in vitro release are: (i)

mer, increases the association of drug, but a reverse side-by-side diffusion cells with artificial or bio-trend is observed with the drug concentration in the logical membranes; (ii) dialysis bag diffusion tech-

dispersed solution. This observation was further nique; (iii) reverse dialysis sac technique; (iv) ultra-

substantiated by Radwan [79] who studied the effect centrifugation; (v) ultrafiltration; or (vi) centrifugal

of monomer concentration on % drug loading. These ultrafiltration technique. Despite the continuous ef-

results indicate that there is a need to optimize the forts in this direction, there are still some technical

amount of monomer available for the drug entrap- difficulties to study in vitro drug release from NPs

ment. [86,87]. These are attributed to the separation of NPs

The type of surface-active materials and stabilizers from the release media. In order to separate NPs and

has an effect on drug loading [80]. Chukwu et al. to avoid the tedious and time-consuming separation

[81] studied the adsorption of different psycho- techniques, dialysis has been used; here, the suspen-

pharmacological agents onto NPs of poly- sion of NPs is added to the dialysis bags/tubes of(isobutylcyanoacrylate), PIBCA, in the pH range different molecular mass cut-off. These bags are then

between 2.0 and 7.4. Adsorption of drugs onto NPs incubated in the dissolution medium [8890].

followed the Langmuir mechanism [82,83]. In Another technique involves the use of a diffusion

another study [84], a dielectric method was used to cell consisting of donor and acceptor compartments;

investigate the adsorption ofb-blockers onto PIBCA this technique was used to separate through the

NPs. In this method, the NP suspensions were taken artificial/ biological membranes [91]. In this method,

into a capacitance cell, exposed to a high-frequency kinetic study was not performed under the perfect

field (10 MHz) and the complex impedance was sink conditions, because the NPs were not directly

measured. This technique is rapid and inexpensive diluted in the release media, but were separated from

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the release media through the membrane. Thus, the drug from the core across the polymeric barrier

amount of drug in the release media did not reflect layer. Hence, theoretically, the drug release should

the real amount released. In order to avoid the follow the zero-order kinetics. Calvo et al. [17]

enclosure of NPs in the dialysis bag, Leavy and obtained almost the similar release profiles for

Benita [92] used a reverse dialysis technique for the indomethacin from both NPs and nanocapsules. ThisO / W emulsion. In this method, NPs were added indicated that the polymer coating does not show any

directly into the dissolution medium. The same barrier properties for the drug release. The drug

technique was adopted by Calvo et al. [17] for the release from the nanocapsule takes place mainly by

evaluation of NPs, nanocapsules and nanoemulsions. the partitioning of the drug; however, the main factor

However, the method is not very sensitive for controlling the release is the volume of the aqueous

studying the rapid release formulations; but can only medium. For instance, with higher dilution of the

be used for the release of formulations having the dissolution media, a faster and complete release of

release time longer than 1 h [93]. the drug takes place. However, Lu et al. [97]

Release profiles of the drugs from NPs depend reported that the release of bovine serum albumin

upon the nature of the delivery system. In the case of from PLA nanocapsule depends upon the molecular

a matrix device, drug is uniformly distributed/ dis- mass of the polymer, which indicates that the releasesolved in the matrix and the release occurs by may not occur by partitioning of the drug, but may

diffusion or erosion of the matrix. If the diffusion of be due to diffusion across the polymer coating.

the drug is faster than matrix degradation, then the The method of drug incorporation into NPs has

mechanism of drug release occurs mainly by diffu- also shown an effect on drug release. Fresta et al.

sion, otherwise it depends upon degradation [28]. [90] reported a higher burst up to 6070% for the

Rapid initial release is attributed to the fraction of NPs loaded with drug by adsorption; here, the burst

the drug which is adsorbed or weakly bound to the effect is less and the remaining drug release is quite

large surface area of the NPs, than to the drug slow. This study demonstrated that the incorporation

incorporated in NPs. Following the dilution of the method has shown better sustained release charac-

dissolution media under perfect sink conditions the teristics. When the drug is chemically conjugated

drug partition showed an increase due to the immedi- with PLGA NPs, the release took place over 25 days,

ate release phase. Later, an exponential delayed whereas with those NPs containing unconjugatedrelease rate is observed probably due to the drug free drug, a rapid release in about 5 days occurred

diffusion from the matrix [94,95,35,17,28]. Release [85]. Here, the CR properties have been attributed to

in the matrix type of NPs follows the first-order chemical degradation of the conjugated PLGA,

kinetics [90,79]. which permitted water solubilization and subsequent

Recently, Polakovic et al. [96] theoretically release of the drug-conjugated PLGA oligomers into

studied the release of PLA NPs loaded with varying the medium. In case of drug release from hydrogel

amounts (732% w / w) of lidocane. Two models NPs, release occurs mainly due to swelling, which

were used to study the drug release: (i) by crystal can be controlled by either adding the hydrophilic

dissolution and (ii) by diffusion through the polymer functional groups or by monitoring cross-linking of

matrix. When the drug loading is ,10% (w/ w) (the the matrix.

drug is molecularly dispersed), the release kineticsshows a better fit to the diffusion model. The

existence of lidocane crystals at higher concentration 5. Surface properties of NPs

(.10%) is observed. Since the drug should dissolve

first from the crystals and then diffuse from the 5.1. Protein adsorption and phagocytosis of NPs

matrix, the overall release mechanism could be

described by the dissolution model. Plasma protein adsorption and phagocytosis of

In the case of nanocapsules (reservoir-type drug- NPs is a subject that has been widely studied in

delivery systems) the drug core is coated with the recent years. When the NPs are administered in-

polymer and the release occurs by diffusion of the travenously they are easily recognized by the body

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immune systems, which are then cleared from the of poly(oxyethylene) in the polymer has drastically

circulation. Apart from the size of NPs, their surface decreased the protein adsorption when compared to

hydrophobicity determines the amount of adsorbed the pure polyesters.

blood components, mainly proteins (opsonins). These In another study by the same group of researchers

will determine the in-vivo fate of NPs [98,99]. [105], an attempt was made to correlate the ad-Binding of these opsonins onto the surface of NPs, sorption results with the in-vivo circulation of NPs.

called opsonization, acts as a bridge between NPs The di-block and multi-block copolymers of PEG

and phagocytes. Hence, for a qualitative and quan- were used as model polymers to show the decrease

titative understanding of the interaction of blood in adsorption of proteins; these NPs have shown

proteins with NPs, it is necessary to design long- long-circulating properties. The reduced liver uptake

circulating NPs by surface modification. of NPs was dependent on the molecular mass and

In a study by Allemann et al. [100], it was surface density of PEG. The in-vitro protein rejection

reported that when the PLA NPs are incubated in properties of the PEG-coated poly-

human plasma and serum, the IgG was found to be (alkylcyanoacrylate) NPs were investigated after

the major protein along with albumin, apolipopro- when the freeze fracture of NPs were pre-incubated

tein-E, which were adsorbed on the surface. Compli- with fibrinogen as model blood protein [106]. Thement C components (part of immune system used decrease in protein adsorption onto PEG-coated NPs3for the recognition of foreign surfaces) were also was evident by 2-DPAGE after incubating them in

adsorbed onto the surface of NPs after incubation in human serum. The NPs were also long-circulating as

the serum reaching the level of antibody IgG. Blunk proved from in-vivo tests.

et al. [101] studied the kinetics of protein adsorption

onto polystyrene NPs and confirmed that albumin 5.2. Surface characterization methods

and fibrinogen were adsorbed in a highly diluted

plasma (0.08 and 0.8%). However, in the plasma of Many techniques have been developed and used to

high concentration (80%), proteins were displaced study the surface modification of NPs. The efficiency

within seconds or even fractions of a second. The of surface modification can be measured either by

study indicated that apolipoproteins A-I, C-III, E and estimating the surface charge, density of the func-

J were the major proteins adsorbed onto NPs. tional groups or an increase in surface hydrophilicity.A two-dimensional polyacrylamide gel electropho- One method used to measure the surface modi-

resis (2-DPAGE) was used to estimate quantitatively fication is to determine zeta potential (j) of the

the interaction of plasma proteins with iron oxide aqueous suspension containing NPs. In this method,

NPs in the presence of plasma proteins stabilized by the mobility of charged particles is monitored by

polysaccharide. Particles incubated in the plasma applying an electrical potential. The zeta potential

were separated and were then washed with different values may be positive or negative depending upon

washing media. The protein adsorbed on NPs was the nature of the polymer or the material used for

then estimated by 2-DPAGE. By this, it was found surface modification. The extent of surface hydro-

that fibrinogen, IgG and albumin were the major philicity can then be predicted from the values ofj.

plasma proteins adsorbed onto NP surface [102,103]. This is a widely used technique to understand the

In another study by Luck et al. [104], the interaction surface charges of NPs.of proteins with NPs was shown to depend upon the Another commonly used technique is electron

method of NP preparation. For example, the amount spectroscopy for chemical analysis, ESCA, also

of several apolipoproteins in plasma protein adsorp- called X-ray photoelectron spectroscopy (XPS). This

tion patterns of the spray-dried PLGA and PLA NPs technique is based on the emission of electrons from

were distinctly higher than when compared to the materials, in response to irradiation by photons of

adsorption patterns of the particles produced by W/ sufficient energy, to cause ionization of the core-

O / W emulsion technique. Some adsorbed proteins level electrons. These electrons are emitted at ener-

were found to be specific for particles produced by gies characteristic of the atoms from which they are

the same method. The presence of hydrophilic chain emitted. Since photons have low penetration energy,

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only those electrons pertaining to atoms at or near action with the surface even at lower concentrationsthe surface (up to 100 A) escape and these can be of the protecting polymeric layer. The biological

counted. For each atom type, the number of electrons consequences of steric protection of drug carriers

emitted is related to the number of atoms of a with the surface-grafted polymers have been dis-

particular type of atom. Using this technique, surface cussed and clinical applications of the long-circulat-elemental analysis was performed [107]. ing NPs have been studied [10]. A theoretical model

In another technique, the surface hydrophobicity of repulsion of proteins from the solid substrate was

of NPs can be directly measured by hydrophobic proposed by Joen et al. [110]. The steric repulsion,

interaction chromatography. This technique involves van der Waals attractions and hydrophobic inter-

the column chromatography, which is able to sepa- action free energy have been correlated. The model

rate materials based on the interaction with a hydro- provides a basis for the prevention of opsonin

phobic gel matrix [108]. The nanoparticle and the gel deposition. High surface density and long chain-

interaction is a function of surface hydrophobicity of lengths of PEG are necessary for low protein ad-

NPs. Propyl agarose gel is used as a stationary phase sorption. However, surface density has a greater

and elution of NPs can be achieved by using the effect than the chain-length on steric repulsion and

phosphate buffer. Eluent samples can be collected van der Waals attraction.and the optical density measured spectrophotomet- Bazile et al. [111] developed the NPs based on

rically at 400 nm. The gel matrix can then be washed methoxy PEGPLA i.e., Me-PEGPLA and blends

to remove the NPs. of PLA with Me-PEGPLA. These NPs, labeled by14

introducing C-labeled PLA in the formulation were5.3. Methods of surface modification more slowly captured by the cultured THP-1 mono-

cytes when compared to pluronic F68-coated PLA

Surface modification of biodegradable and long- NPs. The half-life of Me-PEGPLA NPs was im-

circulating polymeric NPs has been achieved mainly proved by a factor of 180 (360 min) when compared

by two methods: (i) surface coating with hydrophilic to the uncoated and F68-coated NPs. Even though, a

polymers/ surfactants; and (ii) development of bio- high amount of radioactivity was located in the heart

degradable copolymers with hydrophilic segments. and blood vessels due to particle circulation, in other

Some of the widely used surface-coating materials phagocytic organs, radioactivity was found evenare: polyethylene glycol (PEG), polyethylene oxide after 6 h of i.v. administration indicating a delay in

(PEO), poloxamer, poloxamine, polysorbate (Tween- phagocytosis. Tobio et al. [112] observed much

80) and lauryl ethers (Brij-35). greater penetration of tetanus toxoid (TT) encapsu-

lated PEGPLA NPs than PLA NPs after nasal5.3.1. PEG and PEO-coated NPs administration. A high persisting radioactivity was

PEG-coated NPs have received a lot of attention. found in body compartments up to 8 h after the125

Gref et al. [109] described the one step method to introduction of I TT-loaded NPs.

prepare the PEG-coated NPs using amphiphilic Gref et al. [113] reported the preparation of blend

PEGpolyester diblock copolymer as the starting NPs of PLA with monomethoxy polyoxyethylene

material and showed that the protective coating (MPOE) by solvent evaporation method using so-

affecting against the phagocytes depends upon den- dium cholate surfactant. The zeta potentials mea-sity and molecular mass of PEG. They also studied sured at various concentrations of NaCl varied from

the biodistribution of covalently-attached PEG 255 mV for PLA to 0 mV for blends depending

PLGA NPs. The protective effect of PEG on carriers upon the composition of MPOE in the NPs. The zeta

like liposomes, NPs and micelles was studied by potential increased with an increasing amount of

Torchilin [11] in terms of the statistical behavior of MPOE suggesting that the MPOE chains that are

polymers. A mechanism was proposed which as- present on the surface of NPs mask the ionized2

sumes that the surface-grafted chains of flexible and COO end-group of PLA. These results are sup-

hydrophilic polymers form dense conformational ported by a phagocytosis study on the monocytes.

clouds thus preventing other polymers from inter- When MPOE content in the blend is greater than

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23%, the MPOE chain adopts a brush-like configu- the PEG coated NPs. Peracchia et al. [121] also

ration forming a sterically-uncharged barrier, thereby prepared the methoxy PEG cyanoacrylatehexadecyl

reducing the zeta potential and phagocytosis. cyanoacrylate amphiphilic NPs by polymer precipi-

Govender et al. [114] examined the drug-encapsu- tation or by solvent evaporation method; the PEG

lation characteristics of PLAPLA NPs using coating was confirmed by XPS. The particles ex-procaine hydrochloride, a water-soluble drug. The hibited a reduced cytotoxicity and enhanced degra-

PLAPEG NPs were produced by the nano-precipi- dation. NPs prepared in the presence of PEGs have

tation technique. The drug-entrapment efficiencies of shown some advantages in preventing opsonization

these NPs were compared with those of PLGA NPs. and thereby avoiding the MPS uptake [122]. This

Kim et al. [115] used the ESCA method to evaluate mechanism is explained in Fig. 3.

the presence of PEG on the surface of indomethacin- PEO-surface modified systems have received an

loaded Me-PEGPLA NPs. The in-vitro cytotoxicity increased attention in recent years. Jaeghere et al.

of these NPs did not show any remarkable cytotox- [123] studied the freeze-dried PEO-surface modified

icity against the normal human fibroblast cells. NPs as a function of PEO chain length and surface

The optimum surface density of PEG on NPs density to avoid the MPS uptake. NPs were produced

plays an important role in steric repulsion. These by salting-out method using the blends of PLA andNPs have shown a lower accumulation in the liver, PLAPEO copolymers. In an effort to study the

but the observed high spleen uptake is due to the effect of surface density of PEO on the compliment

removal of PEG coating from the surface of NPs, an consumption, Vittaz et al. [124] used the diblock

important property in spleen targeting [116]. In polymer of PLA and polyethylene oxide (PLA

addition, the distance between PEG chains on the PEO). It was found that as the PEO density on the

surface of NPs is critical to avoid the adsorption of surface of the NPs increases, a decrease in compli-

plasma proteins. For instance, a decrease in the ment consumption is observed due to steric repulsion

distance between PEG chains on the surface from 6.2 of the surface to proteins. A preliminary study was

to 5.1 nm drastically decreases the adsorption of made on the synthesis of amphiphilic PEOPPO

apolipoproteins up to 90%. This further confirms that

the density of hydrophilic segment on the surface of

NPs is important in opsonization. However, anyfurther decrease in this distance did not show

significant effects on the adsorption of plasma pro-

teins [117].

Peracchia et al. [118] used the emulsification and

solvent evaporation method to prepare the diblock

Me-PEGPLA copolymeric NPs containing 20 and

33% of lidocaine. They confirmed high-density of

the surface PEG by ESCA. However, the size of NPs

produced by the block copolymer was twice as high

as those of PLGA NPs. This was attributed to an

increase in the chain length of PEG. Peracchia et al.[119,120] reported the chemical coupling of PEG

with PBCA NPs prepared by emulsion polymeri-

zation in the presence of PEG, Me-PEG and (Me) -2PEG. Polymerization was possible only in the pres-

ence of PEG and Me-PEG as hydroxyl group wasFig. 3. Effect of surface PEG density and its conformation on thenecessary for polymerization and association of PEGopsonization process: (A) opsonization takes place when the

on the surface of NPs. Higher PEG density wasdensity is low, (B) opsonization is not possible at higher surface

observed on the surface of NPs when Me-PEG was density and (C) when both the end groups of PEG participate inused. A decrease in hydrophobicity was observed for surface modification.

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PEO block copolymers (Plunoric) and poly(e-cap- uptake pathways are observed for NPs depending

rolactone) by bulk polymerization [125]. The size of upon their surface characteristics and the rodent

the NPs prepared varied from 116 to 196 nm, species. Coating was effective in stimulating the

depending upon the type of copolymer used. spleen uptake in rats and mice. Spleen uptake of

Fluoresbrite NPs was higher than Estapor NPs,5.3.2. Poloxamine and poloxamer coated NPs probably due to differences in the surface charac-

Poloxamer and poloxamine have been widely used teristics of NPs.

in surface coating studies. Storm et al. [126] pre- Polystyrene-latex nanospheres (PSL-NS, mean

sented an overview of the advances made up to 1995 diameter, 85 nm) were coated with lactosyl-poly-

on the surface modification of NPs to oppose the styrene (LPS, high affinity to hepatocytes) to evalu-

MPS uptake. In a study by Illum and Davis ate their targeting characteristics to hepatocytes and

[127,128], poloxamer and poloxamine were used as PSL-NS surfaces [133]. Hepatocytes were adhered

the coating materials to prepare the long-circulating specifically with the LPS-coated dishes made of the

NPs of polystyrene and poly(methyl methacrylate). A same materials as PSL-NS. Flow cytometry inves-

prolonged circulation time and reduction in liver tigations showed that the LPS-coated fluorescein-

uptake in rabbits was found for the poloxamine- isothiocyanate (FITC)PSL-NS were taken up bycoated polystyrene NPs (60 nm size) when compared hepatocytes when compared to the noncoated FITC

to the uncoated NPs of the same size. A decrease in PSL-NS as a control. These findings indicated that

hepatic uptake of about 20% for the NPs prepared LPSPSL-NS could target to hepatocytes. The sur-

with poloxamer-188 and about 40% for the NPs face of LPS on PSL-NS showed higher hydrophil-

coated with poloxamer-338 was observed. Rabbit icity than PEG-6000, Tween-80, poloxamer-407 and131

experiments with I-labelled polystyrene poloxamer-908, which indicated that LPSPSL-NS

poloxamer-407 coated NPs showed the superior may avoid the reticuloendothelial system capture and

performance over that of poloxamer-338 to avoid the have a long plasma duration after the in-vivo i.v.

hepatospleenic uptake. adminstration. Plasma coagulation can be prevented

Rudt and Muller [129] studied the uptake of by the addition of 0.1% of PVA in LPSPSL-NS

surface modified poloxamine-coated polystyrene NPs solution when LPSPSL-NS were injected. The

and found extremely low levels of uptake for 100 nm LPSPSL-NS were the potential hepatocyte targetingsize NPs. Compared to poloxamer, poloxamine was carriers for the injectable formulations.

more effective as a coating material to avoid the liver

capture of rabbits [130]. Moghimi and Gray [131]

developed the long-circulating poloxamine-908 5.3.3. Cyclodextrin/carbohydrate coated NPs

coated polystyrene NPs (60 nm) that are resistant to Carbohydrates were also found to avoid the MPS

MPS uptake. The time interval of administration was uptake when coated on the surface of NPs. To avoid

important in maintaining the long circulation time. the MPS uptake the coated NPs with carbohydrate

Spleen-capture study of the fluorescent-labeled was reported by Cho et al. [134]. The NPs of PLA

polystyrene NPs coated with poloxamer 407 or and poly(L-lysine)-grafted-polysaccharide were also

poloxamine 908 was made [132] on two rodent developed for the delivery of DNA [135] and these

species viz., mouse and rat in order to assess the were found to be resistant against self-aggregationeffect of coating on their intraspleenic distribution. and nonspecific adsorption of the serum proteins.

Two fluorescent polystyrene NPs used were: Recently, Duchene et al. [136] used amphiphilic

Estapor (FX-010, 185 nm, Prolabo, France) and cyclodextrin NPs to increase the loading of water-

Fluoresbrite (Plain YG, 260 nm, Polysciences, soluble drugs and bioavailability of the poorly water-

UK). A fluorimetric investigation indicated that the soluble drugs intended for targeted delivery by the

Fluoresbrite NPs were more efficiently trapped by oral or parenteral route. In order to further increase

the spleen than the Estapor -based NPs in mice and the loading capacity, PIBCA NPs were loaded with

rats. Results indicate an increase in the size of NPs the natural or hydroxypropyl cyclodextrins. The

after coating the Estapor NPs. Different spleen loading capacity increased with an increase in stabili-

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ty constant of the inclusion drug/ parent g-cyclo- biological membrane was studied and an increase in

dextrin and with a decrease in water solubility. the permeation of polysorbate-80 coated NPs

The PIBCA NPs were prepared by the anionic occurred [91]. A schematic representation of the

polymerization of isobutylcyanoacrylate in 0.01 M increased drug permeation from the polysorbate-80

HCl containing 1% poloxamer-188 and in the pres- coated NPs through the biological membrane isence of cyclodextrins. The size, zeta potential and shown in Fig. 4.

cyclodextrin content were influenced by the nature of Borchardt et al. [142] studied the uptake of

cyclodextrin. The smallest size particles were ob- polysorbate-80 coated poly(methyl methacrylate)

tained from hydroxypropyl b-cyclodextrin, but the (PMMA) NPs by bovine brain microvessel endo-

highest cyclodextrin content was obtained for b- thelial cell monolayers. These NPs showed an in-

cyclodextrin. The cyclodextrin NPs or the polymeric creased uptake by the endothelial cells of the BBB.

NPs containing cyclodextrin were useful in targeting Troster et al. [143] demonstrated a nine-fold increase

the water-insoluble drugs through oral or parentral in the accumulation of radioactivity in the brain area

route. The presence of cyclodexrins in these NPs has after i.v. administration of polysorbate-80 coated14

drastically reduced the surface negativity probably C-PMMA NPs. A recent study by Steiniger et al.

due to their hydrophilicity; hence, the cyclodextrin [144] suggested that polysorbate-80 coated poly-coated NPs may help in avoiding the MPS.

5.3.4. Polysorbate-coated NPs to penetrate the

bloodbrain barrier

Targeting drugs to the brain by crossing the

bloodbrain barrier (BBB) has been a challenge. In

this pursuit, many attempts have been made to

develop novel drug delivery systems. BBB is formed

by the tight endothelial cell junctions of the capil-

laries within the brain, which limits the ability of

many drugs to penetrate through the brain tissue in

order to enter the central nervous system (CNS). It isknown that many regulators of the brain functions

such as cytokines, transferrin, enkephalins, endor-

phins or delta sleep inducing peptides pass through

BBB from the vessels into brain [137,138] as well as

some excitatory and depressant amino acids, pene-

trate poorly through BBB. The poor BBB penetration

of such substances makes the problem of drug

targeting to the brain highly pertinent. However, the

surface modified NPs have been used to deliver the

anti-inflammatory drugs acting on the CNS because

these can pass through BBB [139,140].The mechanism of enhancement of drug transport

from the coated NPs through BBB is due to the

number of mechanisms: (i) by binding the NPs to the

inner endothelial lining of the brain capillaries and

subsequently, particles deliver drugs to the brain by

providing a large concentration gradient, thus en-

hancing the passive diffusion; (ii) brain endothelialFig. 4. The schematic representation of the drug uptake through

uptake by phagocytosis [141]. The effect of surfac- biological membrane from (A) free drug and (B) polysorbate-80tant coated NPs on drug permeation across the coated nanoparticle bound drug [91,141].

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(alkylcyanoacrylate) NPs are superior over the un- also reported an increased analgesic activity of

coated NPs to transport drugs across BBB. dalargin-loaded PBCA NPs coated with polysorbate-

Recently, investigations have been carried out 80 when administered in mice. In a further study,

[145] with PBCA NPs as well as with the non- Alyautdin et al. [148] found that BBB crossing was

biodegradable polystyrene (PS) NPs (200 nm in observed for low molecular mass and polar hydro-diameter) to study the transport of analgesic peptide, philic drug like tuborcurarin after loading it into

dalargin to the brain. Its entry into the CNS of the polysorbate-80 coated PBCA NPs. An in-vivo per-

mice was evaluated using the tail-flick procedure. fused rat brain was used along with the simultaneous

Locomotor activity measurements were performed to recording of an electroencephalogram (EEG) since

compare the toxicity of NPs. BBB permeability of the drug induces epileptic form seizures. An i.v.

PBCA NPs was studied in-vitro using a co-culture of injection of the NPs demonstrated the appearance of

bovine brain capillary endothelial cells and rat EEG seizures 5 min after the administration.

astrocytes. Dalargin associated with PBCA NPs and Schroeder et al. [149] studied the transport of

polysorbate-80 induced a potent and prolonged anal- dalargin, kytorphin (centrally-acting analgesics) and

gesia, which was not observed by using polystyrene amitriptyline (antidipressant)-loaded PBCA NPs

NPs, but not using the PBCA NPs. Locomotor coated with polysorbate-80 across the BBB. In-vivoactivity dramatically decreased in the mice dosed analgesic activity carried out in mice showed a

with PBCA NPs, but not with the polystyrene NPs. drastic enhancement of analgesia for the drug-loaded

The in-vitro and in-vivo results suggested that the NPs coated with polysorbate-80. The amitriptylin

PBCA NPs induce a nonspecific opening of the BBB concentration in the brain increased, but the con-

in the presence of polysorbate-80 allowing the centration in serum decreased for dextran-stabilized

transport of dalargin into the CNS. Although polysorbate-80 coated NPs. These results indicate

polysorbate-80 coated PBCA NPs are useful in that the surface modification of NPs by coating with

increasing the penetration of drugs into the CNS, polysorbate-80 is effective in drug delivery through

potential therapeutic applications are limited because BBB.

of the high systemic NP concentration needed to

deliver drugs to the CNS.

In an effort to deliver anticancer drugs to the brain 6. Delivery of proteins and peptides using NPsusing NPs, Gulyaev et al. [146] demonstrated that

the brain concentration of systemically administered Peptide drugs are attracting, as their role in

doxorubicin was enhanced by more than 60-fold by physiopathology is better understood and because of

binding it to polysorbate-80 coated PBCA NPs. the progress made in biotechnology and bioengineer-

Doxorubicin was selected as a model drug due to its ing. Particularly, the development of DNA-recombi-

potent antitumor activity and because the drug is not nant technology has made these compounds available

able to cross the BBB by i.v. injection. Polysorbate- on large scale than in the past. However, the use of

80 coated NPs reached the brain intact and released peptide in medicine is partly limited by their rapid

the drug after endocytosis by the brain blood vessel degradation by proteolytic enzymes in the gastroin-

endothelial cells. High brain concentrations achieved testinal tract; thus, they need to be administered

in this study suggested a significant improvement in through the parentral route. The biological half-lifethe treatment of brain tumors. of peptides is short and needs frequent administra-

Alyautdin et al. [147] studied the efficiency of tions. On the other hand, their transport across

polysorbate-80 coated PBCA NPs in crossing BBB biological barriers is poor due to poor diffusivity and

to deliver the water-insoluble analgesic drug, loper- lower partition coefficients. In this pursuit, the

mide, in mice. Intravenous injection of the particulate biodegradable delivery systems have been

polysorbate-80 coated NPs resulted in a long and proposed for the safe and controlled parentral ad-

significant analgesic effect, which was measured by ministration of peptides [150].

the tail flick method, while the uncoated NPs were Proteins and peptides are unstable in PLGA

unable to produce analgesia. Alyautdin et al. [141] because of the hydrophobicity and acidity of PLGA

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[151]. Another problem is the fast burst release of release insulin from the nanospheres over a span of 6

protein drugs from the PLGA matrices. In order to h. The 1.6% zinc insulin in PLGA with fumaric

circumvent these problems, different approaches anhydride oligomer and iron oxide additives was

have been explored to modify the properties of shown to be active orally and was able to control the

PLGA matrices by using the hydrogel NPs plasma glucose levels. A number of properties of this[152,153]. This has prompted the development of formulation, including size, release kinetics, bioadhe-

novel protein delivery systems. In these studies, siveness and ability to traverse the gastrointestinal

bovine serum albumin (BSA) was encapsulated first epithelium have contributed to its oral efficacy.

in PVA NPs, which were then loaded into PLGA In recent years, greater advances have been made

microspheres using the phase separation method. The particularly by the research group of Professor

protein loaded PLGAPVA composite NPs were Robert Langer at MIT (USA) on the development of

then characterized and were having the nonporous gene delivery systems. However, a discussion on

surface to release BSA for over 2 months. In a recent these systems is beyond the scope of this review.

study by Gasper et al. [154], it was shown that the

presence of end carboxyl group in PLGA resulted in

a high protein loading of up to 4.86 mass% and the 7. Conclusions

release continued for about 20 days. On the other

hand, the presence of esterified carboxyl end groups The use of biodegradable polymers for the CR of

in PLGA led to a lower loading (2.65 mass%) of therapeutic agents is now well established. Although

proteins and a release of up to 14 days. currently there are only a small number of commer-

The release kinetics and in-vivo effects of NPs cially available products that utilize this technology

containing PGDF-Receptor b (PDGFRb) tyrphostin (e.g., Lupron Depot ), these polymers have great

inhibitor, AG-1295, AG-1295-loaded PLA NPs were utility for the CR of several drugs like vaccines,

prepared by the spontaneous emulsification/ solvent human growth hormone, insulin, anti-tumor agents,

displacement technique [155]. The in-vitro release contraceptives and also vaccines. Long circulation of

rate and the impact of drug/ polymer ratio on the size drugs in the body is the key in successful drug

of NPs were determined. It was shown that by delivery and drug targeting to the site of action.

modulating the formulation variables, release kinet- Many polymeric NPs have been developed for thisics and particle size were tailor-made to address the purpose. Certainly, surface modification is useful in

clinical needs. A novel pulmonary delivery system of achieving these goals. From the polymer chemistry

PLGA nanosphere (400 nm size) encapsulating the viewpoint, it is important to synthesize newer poly-

physiologically active peptide was developed by mers and copolymers to match the hydrophilic and

Kawashima et al. [156]. These were prepared by hydrophobic properties. Production of NPs using the

using the modified emulsion solvent diffusion meth- environmentally friendly processes like supercritical

od in water. The aqueous dispersions of PLGA fluids is quite a promising area of research to

nanospheres administered pulmonarily to guinea pig develop the products that are free from the unwanted

via nebulization reduced significantly the blood toxic residual solvents. Although many important

glucose level for over 48 h when compared to the goals have been reached in achieving stabilization of

nebulized aqueous solution of insulin as a reference. drugs in circulation, yet more investigations areAbout 85% of the drug was released from the needed to develop the newer materials in this area.

nanospheres during the initial burst, followed by a

prolonged release of the remaining drug for few

hours in saline solution at 378C. Acknowledgements

Zinc insulin was successfully encapsulated in

various polyester and polyanhydride nanosphere We immensely thank the Council of Scientific and

formulations using the phase inversion nanoencapsu- Industrial Research, New Delhi, India [Grant [

lation technique [157]. The encapsulated insulin 80(0025)97/ EMR-II] for a major financial support

maintained its biological activity and was able to of this study. Dr. Walter E. Rudzinski thanks the

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