Recent Advances in Drug Delivery Systems

doi:10.4236/jbnb.2011.225062

Paper Menu >>

Journal Menu >>

Journal of Biomaterials and Nanobiotechnology, 2011, 2, 510-526

doi:10.4236/jbnb.2011.225062 Published Online December 2011 (http://www.scirp.org/journal/jbnb)

Recent Advances in Drug Delivery Systems

Nuno Martinho1, Christiane Damgé2, Catarina Pinto Reis1*

1CBIOS—Laboratory of Nanoscience and Biomedical Nanotechnology, Faculty of Sciences and Health Technologies (FCTS), Lu-

sophone University of Humanities and Technologies (ULHT), Lisbon, Portugal; 2Institute of Physiology, Faculty of Medicine,

University of Strasbourg, Strasbourg, France.

E-mail: *catarinapintoreis@gmail.com

Received October 3rd, 2011; revised November 12th, 2011; accepted November 20th, 2011

ABSTRACT

Drug targeting to specific organs and tissues has become one of the critical endeavors of the century since the use of

free drugs in conventional dosage forms generally involves difficulties in achieving the target site at the appropriate

dose after or during a proper time period. Consequently, the search for new drug delivery approaches and new modes

of action represent one of the frontier research areas. New drug delivery systems include lipidic, proteic and polymeric

technologies to provide new sustained drug delivery with better body distribution, drug protection from the harsh ex-

ternal environment and avoidance of drug clearance. Many of these technologies have reached the market therefore

proving the benefits of these new carriers. This review covers the generalities of those new carriers and their new ad-

vances in drug delivery.

Keywords: Nanomedicine, Nanoparticles, Liposomes, Cyclodextrins, Dendrimers, ADEPT

1. Introduction

Drug targeting to specific organs and tissues has become

one of the critical endeavors of the new century. The

search for new drug delivery approaches and new modes

of action represent one of the frontier areas which in-

volves a multidisciplinary scientific approach to provide

major advances in improving therapeutic index and

bioavailability at site specific-delivery [1-4]. The hard to

target tissues such as blood-brain barrier permeation

limitation can now be overcome allowing the use of

therapies otherwise excluded by conventional dosage

forms [5]. These new systems can hinder solubility prob-

lems, protect the drug from the external environment

such as photodegradation and pH changes, while reduc-

ing dose dumping by controlling the release profile [3,4].

Moreover, controlled targeting at the site of action and

reduced time of exposure at non-targeting tissues in-

creases the efficacy of treatments and reduce toxicity and

side effects [6] thus improving patient compliance and

convenience.

Biocompatibility is one of the major pre-requisites for

pharmaceutical use, and designing a formulation to fit the

physicochemical properties of the drug poses the chal-

lenge to new dosage forms. Nowadays, the versatility

and biodegradability of polymers such as poly(D-L-lac-

tide-co-glycolide) (PLGA) constitute a leading approach

to new dosage forms to avoid physiological and patho-

logical hurdles encountered in developing targeting stra-

tegies. This approach can improve the pharmacokinetic

profiles of numerous drugs through the delivery of a

higher dose at the site-specific organs by using ligands [7]

while conferring a controlled release and degradation to

non-toxic products. Meanwhile, oral administration is the

most convenient route for drug delivery and the focus of

recent research concerns the development of carriers that

can cross biological barriers such as the gastrointestinal

(GI) tract. In such a way it is necessary for the carrier to

protect the drug against the hostile and degrading milieu

of the GI tract while increasing the residence time (e.g.

bioadhesion) and target specific cells to enhance absorp-

tion which will most likely require less frequency regi-

mens.

A number of drug delivery systems are currently under

investigation to circumvent the limitation commonly

found in conventional dosage forms and improve the

potential of the respective drug. On the other hand, there

has been a focus on the microenvironment of the cells

and their interaction with these new dosage forms [8]. As

a result, these new technologies have prompted the old

concept of the magic bullet proposed by Paul Ehrich’s

vision [1].

Recent Advances in Drug Delivery Systems511

2. Type of New Drug Carriers Systems

Microencapsulation has been important to the develop-

ment of new therapeutics and has been used to produce

microspheres containing both hydrophilic and hydropho-

bic drugs entrapped within biocompatible polymers [9].

The purpose of using these carriers is to obtain a con-

trolled release thus maintaining therapeutic drug levels

over a specified time period while reducing systemic

abso rpt ion [9]. These systems have been used in food and

cosmetic industry [4] and drug [10] and gene delivery [11].

Microparticles are a generic term to mention micro-

capsules and microspheres which can be made of poly-

mers or lipids (liposomes) with sizes ranging from 1 to

250 µm (ideally <125 µm and exceptionally 1000 µm)

[12,13]. This technology is very important in drug deliv-

ery. Reduced doses due to higher absorption and pro-

longed absorption time by using adhesion properties of

microparticles have been envisioned [14]. On the other

hand, good in vitro/in vivo correlations have been ob-

served [14]. Biodegradable microparticles are easily

cleared by physiological systems thus avoiding the pos-

sible cytotoxicity caused by accumulation in cells and

tissues. Active substances may be either adsorbed at the

surface of the polymer or encapsulated within the particle.

Furthermore, controlled release can be achieved by pH-

sensitive (especially useful in intravenous delivery) and/

or thermo-sensitive microparticles. Microparticles have

been used to encapsulate several peptides (e.g. calcitonin

and insulin), anesthetics, anti-viral drugs, hypertension

and anticancer drugs [12,14], among others. There are

several methods for the preparation of microparticles

including the polymerization of synthetic monomers and

synthesis from preformed polymers [14].

However, sub-micron size particles have shown to of-

fer marked advantages over microparticles [15,16]. For

example PLGA micro- and nanoparticles were compared

for their uptake in caco-2 cells and revealed a higher up-

take from nanoparticles (41% vs. 15%) [17]. Moreover,

targeting to specific tissues such as inflamed and can-

cerous tissues may be limited on ly to nanoparticles [18].

2.1. Microsponges

Microsponges are biologically porous inert particles that

are made of synthetic poly mers with the capacity to store

a volume of an active agent up to their own weight [19].

They can protect the drug from the environment and pro-

vide a controlled release. Market products are available

such as Retin-A micro® for acne vulgaris and Carac®

containing fluorouracil for actinic keratosis treatments.

2.2. Nanotechnology

The use of nanotechnology for drug delivery rapidly

produced commercially available products and the term

nanomedicine emerged. Nanomedicine is the application

of nanometer scale materials in an innovative way to

develop new approaches and therapies. At this scale,

materials display different physicochemical properties

due to their small size, surface structure and high surface

area [2]. These properties allow nanoparticulate systems

to overcome current limitatio ns of conventional formula-

tion as they facilitate the intracellular uptake to specific

cellular targets. Thus, nanotechnology has been adopted

in several fields such as drug/gene delivery [20,21], im-

aging [22] and diag no st i cs [23 ] .

2.3. Immunoconjugates

Antibody drug-conjugates or immunoconjugates are re-

combinant antibodies covalently bound through a linker

to a drug [24]. The idea behind this technology is to tar-

get potent drugs to th e specific site by using the specific-

ity of monoclonal antibodies (mAb) thus avoiding non-

targeted organs toxicity [24,25]. These immunoconju-

gates can be used across a wide spectrum of diseases by

selecting the appropriate molecular domains [26]. How-

ever, initial works showed some limitations such as shor t

half-lives, immunogenicity or even lack of efficient in-

teraction [25,26]. To avoid this limitation strategies such

as PEGylation, conjugation with proteins such as albu-

min or the use of chimeric humanized and fully human

mAbs has been envisioned [26]. As a result, the first ap-

proved immunoconjugate (Mylotarg, gemtuzumab ozo-

gamicin) was used for the treatment of acute myeloid

leukemia [25]. Several other immunoconjugates are on

the pipeline and in ongoing phase 3 clin ical trials such as

Naptumomab estafenatox for the treatment of advanced

renal disease or Brentuximab vedotin for the treatment of

Hodgkin lymphoma [27]. On the other hand, new strate-

gies have been developed to use antibodies attached on

nanoparticles and liposomes (so called immunonanopar-

ticles and immunoliposomes, respectively) [22,28,29].

These systems can be applied to encapsulate multiple

drugs while protecting from the external environment

and exert a controlled release. Moreover, they can target

hard-to-target tissues such as blood-brain barrier (BBB)

by targeting transferrin, insulin or glutathione receptors,

triggering their activation and consequent internalization

[20,29].

2.4. Virus

Viruses are potential vehicles for drug and gene therapies

due to their natural ability to infect specific cells and

transport genomic material to the nucleus [30-32]. Using

recombinant virus can improve transfection efficiency

[31] while evading degradation by lysosomes [32] thus

enhancing drug delivery. The main difficulties involve

Recent Advances in Drug Delivery Systems

512

creating viral vectors lacking replication machinery

while maintaining the ability to infect mammalian cells

[32]. Various viruses have been tested and the most

common used are lentivirus, retrovirus and adenovirus

[21,32]. However, the use of viruses raises concerns re-

lated to their safety due to the risk of insertional mistakes

and activation of proto-oncogenes, viral replication and

strong immune responses [30]. Moreover, retroviruses

have size loading limitation as they can only infect di-

viding cells therefore they are most used for ex vivo de-

livery. Lentivirus on the other hand can deliver gene into

nondividing cells as well as adenovirus (the virus re-

mains extrachromosomal which reduces the chances of

disrupting cellular genome) [30]. These systems are most

likely to be applied in cytotoxic gene therapy [30,33]. In

contrast to these, nonviral vectors such as liposomes (vi-

rosomes) and nanoparticles have rapidly increased due to

their low immune response and ease of synthesis [34].

However, limitation of inefficient transfer and low gene

expression have been reported and have to be overcome

[31].

somes are liposomes with increased flexibility due to the

addition of ethanol and surfactants, respectively [3,40,

41]. Niosomes are a non-ionic surfactant vesicles made

up from polyoxyethylene alkyl ethers, polyoxyethylene

alkyl esters or saccharose diesters [3]. These systems are

specially designed for skin delivery (ethanol is a known

permeability enhancer) due to their facilitated fu sion and

malleability (transferosomes are ultradeformable) with

membranes and have shown that they can be modulated

from superficial skin (e.g. treatment of Herpes virus) to

full dermal penetration (e.g. required for transdermal

delivery of insulin) [40,41] overcoming limitation com-

monly found in liposomes [41]. The other type of lipo-

somes are classified as virosomes which are liposomes

carrying viral proteins removed from virus on their sur-

face. This strategy has been proposed to immunization

[34] and can be administered via mucosal (nasal, vaginal,

etc.), intradermal and intramuscular routes. Those sys-

tems can incorporate a variety of molecules and can be

designed to imp rove th e up tak e by dend ritic cells th rough

different receptor-mediated routes [31]. Furthermore,

cochleates are stable particles (more than other lipidic

structures) derived from liposomes composed mainly of

charged phosphatidylserine in the presence of divalent

counter ion such as Ca2+ which forms a continuous large

lipid bilayer sheet with no internal aqueous space [35,42,

43]. Cochleate delivery has shown potential use for am-

photericin B, factor VIII delivery, proteins, peptides and

DNA [43,44]. Finally, there are cubosomes. Because of

their multilayer structure of continuous lipid bilayer cu-

bosomes are similar to cochleates but they are considered

as novel lipid delivery systems. They have self-assembly

cubic-like appearance, are biocompatible and show bio-

adhesive properties ideal for oral administration [45,46].

Example, the oral administration of cubosomes loaded

with insulin resu lted in a hypo glycemic effect in rats [47].

More recently, the problems associated with the use of

ultrasound in liposomes was overcome and a new kind of

liposomes named eLiposomes were produced [6]. The

eLiposome can be used as drug carriers which can be

induced to vaporize and cavitate when exposed to ultra-

sound being useful in several applications such as in

cancer therapy [6]. A variety of commercially available

products constituted from liposomes are available such as

Pevaryl® containing econazole which have been used to

treat dermatomycosis, Diclac® for therapy of osteoarthri-

tis and Daylong® containing UV filters for patients with

high risk of actinic keratosis.

2.5. Vesicular Systems

2.5.1. Liposomes, Transferosomes, Ethosomes,

Niosomes, Virosomes, Cochleate, Cuboso mes

These are phospholipid based vehicles composed of a

bilayer membrane that can be divided into small unila-

mellar vesicles (or SUV from 20 nm to 100 nm), large

unilamellar vesicles (LUV from 100 to 500 nm) and

multilamellar vesicles (MVL exceeding 500 nm) [3].

These systems have the ability to encapsulate both lipo-

philic drugs within their membrane and hydrophilic

drugs inside or outside the aqueous core and the mem-

brane of these carriers can be altered and tuned [6]. Li-

posomes which are most commonly produced with phos-

phatidylcholine show great compatibility, ease of prepa-

ration, wide range of drug compatibilities, increased so-

lubility of drugs (e.g. cycloporin A [35]), tuned pharma-

cokinetic profile and improved oral absorption. Com-

monly, they present difficulties when orally delivered

due to the poor stability o f the vesicles under the physio-

logical conditions typically found in the GI tract [4,35,

36]. Liposomes can also act as a drug depot injected

subcutaneously and intact vesicles were found after 96h.

However, liposomes are metastable systems and their

pharmaceutical use may be limited due to content leak-

age with poor controlled release, low encapsulation effi-

ciency and loading. Moreover, weak chemical and phy-

sical protection of sensitive drugs, aggregation into large

particles and hydrolysis with formation of oxidation

products with difficulties in industrial scale production

and stability problems during storage have been also de-

scribed [3,37-39]. As a result, ethosomes and transfero-

2.5.2. Solid Lipid Nanoparticles (SLN) and

Nanostructure Lipid Carriers (NLC)

Solid lipid nanoparticles (SLN) are made up from lipids,

solid at room and body temperature, such as glycerol

Recent Advances in Drug Delivery Systems513

behenate, glycerol palmitostearate, lecithin, triglycerides

and tristearin glyceride [4,35]. Contrary to liposomes,

SLN have shown to be stable for a long period, protect

labile compounds from chemical degradation and can be

processed up to large-scale production. However, they

still present problems related to their loading efficiency

due to the formation of a lipid crystal matrix and possib le

changes of the physical state of the lipids [3,35,39]. To

overcome this limitation, a novel structure composed of a

mixture of lipids solid and fluid at room temperature

(semi-liquid formulations) named nanostructured lipid

carriers (NLC) were produced [3]. This system shows

high encapsulation efficiency and loading capacity due to

the formation of less ordered lipid matrix, and th ey show

long term stability with a controlled release and without

burst effect. These colloidal carriers have emerged as a

potential alternative to other recent colloidal systems like

polymeric nanoparticles [35].

2.6. Microemulsions and Nanoemulsions

Micro- and nanoemulsions are isotropic mixtures of oil/

water stabilized by surfactants frequently in combination

with co-surfactants [3,4,41]. They have shown high solu-

bilization and dissolution properties, thermodynamic sta-

bility and the stabilizers prevent particle agglomeration

and/or drug leakage. Thus, they have improved permea-

tion enhancement ideal for transdermal delivery as they

act in synergy [41]. Microemulsions may work by en-

hanced disruption of skin-lipid structure or by improving

the stability of the drug in the formulation.

2.7. Cyclodextrins

Cyclodextrins are cyclic oligosaccharides containing at

least 6 D-(+)-glucopyranose units attached by α-1,4-

linkage. Three types of cyclodextrins are found in the

nature named α (6 units), β (7 units) and γ-cyclodextrins

(8 units). β-Cyclodextrin is ideal for drug delivery due to

the cavity size, efficiency drug complexation and loading,

availability and relatively low cost [41,48]. They can

prevent the drug degradation, improve the drug stability

and solubility resulting on an higher bioavailability [4,

48]. An example of cyclodextrins in drug delivery system

is the derivate 2-hydroxylpropyl (HPβCD) which is a

powerful solubilizer and has a hydrophilic outside and

hydrophobic inside [48]. For absorption in the GI tract,

the complexes must contact with the surface thus pro-

moting dissociation and drug permeation across the

membrane [41]. Moreover, cyclodextrins can work syn-

ergistically as permeation enhancers to improve their ab-

sorption across th e skin.

2.8. Metal Nanoparticles and Quantum Dots

Inorganic nanoparticles have emerged a few years ago as

drug and gene delivery systems, imaging agents and di-

agnostic biosensors [22,49]. Magnetic drug targeting

(such as the use of iron) is characterized by conjugating a

magnetic material under the action of the external mag-

netic field, which can accumulate in target tissue areas

under the action of the external magnetic field [4,23,50].

However, magnetic particles alone are not suited for drug

vehicles because of limitations in the controlled release.

A mixed composition of a magnetic nucleus and a poly-

meric shell could take advantage of the two components

[50].

Quantum dots are colloidal cores surrounded by one or

more surface coatings that reduce leaching of metals

from the core. These nanoparticles are of extreme im-

portance for diagnosis.

Furthermore, titanium dioxide and zinc oxide demon-

strate the potential of nanoparticles to improve therapeu-

tic/prevention performance being particularly useful as

sunscreen agents [51]. The micronization of these com-

pounds to nanometer range removes the opacity charac-

teristic associated with them and increases the UV pro-

tection [51,52].

Finally, gold nanoparticles have shown a selective

transportation of drugs to cancer cell nucleus specially

when incorporated with conjugated arginine-glycine-

aspartic acid peptide (RGD) and PEG [53]. When reach-

ing the tumor cells, they can induce hyperthermia using

non-invasive r a di o frequency.

2.9. Polymers

2.9.1. Dendrimers

Dendrimers are tree-like branched synthetic polymer

macromolecular nanoparticles in a dendron-like structure

which can be designed to target specific structures [54].

They have a remarkable well-defined control over size

(comparable size to proteins) with narrow polydispersity

[54-56]. In addition, they have a large surface fun ctional-

ity providing a wide range of applications such as drug

[57] and gene delivery [58], biological adhesives [59],

imaging agents (e.g. MRI) [56]. Thus, they can be used

for oral, transdermal, ocular and intravenous deliveries

[60,61]. Moreover, dendrimers have shown that they can

easily cross cell barriers by both paracellular and tran-

scellular pathways [56]. Dendrimers can be structurally

modified. This modification can be made to the nature of

the core and the scaffold giving polyfunction capacity to

the dendritic structure. This can be copulated to an anti-

body and its production can be through divergent and

convergent routes or other techniques such as self-as-

sembling synthesis, lego chemistry and click chemisty

[54,57]. Their size, molecular weight and number of sur-

face functional groups can be modulated through the

increase in generation number ( 1 nm per generation) [56,

Recent Advances in Drug Delivery Systems

514

57]. In general, dendrimers are terminated with amine

surface groups (G1, G2, G..) but can also be terminated

with carboxylate (G1.5, G2.5, G..) [62]. Moreover, the

interior is characterized by the availability of a wide

amount of solvent-filled void space that can accommo-

date the drug [56]. Additionally, dendrimers are non-im-

munogenic and are small enough to escape the vascula-

ture and target tumor cells. Their size can be tailored to

be below the threshold for renal filtration [55]. There are

several systems available such as poly(amidoamine)—

PAMAM, poly(etherhydroxylamine)-PEHAM and poly

(propyleneneimine)—PPI, and phosphorous containing

dendrimers [56]. PAMAM is the most used dendrimer

due to the fact that it provides a large range of reactive

sites for the conjugation for drug or other chemical moi-

ety complexation [55,57]. Dendrimers provide a high

loading capacity with controlled release which can be

modulated to actively release the agent by pH-triggering

cleavage. The rate of drug release from the matrix is in-

fluenced by the nature of the linking bond or spacer be-

tween the drug and scaffold and the targeted physiologi-

cal domain for intended release. The surface ligands can

also control the release from the dendrimers such as in-

creased steric hindrance of mannose and folate.

A novel concept that enables simultaneous release of

all functional groups by a single stimulus has been re-

ported which has been named cascade-release dendri-

mers (or dendrimer disassembly or self-immolative den-

drimers). However, this system raises concerns about

drug release at the wrong time and place which can raise

toxicity profiles [56]. Several dendrimer-based diagnos-

tic and/or in vitro technologies are already in the market

such as Stratus CS which is a dendrimer-coupled anti-

body reagents [63], Superfect (activated dendrimer tech-

nology for DNA transfection into a broad range of cell

lines) [64] and PriofectTM which is a transfection reagent

[65]. Priostar™ and STARBURST® have also been de-

signed to be used as targeted diagnostic and therapeutic

delivery systems for a wide variety of drugs to cancer

cells and other diseases [66,67]. As well, Vivagel® is a

microbicide for prevention of HIV and HSV and it is

based on dendrimers [68].

2.9.2. Natural and Synthetic Polymeric Nanoparticles

Drug/gene encapsulation can be achieved by embedding

into the matrix or ab sorbed onto th e surface of nanoparti-

cles homogenously dispersed or not. As for the micro-

particles, the term nanoparticles is a collective name for

both nanospheres and nanocapsules [16]. Nanoparticles

are solid carriers that can be either made up of natural or

synthetic polymers and whether or not biodegradable

[16]. Nanoparticles have received more attention than

have liposomes because of their therapeutic potential and

greater stability in biological fluids as well as during

storage [69]. Nanoparticles are advantageous in many

ways since they use the unique micro-anatomy of the

inflamed tissue blood capillaries, which have gaps be-

tween the lining of endothelial cells causing vessel

leakiness. Moreover, they show high encapsulation effi-

ciency and protection of instable drugs against degrada-

tion of the external environment in comparison to lipo-

somes [3,70].

Several methods have been described and nanoparti-

cles can be obtained by polymerization of a monomer or

from pre-formed polymers [16] but recent methods make

use of safe solvents with industrial applicatio n.

The nanoparticles properties can be tailored by using

different polymers and co-polymers or proteins. The new

strategies use new biodegradable synthetic polymers and

modified polymers from natural products such as chito-

san and albumin. Chitosan has been shown to be rela-

tively safe and is used as a food additive. Moreover, chi-

tosan is widely used due to its biocompatibility, muco-

adhesiveness and permeability enhancing properties [35,

71,72] and its derivates have shown improved character-

istics. Albumin is a natural carrier of hydrophobic mole-

cules such as fatty acids, hormones and fat-soluble vita-

mins. Albumin has been extensively used as it is non-

toxic and non-immunogenic.

However, natural polymers raise concerns in purity

and stability and thus synthetic polymers have been ap-

plied. Synthetic polymers from the ester family such as

poly(lactic acid) (PLA), poly(cyanoacrylates) (PACA),

poly(acrylic acid), poly(anhydrides), poly(amides), poly

(ortho esters), poly(ethylene glycol), and poly(vinyl al-

cohol) (PVA) and other like poly(isobutylcynoacrylate)

(PIBCA), poly(ethylene oxide) (PEO), poly(ε-caprolac-

tone) (PCL) are suitable for drug delivery due to their

biodegradability. They can be conjugated between them

to form different structures with different properties such

as controlled release profiles and strong cell biocompati-

bility. In fact, PLGA, another synthetic polymer, has

been extensively used in medical applications such as

suture materials [73] and bone fixation nails and screws

[74] as well as in diverse drug delivery applications [20,

75,76]. It is biocompatible and biodegradable forming

compatible moieties of lactic acid and glycolic acid

which are further removed by the citric acid cycle [2]. As

this process is slow it does not affect normal cell function

[2,71].

Recently, poly(β-amino ester) (PbAE) has emerged in

the spotlight because it demonstrates a pH sensitive re-

lease [7,77,78] in which at acid pH it rapidly releases its

contents. This polymer has shown to be less toxic than

other cationic polymers such as poly(ethyleneimine) and

poly(L-lysine) (PLL) [78]. PbAE are insoluble at phy-

Recent Advances in Drug Delivery Systems515

siological pH but become instantly soluble in aqueous

media when the pH of th e solution is reduced below 6.5.

These agents are useful for therapeutics in the vicinity of

tumor mass [77,78] and for others they must escape en-

dosomal compartmentalization prior to fusion with ly-

sosomes [78].

3. General Mechanisms Consideration

3.1. Surface Functionalization, Controlled

Release and Tissue-Targeting Design

A number of methods have been investigated to target

drugs to a specific site of interest either by passive (in-

creased accumulation due to passive physiological fac-

tors) or active diffusion (use of ligan ds to specific target)

[6].

Surface modification of drug carriers with bioactive

molecules that can be adsorbed, coated, conjugated or

linked to them which interact with cell receptors demon-

strate a selective affinity for a specific cell or tissue type

and can subsequently enhance drug uptake (Figure 1). The

modified-coating (e.g. combined albumin and chitosan)

can also be used to prevent enzymatic degradation both

on the GI tract and plasma [72]. Monoclonal antibodies

(or fragments) or non-antibody ligands like carbohy-

drates specific for cell surface such as lectins have been

investigated [79]. Also, most recently small molecules or

peptides agonists/substracts or antagonists/inhibitors for

receptors that are overexpressed on cell surface of spe-

cific tissue (e.g. folate, transferrin as well as galactosa-

mine) have shown promising results [6,54,79,80]. Sev-

eral considerations have to be taken as the use of target-

ing ligands which can enhance distribution to secondary

target sites of non-intended tissues [54]. In fact, the dis-

advantage of using non-antibody ligands is their non-

selective expression [79]. On the other hand, immuno-

conjugates poses problems related to immunogenicity

and retention in the reti culoendothelial system (RES) [55] .

The carrier surface modification can also incorporate

coatings to chan ge the lipophilicity/hydrophilicit y profile,

prevent the uptake by immune cells and improve cell

recognition (e.g. the synergy between the distribution and

signaling of antibodies). As a result, per example, once

IV injection occurs, nanoparticles are cleared from the

plasma within a few minutes due to opsonization and

subsequent phagocytosis by the cells of the RES [81].

Opsonization can be reduced by applying some surface

ligands. An example is PEG, a hydrophilic polymer,

which promotes the resistance to the binding of plasma

proteins and prevents aggregation induced by salts and

proteins in the serum [21]. This fact prevents opsoniza-

tion and recognition from phagocytes and thus avoiding

immune responses. Moreover, PEG can also reduce the

access of enzymes to dendrimers scaffold and can there-

fore reduce their degradation [54]. In fact, in vivo nano-

particles and liposomes coated with PEG increase circu-

lation time from several minutes to many hours and en-

hance residence times up to 200-fold in humans [82-84].

On the other hand, the effectiveness of PEG depends on

surface density, chain length [85] and ability to avoid the

liver uptake. However, PEG carriers are intended for in-

tracellular penetration and sometimes PEG prevents nor-

mal interactions of the carrier with cells. Also,

PE-Gylated nanocarrier systems have shown to induce an

immune response, known as the accelerated blood clear-

ance (ABC phenomenon) after repeated injection with

subsequent increased accumulation on the liver and

spleen [86].

Thus, new strategies have been pursued such as re-

placing PEG with polyamino acid polyhydroxyethyl-L-

aspargine (PHEA). This strategy demonstrated favorably

long circulation times and reduced ABC phenomenon

compared to PEG [86]. Moreover, using a hydrazone-

cholesteryl hemisuccinate linkage to the PEG which

could be cleaved by esterases showed pH-response at pH

5.5 (with a t1/2 of 6.7 h) and was stable at physiological

pH (with a t1/2 of 40.9 h) and thus can be used for tumor

targeting [86]. Additionally, PEO (poly(ethylene glycol)

and its derivates also promote stealth shielding and pro-

longed circulation [7,78,87] and have been extensively

used as biomaterials due to excellent biocompatibility

and low toxicity [78]. PLA and PLGA have also demon-

strated some stealth shielding [16]. All these syste ms can

also be used as prom o t ers of GI absorption [88] .

Another key factor to improve the carrier targeting is

the surface charge (zeta potential). This determines the

interaction with plasma proteins, cell membranes and

surface, thus ultimately affecting clearance and distribu-

tion patterns [54,79,89]. For instance, cationic surfaces

(obtained per example by chitosan coating) demonstrate

a strong interaction with cell membranes and surfaces

due to their overall anionic charge [54]. However, PLGA

nanoparticles are slightly negative at the surface and this

tends to limit their interaction with both negatively

charged plasmids and their intracellular uptake [71].

After reaching the cell, the drug release can be made

from two different mechanisms including release from

the carrier as well as absorption from the cell and the

carrier can be taken into the cell and slowly release its

contents [79]. Nanoparticles are absorbed by different

mechanisms but endocytosis is the most significant con-

tributor to cell entry [54,90]. Caveolae-mediated endo-

cytosis is thought to be the primary uptake mechanism

for particles above 200 nm [90] but also lipid raft-asso-

ciated receptors [90], actin and clathrin, microtubules,

and cholesterol-dependent process might be implied in

Recent Advances in Drug Delivery Systems

516

the nanoparticle uptake mechanisms [54,90]. The surface

charge is a key factor as anionic dendrimers were endo-

cytosed by clathrin dependent processes (with promotion

of tight junction opening) but were independent of cave-

olin-mediated endocytosis.

Earlier research on internalization of PAMAM den-

drimers showed that the interaction was mediated by

electrostatic interaction between the cationic primary

amine surface groups and the negatively charged pro-

teoglycans displayed on the surface of mammalian cells

which trigger macropinocytosis and clathrin-mediated

endocytosis [57].

When considering this uptake by cells, they have to be

designed to avoid the acidic environment of lysosomes

which are the common degradation pathway of nanopar-

ticles inside the cell [90]. Moreover, once dendrimers

saturated the lysosomal pathway, they were eventually

found in endosomes [54]. Recent advances taking ad-

vantages of the microenvironment of the cell have been

investigated and new carriers can reach the nucleus (gene

therapy) or other organelles involved in the disease state

leading to a direct release of the loading drug in consid-

erable concentrations at the specific site [90].

Another approach is the use of an external stimulus to

increase cellular ability for drug uptake such as ultra-

sounds to temporarily increase the junctions between

cells. Here eLiposomes may find a potential use [6]. Pas-

sive targeting refers to the increased accumulation of

drug or drug-carrier at a particular site due to passive

physiological factors. For cancer therapy, this typically

includes taking advantage of enhanced permeability and

retention (EPR) [6].

On the other hand, a major problem associated with

the new drug carriers is their release profile because

these can be associated with burst releases [91]. While

burst releases are useful in dermal and systemic delivery,

they may lead to a significant and unpredictable toxicity

especially for potent drugs and treatments of chronic

diseases. Several strategies have been proposed and con-

trolled release can be achieved by bi-association of lipo-

somes encapsulated inside a polymeric particle [92] as

well as chitosan associated with alginate which demon-

strate a controlled release and prevention of burst release

[93]. Similar strategies can be achieved by using mi-

croparticles containing nanoparticles [91]. Also changing

some technological features such as production method

[91] and use of surfactant can promote different control

release [91].

Other technological features include deficient hetero-

geneous drug distribution (e.g. surface-associated drug),

temperature of solvent removal, the physicochemical

nature of the polymeric matrix (use of non water soluble

polymers to avoid water uptake), porosity and recovery

method as well as the concentration of drug incorporated

[94-97], among others.

3.2. Combined Therapy by Simultaneously

Encapsulated Drugs

These are systems that have the potential to deliver more

than one drug at once. For example, PLGA nanoparticles

were simultaneously loaded with vincristine sulfate and

verapamil hydrochloride to deliver the effective chemo-

therapeutic agents while inhibiting P-gP efflux system.

This system allows overcoming tumor lack of sensitivity

and increases therapeutic index. As a result, the same

strategy was planned for delivery of doxorubicin and

cyclosporine A [98,99]. However, recent studies suggest

that PLGA-PEG interact with P-gP [20] and this could

improve the efficacy of this system. The design of these

types of systems has to take into consideration the char-

acteristics of the drugs to be encapsulated. Example, hy-

drophobic drugs are more likely to be encapsulated in

hydrophobic polymers and vice-versa [95]. To overcome

this limitation, synthesis of new polymers such as (PLA-

PEG-PLA)n or PCL-PEG can be produced [95] and reti-

noic acid (hydrophobic) and calf thymus DNA (hydro-

Figure 1. Different possibilities for nanoparticles specific targeting. In the left nanoparticle functionalized with: (A) protective

polymer with targeting ligand/probe copulated; (B) Antibody; (C) Enzyme; (D) Complexation with DNA; (E) protective

polymer; (F) ligand; In the right: nanoparticles can either release their content after cell internalization or near the cell after

argeting a specific receptor. t

Recent Advances in Drug Delivery Systems517

philic) were both encapsulated in this system with satis-

factory loading [95]. Another strategy is to have two dif-

ferent release rates of the two drugs to improve treat-

ments (such as cancer treatment). In fact, a paclitaxel and

a C6-ceramide were encapsulated in a controlled blend

polymer of PLGA-PbAE to effectively overcome the

cancer drug resistance mechanisms [7].

3.3. Carrier Distribution

As stated above the RES mainly in the liver and spleen

are the major obstacles to carrier systems due to their

ability to internalization and removal from systemic cir-

culation [16]. In fact, after IV administration of PLGA

nanoparticles, the majority were found in the liv er (about

40%) followed by kidney (26%), heart (12%) and brain

(13%) and only a small amount was found in the plasma

[2]. Similar results were obtained with PLGA-PbAE [7].

The route of administration is also important for the

distribution pattern as after IP injection for all types of

charged particles due to lymphatic clearance [49]. More-

over, lipophilicity of carriers influence the uptake from

cells and as a result more hydrophilic particles may be

rapidly eliminated [16].

The medium pH modulates surface charge thus chang-

ing cellular uptake and subsequently the distribution of

the carrier through the system [71]. The nanoparticles

charge surface and route of administration were further

explored by using 10 nm Gold nanoparticles functional-

ized with different groups aiming different zeta potential

(neutral, negative, positive and zwittteronic) by IV and

IP administrations. Following IV injection, a 10 fold

lower peak plasma concentration was observed with

positive charged particles and clearance within 15 min-

utes was more pronounced for negative and positively

charged particles [49]. On the other hand, after IP injec-

tion low concentrations of both negative and positive

charged particles were found [49]. These results evidence

that neutral and zwitteronic nanop articles show enhanced

circulation. These marked differences in bioavailability

could be primarily due to opsonization of the nanoparti-

cles with antibodies for recognition by resident macro-

phages [49] and the same effect was observed in den-

drimers [54].

Nanocarriers can be modulated to deliver drugs to

specific tissues and organs. Branching size of dendrimers

can be modulated to determine their distribution and

elimination throughout the body. Thus, they can avoid

renal clearance with a cut-o ff of 40 - 60 kDa which is ap -

proximately the G7 [54,56]. From G1 to G5 the den-

drimers are rapidly cleared to the kidneys/bladder and

from G3 - G7 they are mainly seen in circulation while

G8 are found in the lymph node and, finally, superior to

G9 are found in the liver [56].

As stated previously, PEG influences the distribution

of the carrier in the body. In general, as the molecular

weight of the PEGylated dendrimers increases, uptake

from the injection site into the lymph becomes a more

important contributor to the overall absorption profile,

revealing potential drug delivery systems as well as

improved lymphatic system imaging agents [54].

4. Pharmaceutical Applications

4.1. Brain Delivery

The blood brain barrier (BBB) is an extraordinary gate-

keeper toward exogenou s substan ces be ing estimated that

98% of all drug never reach the brain in therapeutic con-

centrations [23]. There have been several experimental

strategies to address these problems and enhance brain

bioavailability of existing therapeutics into the CNS

[100]. These included injecting drugs directly into the

brain or CSF (intraparenchymal or intracerebral admini-

stration), various implants or convection-enhanced de-

livery, slow-release devices, transient disruption of the

BBB such as MRI-guided focused ultrasound and che-

mical or osmotic modulation of tight junctions—with the

use of hyperosmotic solutions of saccharides (e.g. man-

nitol) or vasoactive compounds (e.g. RMP-7) [84,101].

Overall, the idea of using an appropriate drug carrier

to delivery across the BBB is reinforced. Nanovectoring

with tissue-specific targets is an ideal pathway since it

delivers both hydro-and lipophilic drugs, as well as mac-

romolecules such as peptides and genes through a con-

trolled release profile over an extended period of time [5,

81,102]. Since nanoparticles are small in size, they easily

penetrate into small capillaries and through the physical

restrictions presented by the brain interstitial space.

Consequently, they can be transported within cells, al-

lowing an efficient drug accumulation at targeted sites in

the body [81,102]. However, nanoparticles cannot freely

diffuse through the BBB and require receptor-mediated

transporters [103]. Hence, the use of the specific peptid es

for targeting the receptor-mediated transcytosis across

BBB can be a successful strategy for improving drug

delivery to the brain [5]. In this way, promising results

have been achieved by directly delivering drugs to the

brain interstitium through the design of polymer-based

drug delivery systems [102,104].

Different approaches have been pursued and in recent

researches using the combination of two techniques such

as improvement of target-specificity and bioavailability

[5,101]. Antibodies for different receptors, chimeric pep-

tides fused molecules [101], pro-drugs resembling the

natural ligands, viral vectors [105] and nanoparticles are

the most common techniques [5,103].

In nanoparticle field, dalargin or loperamide-loaded

Recent Advances in Drug Delivery Systems

518

PBCA nanoparticles coated with polysorbate 80 showed

a pronounced analgesic effect in comparison with that of

free drug [106]. Several mechanisms were proposed and

endocytosis and transcytosis mediated by carriers were

evidenced, as nanoparticles were overcoated with Apo-A,

B, C, E or J. The effect was only achieved when ApoB or

E were in the coating surface. In this study, polysorbates

(and also poloxamers) can act as an anchor for several

Apo which are then able to interact with the LRP recap-

tor, before being taken up by the microvessel endothelial

cells via receptor-mediated endocytosis [80,85,107,108].

Another approach to LRP receptor is by the use of a

series of peptides called “angiopep” at the surface of

nanoparticles which have shown specific targeting of the

LRP [109,110]. The most used is angiopep-2 as it shows

enhanced transcytosis across the brain and it has been

effective against glioblastoma [109,111].

Other receptors that have been proposed to targeting

are insulin, albumin, transferrin, lactoferrin [110] and

more recently, the glutathione receptor [20]. In the last

case, liposomes were coated with glutathione-conjugated

PEG (G-Technology®) and they successfully delivered

free drug (doxorubicin or ribavirin) [83,101]. For all the

reasons stated, in 2010, EMA granted an orphan designa-

tion (EU/3/10/781) for the GSH-PEG liposomal doxoru-

bicin hydrochloride for the treatment of glioma [112].

4.2. Mucosal Drug Delivery

The oral route is the most desirable route for the admini-

stration of drugs as it is simple and free from complica-

tions arising from more invasive methods. When design-

ing such formulation, several parameters have to be ac-

cessed as charges from the carrier system and content,

the solubility of the drug carrier, among others. Those

factors will ultimately alter their uptake from mucosal

membranes. Moreover, mucosal surfaces are typically

efficiently removing the drugs by mucus clearance me-

chanisms and the GI tract acts as a physiological and

chemical barrier posing several challenges. Also, the

drug can cause irritatio n and limit its use by this route.

To overcome these limitations, several methods have

been investigated and nanoparticles are also a useful tool

in mucosal delivery. It has been shown that they can

protect protein and peptide drugs from enzymatic degra-

dation and increase their low permeability across the

intestinal epithelium and circumvent efflux processes [54,

62,69,72,113]. Specifically, nanoparticles can be taken

up by increased residence time in the enterocytes [16], by

targeting to M cells [114,115] or by specific targeting

receptors at the surface. In this area, polymers play a

crucial function. Example, chitosan possesses marked

mucoadhesive properties to the mucosal surface and can

transiently open the tight junctions between mucosal

cells (an effect also observed for PAMAM dendrimers)

[62,99,113]. As a result, nanoparticles composed of chi-

tosan loaded with insulin have been able to enhance in-

testinal absorptio n in vivo [72,116].

Furthermore, oral vaccination has gained new insights

and several studies have been performed [117]. Oral im-

munization has been making use of live attenuated or-

ganisms [118] or the use of peptides [114] and recently

based on DNA vaccines [119]. However, there are still

limitations for effective oral immunization such as the

failure to swallow the vaccine, inactivation in the GI tract

or interference with gut flora [69]. Promising results have

been obtained and humoral and cellular in vivo respon ses

have been observed through the use of specific ligands

(e.g. RGD peptide) to target M cells [114,115]. In addi-

tion, immunization with carriers may be ideal when the

antigen of interest is not immunogenic enough. PbAE

microparticles on their own can activate dendritic cells

[77] acting as an immune-stimulating complex and as a

result, PLGA-PbAE microparticles were able to induce

antigen-specific rejection of transplanted synergetic tu-

mor cells.

Furthermore, nasal vaccination has been investigated

as a promising route for vaccination. PLGA blended with

different stabilizers [76] and cochleates [44] demon-

strated good in vivo vaccination, capable of overcoming

nasal cell membranes. As well, genetic vaccination has

the potential to treat and prevent several diseases for

which conventional vaccines are ineffective and limited

[77]. The use of a carrier to specifically target APC cells

may show promising advantages while protecting the

encapsulated genetic material [77].

Gene delivery to desired cells involves the concept of

delivery the gene for expression (e.g. production of pro-

teins that play a role in drug) or the use of siRNA (to

target a specific mRNA expression) [30,120]. The use of

carriers allows the entry of these genetic materials to the

cells that otherwise would be destroyed by enzymes and

due to their small size and high density are easier to

transfer into cells. As stated, viral vectors are effective

although raising certain concerns, but synthetic systems

have higher flexibility and safety profiles [30]. An ideal

gene delivery carrier would be a system that can safely

transport the genetic materials without exhibiting any

toxicity and immune responses as well as being able to be

produced on large scale [120]. Using virosomes, these can

be processed b y APC cel ls whic h ensure s present ation via

MHC I or II resulting in humoral and cellular responses

[34]. A commercially available product is Epaxal® [121]

which compared to conventional aluminum-adsorbed

hepatitis A vaccine, the virosome-based vaccine may

provide enhanced protection and cause fewer local ad-

verse effects [34]. Other products based on the same

Recent Advances in Drug Delivery Systems519

concept are PEVION’s virosomes for influenza virus

[122]. Using cationic modified particles (such as chitosan

and derivates such as mannosylated chitosan), genetic

material can bind and condense through electrostatic in-

teractions [123]. Recently, PEI polymer has been exten-

sively used both in vitro and in vivo. PEI is the most ef-

fective nonviral carrier with high transfection capacity

and ability to escape from endosomes [31,120,124]. In

fact, ExGen 500TM technology (linear PEI condensed

with genetic material) has been shown to interact with

cell surface proteoglycans resulting in internalization by

endosomes after which PEI acts as an effective proton

sponge buffer protecting the genetic material from ly-

sosomal degradation [32,124]. This proton sponge effect

is due to PEI primary and secondary amines that lead to

an influx of counter ions (chloride) that enhances os-

motic pressure and eventually burst the endocytic vesicle.

Other mechanism has been proposed in that PEI weak-

ened the endosome membrane thus preventing fusion

with lysosomes [124].

Another area of interest is the antibiotics and antiviral

therapy using those drug carrier systems. Again, nano-

carriers are ideal, as they can overcome the defense

mechanisms, can result in higher uptake to the site and

exert better results than the free drug. They may also be

suitable to target drugs where the free drug would not

permeate into (e.g. BBB). Anticancer drug using gold

nanoparticles have shown antibacterial and antifungal

activity against gram-negative bacteria [50]. Ampho-

tericin B PLGA nanoparticles, taken both orally and IV,

were more e ffective in re ducing the lun g burden i n murine

models of pulmonary and disseminated aspargilosis than

commercial available formulations [125]. AmBiso me® is

a liposomal preparation of amphotericin B that is admin-

istered by IV injection and has been effective in the

treatment of cryptococcal meningitis in HIV-infected

patients, Aspergillus Candida and/or Cryptococcus spe-

cies infections refractory to amphotericin B deoxycholate

[36]. Rece ntly, VivaGel ® by Starp harma Pty Ltd. has bee n

investigated as a vaginal m icrobicide for the prevention of

HIV and HSV infections [68,126] using dendrimer tech-

nology (SPL7013). The highly charged surface allows

SPOL7013 to attach to targets on viruses, blocking viral

attachment and/or adsorption to cells thereby preventing

infection. In the case of HIV, SPL7013 is though t to bind

gp120 proteins on the surface of the virus [126]. It has

been able to inhibit by <99% HIV infection of human

macrophages in vitro, and to protect Vero cells from

HSV-2 infection, and effectively to block vaginal trans-

mission of SHIV [126].

4.3. Pulmonary Drug Delivery

The pulmonary route requires a suitable design as the

deposition of the nanoparticles differs according to the

particle size [69]. On the other hand, the mucus may re-

strain the entry of nanoparticles. PSA-PEG nanoparticles

were able to penetrate and diffuse in sputum expectorate

from lungs of cystic fibrosis patients and this system

could be used to improve drug therapies in various mu-

cosal surfaces [88].

4.4. Skin Drug Delivery

Application to the skin desires two effects: transdermal

and topical effects. The transdermal delivery has gained a

significant importance fo r systemic treatment as it is able

to avoid first-pass metabolism and major fluctuations of

plasma levels typical of repeated oral administration.

SLN, due to an initial burst release followed by water

evaporation, proved to penetrate human and pig skin ex

vivo more rapidly and to a higher extent than conven-

tional dosage forms and a nanoemulsion [3]. The same

results were observed for SLN and NLC incorporating

red nile (4 fold enhancing). The rapid degradation of

those systems may promote contact with the skin and the

occlusion may promote drug uptake. Additionally, SLN

were able to induce epidermal drug targeting for pred-

nicarbate [127] and podophyllotoxin [128]. Other drug

carriers have been used in skin drug delivery. Example,

transfersomes with ketoprofen (Diractin®) [129] were

applied as a transdermal system in a multicentre, ran-

domized, double-blind trial and showed similar efficacy

in relief of knee osteoarthritis compared to celecoxib. In

addition, liposomes tend to fuse at the skin surface [3]

and marked changes can be induced in the horny layer

depending on the phospholipids used as intercellular

deposition can occur and destroy lipid membranes [3].

Antifungal drugs are of special interest and although

current formulations cure the majority of th e problems an

econazole liposome formulation in vitro has shown better

cure rates [3]. In general, percutaneous drug absorption

appears to be increased via association with dendrimers

due to their ability to interact with lipid bilayers in the

skin [54]. Moreover, targeting specific areas of the skin

can be tailored. As an example, OMC-coated PCL nano-

particles were found 3.4 fold greater in the stratum

corneum compared to an emulsion.

Finally, the role of skin appendages is sometimes ne-

glected due to the fact that they only represent 0.1% of

the skin surface [130]. It was found that microparticles

ranging from 3 - 10 µm selectively penetrate the follicu-

lar ducts, whereas particles larger than 10 µm remain

randomly distributed in the hair follicles and stratum

corneum [130]. Moreover, 5 µm PLGA microparticles

were visualized in the follicular ducts, while 1 µm was

randomly distributed into the stratum corneum and hair

follicles.

Recent Advances in Drug Delivery Systems

520

Recently, a new study performed a similar experiment

and 200 nm were able to aggregate and penetrate along

the follicular duct and this was the major penetration

pathway [131] displaying an increasing interest for a

potential vaccination therapy. On the other hand, 40 nm

nanoparticles were able to enter Langerhans cell in the

hair follicles while 750 and 1500 nm could not. The 40

nm nanoparticles were able to penetrate deep into the

hair follicle while 750 and 1500 nm aggregate in the in-

fundibulum of human hair follicles and could not target

the pilosebaceous unit [132]. Smaller molecules with a

ranging diameter between 7 and 20 nm were tested in

skin permeation and were found almost exclusively in

the hair follicle infundibulum and below. On the other

hand, polystyrene nanoparticles ranging from 20 to 200

nm were found in the follicle openings [133]. Further-

more, liposomes showed that they can target the pilose-

baceous unit rich in Langerhans cells and gained interest

in immunizations.

4.5. Cancer Delivery

Cancer delivery presents a challenging obstacle for every

dosage forms. Targeting cancer cells while avoiding

damage to other cells is the main endeavor of cancer

therapy. Major clinical obstacles raised to chemothera-

peutic agents are due to large body distributions, mul-

tidrug resistance mechanism (MDR), poor absorption,

increased metabolism and excretion while having poor

diffusion through the tumor mass which constitutes the

impaired delivery [7,89]. Herein, the concept of en-

hanced permeability and retention (EPR) in the solid

tumor [134] and the microenvironment of the tumor

(physiological drug resistance) [8] plays a vital role to

the enhancement of nanoparticles’ uptake.

PEG has been a key agent in long circulation of carri-

ers and has shown the ability to passively accumulate in

tumor tissue via EPR effect [7,8,49,54]. In addition, the

lower pH observed (pH 6.5) in some tumors create a pH

gradient that hinders the permeation of drugs and consti-

tutes one of the causes of chemotherapy failure. PbAE-

PEO, a pH sensitive polymer shows a 5.2 fold higher

concentration of Paclitaxel when compared to the aque-

ous solution [87]. Thus, it can be considered as an ideal

carrier to overcome the pH gradient barrier. Moreover,

using PLGA-PbAE nanoparticles with ceramide incur-

porating paclitaxel demonstrates higher accumulation

within the tumor [7].

Another way to achieve selectivity of tumor cells is by

using antibody-directed enzyme prodrug therapy (ADEPT).

This technique involves a two-step approach to cancer

therapy in which an immunoconjugate composed of a

mAb-enzyme is administered to be localized within the

tumor mass. Then, it is allowed to clear from the sys-

temic circulation over time and once the ratio of tumor/

non-tumor is sufficiently high a prodrug (anticancer

agent) is given (Figure 2). After reaching the tissue, it is

mostly converted in tumor cells and consequently exerts

local effects [25].

On the other hand, fenestration within the new vascu-

lature (angiogenesis) is observed exhibiting pores of 200

- 400 nm [7] or with an upper limit of 12 nm in the

blood-brain tumor barrier [135]. So, dendrimers nanopar-

ticles ranging between 7 - 10 nm were developed to de-

liver therapeutic concentrations across the tumor blood

brain barrier protecting from leakage to normal tissues

[135].

Using specific ligands is another approach to target

tumor cells and the high-affinity folate receptor, known

as the folate-binding protein, has been used as a target for

the delivery of a carrier containing folate at the surface to

target drugs to cancer tissue. The folate receptor is over-

expressed in breast, ovary, endometrium, kidney, lung,

head and neck, brain and myeloid cancers [55]. In vivo,

liposomes as well as PAMAM dendrimer conjugated

with folate acid have shown higher efficacy (10-fold) and

lower toxicity compared to those of free dr u g [55].

Other ligands have been used to target more specifi-

cally such as LHRH coupled carrier to deliver siRNA to

Figure 2. Antibody-directed enzyme prodrug therapy (ADEPT). Higher concentrations are found in cells overexpressing a

receptor. The antibody localizes the enzyme at the tumor mass and after the intake of a prodrug it will be converted near the

umor cells. t

Recent Advances in Drug Delivery Systems521

cancer cells [21] and N-acetylgalactosamine (NAcGal)

coupled to G5 dendrimers to hepatic cancer cells [57],

among others.

The use of drug carriers systems can also be used for

topical tumor cancer such as melanoma. Example, 5-

fluorouracil niosomes increased the penetration in the

stratum corneum by 8 fold. The cytotoxicity for the

melanoma increased resulting in more efficiency and less

irritancy than when incorporated to microsponges [3].

5. Concluding Remarks

As seen, the effort to produce these new drug carrier

systems is clearly high. Undoubtedly, those carriers pro-

vide the hope to treat and diagnose several diseases.

Several technologies have advanced into clinical studies

and are nowadays market products that have been shown

favorable results. It was also shown in this review that

these recent drug carriers are a promising set of tech-

nologies that already penetrated the cancer area and they

likely have a strong impact in this field in the future. In

fact, the rationale development of anticancer carriers will

provide new ways of treatment, circumventing current

limitations for conventional dosage forms. However,

there are some issues that need to be understood in order

to ensure their safety and effectiveness. Nevertheless, in

the future, new entities will become available and re-

sponsive and “clever” polymers will offer new perspec-

tives for the treatment of diseases.

REFERENCES

[1] R. Haag and F. Kratz, “Polymer Therapeutics: Concepts

and Applications,” Angewandte Chemie International

Edition, Vol. 45, No. 8, 2006, pp. 1198-1215.

doi:10.1002/anie.200502113

[2] B. Semete, L. Booysen, Y. Lemmer, L. Kalombo and L.

Katata, “In Vivo Evaluation of the Biodistribution and

Safety of PLGA Nanoparticles as Drug Delivery Sys-

tems,” Nanomedicine, Vol. 6, No. 5, 2010, pp. 662-671.

doi:10.1016/j.nano.2010.02.002

[3] H. C. Korting and M. Schafer-Korting, “Carriers in the

Topical Treatment of Skin Disease,” Handbook of Experi-

mental Pharmacology, Vol. No. 197, 2010, pp. 435-468.

[4] S. Wang, M. Tan, Z. Zhong, M. Chen and Y. Wang,

“Nanotechnologies for Curcumin: An Ancient Puzzler

Meets Modern Solutions,” Journal of Nanomaterials, Vol.

Vol. 2011, No. 2011, p. 8.

[5] A. V. Kabanov and E. V. Batrakova, “New Technologies

for Drug Delivery across the Blood Brain Barrier,” Cur-

rent Pharmaceutical Design, Vol. 10, No. 12, 2004, pp.

1355-1363. doi:10.2174/1381612043384826

[6] J. R. Lattin, D. M. Belnap and W. G. Pitt, “Formation of

Eliposomes as a Drug Delivery Vehicle,” Colloids and

Surfaces B: Biointerfaces, Vol. 89, 2011, pp. 93-100.

[7] L. E. van Vlerken, Z. Duan, S. R. Little, M. V. Seiden

and M. M. Amiji, “Biodistribution and Pharmacokinetic

Analysis of Paclitaxel and Ceramide Administered in

Multifunctional Polymer-Blend Nanoparticles in Drug

Resistant Breast Cancer Model,” Molecular Pharmaceu-

tics, Vol. 5, No. 4, 2008, pp. 516-526.

doi:10.1021/mp800030k

[8] R. Li, L. Xie, Z. Zhu, Q. Liu and Y. Hu, “Reversion of

pH-Induced Physiological Drug Resistance: A Novel

Function of Copolymeric Nanoparticles,” PLoS One, Vol.

6, No. 9, 2011, p. e24172.

doi:10.1371/journal.pone.0024172

[9] C. J. Thompson, D. Hansford, S. Higgins, C. Rostron and

G. A. Hutcheon, “Evaluation of Ibuprofen-Loaded Mi-

crospheres Prepared from Novel Copolyesters,” Interna-

tional Journal of Pharmaceutics, Vol. 329, No. 1-2, 2007,

pp. 53-61. doi:10.1016/j.ijpharm.2006.08.019

[10] S. Jhunjhunwala, G. Raimondi, A. W. Thomson and S. R.

Little, “Delivery of Rapamycin to Dendritic Cells Using

Degradable Microparticles,” Journal of Controlled Re-

lease, Vol. 133, No. 3, 2009, pp. 191-197.

doi:10.1016/j.jconrel.2008.10.011

[11] S. Lee, S. C. Yang, C. Y. Kao, R. H. Pierce and N.

Murthy, “Solid Polymeric Microparticles Enhance the

Delivery of siRNA to Macrophages in Vivo,” Nucleic Ac-

ids Research, Vol. 37, No. 22, 2009, p. e145.

doi:10.1093/nar/gkp758

[12] E. Allemann, J. Leroux and R. Gurny, “Polymeric Nano-

and Microparticles for the Oral Delivery of Peptides and

Peptidomimetics,” Advanced Drug Delivery Reviews, Vol.

34, No. 2-3, 1998, pp. 171-189.

doi:10.1016/S0169-409X(98)00039-8

[13] P. Couvreur and F. Puisieux, “Nano- and Microparticles

for the Delivery of Polypeptides and Proteins,” Advanced

Drug Delivery Reviews, Vol. 10, No. 1993, pp. 141-162.

[14] S. Freiberg and X. X. Zhu, “Polymer Microspheres for

Controlled Drug Release,” International Journal of

Pharmaceutics, Vol. 282, No. 1-2, 2004, pp. 1-18.

doi:10.1016/j.ijpharm.2004.04.013

[15] J. Panyam and V. Labhasetwar, “Biodegradable Nanopar-

ticles for Drug and Gene Delivery to Cells and Tissue,”

Advanced Drug Delivery Reviews, Vol. 55, No. 3, 2003,

pp. 329-347. doi:10.1016/S0169-409X(02)00228-4

[16] C. Pinto Reis, R. J. Neufeld, A. N. J. Ribeiro and F. Veiga,

“Nanoencapsulation I. Methods for Preparation of Drug-

Loaded Polymeric Nanoparticles,” Nanomedicine: Nano-

technology, Biology, and Medicine, Vol. 2, No. 1, 2006,

pp. 8-21. doi:10.1016/j.nano.2005.12.003

[17] M. P. Desai, V. Labhasetwar, E. Walter, R. J. Levy and G.

L. Amidon, “The Mechanism of Uptake of Biodegradable

Microparticles in Caco-2 Cells Is Size Dependent,” Phar-

maceutical Research, Vol. 14, No. 11, 1997, pp. 1568-

1573. doi:10.1023/A:1012126301290

[18] Y. Avnir, K. Turjeman, D. Tulchinsky, A. Sigal and P.

Kizelsztein, “Fabrication Principles and Their Contribu-

tion to the Superior in Vivo Therapeutic Efficacy of

Nano-Liposomes Remote Loaded with Glucocorticoids,”

PLoS One, Vol. 6, No. 10, 2011, p. e25721.

Recent Advances in Drug Delivery Systems

522

doi:10.1371/journal.pone.0025721

[19] M. Taglietti, C. N. Hawkins and J. Rao, “Novel Topical

Drug Delivery Systems and Their Potential Use in Acne

Vulgaris,” Skin Therapy Letter, Vol. 13, No. 5, 2008, pp.

6-8.

[20] W. Geldenhuys, T. Mbimba, T. Bui, K. Harrison and V.

Sutariya, “Brain-Targeted Delivery of Paclitaxel Using

Glutathione-Coated Nanoparticles for Brain Cancers,”

Journal of Drug Targeting, Vol. 19, No. 9, 2011, pp. 837-

845. doi:10.3109/1061186X.2011.589435

[21] O. Taratula, O. B. Garbuzenko, P. Kirkpatrick, I. Pandya

and R. Savla, “Surface-Engineered Targeted PPI Den-

drimer for Efficient Intracellular and Intratumoral siRNA

Delivery,” Journal of Controlled Release, Vol. 140, No. 3,

2009, pp. 284-293. doi:10.1016/j.jconrel.2009.06.019

[22] V. V. Mody, R. Siwale, A. Singh and H. R. Mody, “In-

troduction to Metallic Nanoparticles,” Journal of Phar-

macy and Bioallied Sciences, Vol. 2, No. 4, 2010, pp.

282-289. doi:10.4103/0975-7406.72127

[23] D. Brambilla, B. Le Droumaguet, J. Nicolas, S. H.

Hashemi and L. P. Wu, “Nanotechnologies for Alz-

heimer’s Disease: Diagnosis, Therapy, and Safety Is-

sues,” Nanomedicine, Vol. 7, No. 5, 2011, pp. 521-540.

doi:10.1016/j.nano.2011.03.008

[24] A. Beck, J. F. Haeuw, T. Wurch, L. Goetsch and C.

Bailly, “The Next Generation of Antibody-Drug Conju-

gates Comes of Age,” Discovery Medicine, Vol. 10, No.

53, 2010, pp. 329-339.

[25] A. M. Wu and P. D. Senter, “Arming Antibodies: Pros-

pects and Challenges for Immunoconjugates,” Nature

Biotechnology, Vol. 23, No. 9, 2005, pp. 1137-1146.

doi:10.1038/nbt1141

[26] A. L. Nelson, “Antibody Fragments: Hope and Hype,”

MAbs, Vol. 2, No. 1, 2010, pp. 77-83.

doi:10.4161/mabs.2.1.10786

[27] J. M. Reichert, “Antibody-Based Therapeutics to Watch

in 2011,” MAbs, Vol. 3, No. 1, 2011, pp. 76-99.

doi:10.4161/mabs.3.1.13895

[28] J. C. Olivier, R. Huertas, H. J. Lee, F. Calon and W. M.

Pardridge, “Synthesis of Pegylated Immunonanoparti-

cles,” Pharmaceutical Research, Vol. 19, No. 8, 2002, pp.

1137-1143. doi:10.1023/A:1019842024814

[29] J. C. Olivier, “Drug Transport to Brain with Targeted

Nanoparticles,” NeuroRx, Vol. 2, No. 1, 2005, pp. 108-

119. doi:10.1602/neurorx.2.1.108

[30] H. M. Blau and M. L. Springer, “Gene Therapy—A

Novel Form of Drug Delivery,” The New England Jour-

nal of Medicine, Vol. 333, No. 18, 1995, pp. 1204-1207.

doi:10.1056/NEJM199511023331808

[31] Y. Z. Chen, X. L. Yao, Y. Tabata, S. Nakagawa a nd J. Q.

Gao, “Gene Carriers and Transfection Systems Used in

the Recombination of Dendritic Cells for Effective Can-

cer Immunotherapy,” Clinical and Developmental Im-

munology, Vol. 2010, 2010, Article ID 565643, 12 Pages.

doi:10.1155/2010/565643

[32] H. Eliyahu, Y. Barenholz and A. J. Domb, “Polymers for

DNA Delivery,” Molecules, Vol. 10, No. 1, 2005, pp. 34-

64. doi:10.3390/10010034

[33] B. Thaci, I. V. Ulasov, D. A. Wainwright and M. S.

Lesniak, “The Challenge for Gene Therapy: Innate Im-

mune Response to Adenoviruses,” Oncotarget, Vol. 2, No.

3, 2011, pp. 113-121.

[34] M. G. Cusi, “Applications of Influenza Virosomes as a

Delivery System,” Human Vaccine, Vol. 2, No. 1, 2006,

pp. 1-7. doi:10.4161/hv.2.1.2494

[35] G. Fricker, T. Kromp, A. Wendel, A. Blume and J. Zirkel,

“Phospholipids and Lipid-Based Formulations in Oral

Drug Delivery,” Pharmaceutical Research, Vol. 27, No. 8,

2010, pp. 1469-1486. doi:10.1007/s11095-010-0130-x

[36] I. Gilead Sciences, “AmBisome,” 2011.

http://www.ambisome.com/index2.php?section=about&p

age=intro

[37] S. R. Schaffazick, A. R. Pohlmann, C. A. de Cordova, T.

B. Creczynski-Pasa and S. S. Guterres, “Protective Prop-

erties of Melatonin-Loaded Nanoparticles against Lipid

Peroxidation,” International Journal of Pharmaceutics,

Vol. 289, No. 1-2, 2005, pp. 209-213.

doi:10.1016/j.ijpharm.2004.11.003

[38] M. S. Arayne, N. Sultana and F. Qureshi, “Review:

Nanoparticles in Delivery of Cardiovascular Drugs,”

Pakistan Journal of Pharmaceutical Sciences, Vol. 20,

No. 4, 2007, pp. 340-348.

[39] G. A. Castro, R. L. Orefice, J. M. Vilela, M. S. Andrade

and L. A. Ferreira, “Development of a New Solid Lipid

Nanoparticle Formulation Containing Retinoic Acid for

Topical Treatment of Acne,” Journal of Microencapsula-

tion, Vol. 24, No. 5, 2007, pp. 395-407.

doi:10.1080/02652040701288519

[40] E. Esposito, E. Menegatti and R. Cortesi, “Ethosomes and

Liposomes as Topical Vehicles for Azelaic Acid: A Pre-

formul atio n Study, ” Journal of Cosmetic Science, Vol. 55,

No. 3, 2004, pp. 253-264.

[41] P. Karande and S. Mitragotri, “Enhancement of Trans-

dermal Drug Delivery via Synergistic Action of Chemi-

cals,” Biochimica et Biophysica Acta, Vol. 1788, No. 11,

2009, pp. 2362-2373. doi:10.1016/j.bbamem.2009.08.015

[42] R. D. Miclea, P. R. Varma, A. Peng and S. V. Balu-Iyer,

“Development and Characterization of Lipidic Cochleate

Containing Recombinant Factor VIII,” Biochimica et

Biophysica Acta, Vol. 1768, No. 11, 2007, pp. 2890-2898.

doi:10.1016/j.bbamem.2007.08.001

[43] A. M. Sesana, R. Monti-Rocha, S. A. Vinhas, C. G.

Morais and R. Dietze, “In Vitro Activity of Amphotericin

B Cochleates against Leishmania Chagasi,” Memórias do

Instituto Oswaldo Cruz, Vol. 106, No. 2, 2011, pp. 251-

253. doi:10.1590/S0074-02762011000200022

[44] O. Perez, G. Bracho, M. Lastre, N. Mora and J. del

Campo, “Novel Adjuvant Based on a Proteoliposome-

Derived Cochleate Structure Containing Native Lipopoly-

saccharide as a Pathogen-Associated Molecular Pattern,”

Immunology & Cell Biology, Vol. 82, No. 6, 2004, pp.

603-610. doi:10.1111/j.1440-1711.2004.01293.x

[45] Z. Yang, X. Peng, Y. Tan, M. Chen and X. Zhu, “Opti-

mization of the Preparation Process for an Oral Phytan-

Recent Advances in Drug Delivery Systems523

triol-Based Amphotericin B Cubosomes,” Journal of

Nanomaterials, Vol. Vol. 2011, No. 2011, p. 10.

[46] D. Bei, T. Zhang, J. B. Murowchick and B. B. Youan,

“Formulation of Dacarbazine-Loaded Cubosomes. Part III.

Physicochemical Characterization,” AAPS PharmSciTech,

Vol. 11, No. 3, 2010, pp. 1243-1249.

doi:10.1208/s12249-010-9496-7

[47] H. Chung, J. Kim, J. Y. Um, I. C. Kwon and S. Y. Jeong,

“Self-Assembled ‘Nanocubicle’ as a Carrier for Peroral

Insulin Delivery,” Diabetologia, Vol. 45, No. 3, 2002, pp.

448-451. doi:10.1007/s00125-001-0751-z

[48] J. Manosroi, M. G. Apriyani, K. Foe and A. Manosroi,

“Enhancement of the Release of Azelaic Acid through the

Synthetic Membranes by Inclusion Complex Formation

with Hydroxypropyl-beta-cyclodextrin,” International

Journal of Pharmaceutics, Vol. 293, No. 1-2, 2005, pp.

235-240. doi:10.1016/j.ijpharm.2005.01.009

[49] R. R. Arvizo, O. R. Miranda, D. F. Moyano, C. A. Wal-

den and K. Giri, “Modulating Pharmacokinetics, Tumor

Uptake and Biodistribution by Engineered Nanoparti-

cles,” PLoS One, Vol. 6, No. 9, 2011, p. e24374.

doi:10.1371/journal.pone.0024374

[50] J. L. Arias, “Novel Strategies to Improve the Anticancer

Action of 5-Fluorouracil by Using Drug Delivery Sys-

tems,” Molecules, Vol. 13, No. 10, 2008, pp. 2340-2369.

doi:10.3390/molecules13102340

[51] S. K. Jain and N. K. Jain, “Multiparticulate Carriers for

Sun-Screening Agents,” International Journal of Cos-

metic Science, Vol. 32, No. 2, 2010, pp. 89-98.

doi:10.1111/j.1468-2494.2010.00547.x

[52] T. Fauce, “Exploring the Safety of Nanoparticles in Aus-

tralian Sunscreens,” International Journal of Biomedical

Nanoscience and Nanotechnology, Vol. 1, No. 1, 2010,

pp. 87-94. doi:10.1504/IJBNN.2010.034127

[53] P. C. Chen, S. C. Mwakwari and A. K. Oyelere, “Gold

Nanoparticles: From Nanomedicine to Nanosensing,”

Nanotechnology, Science and Applications, Vol. 1, No.

2008, pp. 45-66.

[54] L. M. Kaminskas, B. J. Boyd and C. J. Porter, “Den-

drimer Pharmacokinetics: The Effect of Size, Structure

and Surface Characteristics on ADME Properties,” Nano-

medicine, Vol. 6, No. 6, 2011, pp. 1063-1084.

doi:10.2217/nnm.11.67

[55] J. F. Kukowska-Latallo, K. A. Candido, Z. Cao, S. S.

Nigavekar and I. J. Majoros, “Nanoparticle Targeting of

Anticancer Drug Improves Therapeutic Response in

Animal Model of Human Epithelial Cancer,” Cancer Re-

search, Vol. 65, No. 12, 2005, pp. 5317-5324.

doi:10.1158/0008-5472.CAN-04-3921

[56] A. R. Menjoge, R. M. Kannan and D. A. Tomalia, “Den-

drimer-Based Drug and Imaging Conjugates: Design

Considerations for Nanomedical Applications,” Drug

Discovery Today, Vol. 15, No. 5-6, 2010, pp. 171-185.

doi:10.1016/j.drudis.2010.01.009

[57] S. H. Medina, V. Tekumalla, M. V. Chevliakov, D. S.

Shewach and W. D. Ensminger, “N-Acetylgalactosamine-

Functionalized Dendrimers as Hepatic Cancer Cell-Tar-

geted Carriers,” Biomaterials, Vol. 32, No. 17, 2011, pp.

4118- 4129. doi:10.1016/j.biomaterials.2010.11.068

[58] Y.-B. Lim, T. Kim, J. W. Lee, S.-M. Kim and H.-J. Kim,

“Self-Assembled Ternary Complex of Cationic Den-

drimer, Cucurbituril, and DNA: Noncovalent Strategy in

Developing a Gene Delivery Carrier,” Bioconjugate Che-

mistry, Vol. 13, No. 6, 2002, pp. 1181-1185.

doi:10.1021/bc025581r

[59] A. J. Velazquez, M. A. Carnahan, J. Kristinsson, S.

Stinnett and M. W. Grinstaff, “New Dendritic Adhesives

for Sutureless Ophthalmic Surgical Procedures: In Vitro

Studies of Corneal Laceration Repair,” Archives of Oph-

thalmology, Vol. 122, No. 6, 2004, pp. 867-870.

doi:10.1001/archopht.122.6.867

[60] A. K. Patri, A. Myc, J. Beals, T. P. Thomas and N. H.

Bander, “Synthesis and in Vitro Testing of J591 Anti-

body-Dendrimer Conjugates for Targeted Prostate Cancer

Therapy,” Bioconjugate Chemistry, Vol. 15, No. 6, 2004,

pp. 1174-1181. doi:10.1021/bc0499127

[61] K. Sugisaki, T. Usui, N. Nishiyama, W. D. Jang and Y.

Yanagi, “Photodynamic Therapy for Corneal Neovascu-

larization Using Polymeric Micelles Encapsulating Den-

drimer Porphyrins,” Investigative Ophthalmology & Vis-

ual Science, Vol. 49, No. 3, 2008, pp. 894-899.

doi:10.1167/iovs.07-0389

[62] K. M. Kitchens, A. B. Foraker, R. B. Kolhatkar, P. W.

Swaan and H. Ghandehari, “Endocytosis and Interaction

of Poly(amidoamine) Dendrimers with Caco-2 Cells,”

Pharmaceutical Research, Vol. 24, No. 11, 2007, pp.

2138-2145. doi:10.1007/s11095-007-9415-0

[63] P. Singh, “Dendrimers and Their Applications in Immu-

noassays and Clinical Diagnostics,” Biotechnology and

Applied Biochemistry, Vol. 48, No. Pt 1, 2007, pp. 1-9.

[64] QIAGEN, “SuperFect Transfection Reagent,”

http://www.qiagen.com/products/transfection/transfection

reagents/superfecttransfectionreagent.aspx#Tabs=t0

[65] STARPHARMA, “Transfection Reagents,”

http://www.starpharma.com/life_sciences/transfection_re

agents#article

[66] STARPHARMA, “Coatings, Inks and Adhesives,”

http://www.starpharma.com/wider_uses/coatings__inks_a

nd_adhesives#article

[67] DendriticNanotech n ologiesInc., 2011.

http://www.dnanotech.com/aboutus.asp

[68] C. F. Price, D. Tyssen, S. Sonza, A. Davie and S. Evans,

“SPL7013 Gel (VivaGel(R)) Retains Potent HIV-1 and

HSV-2 Inhibitory Activity Following Vaginal Admini-

stration in Humans,” PLoS One, Vol. 6, No. 9, 2011, p.

e24095. doi:10.1371/journal.pone.0024095

[69] C. Pinto Reis, R. J. Neufeld, A. N. J. Ribeiro and F. Veiga,

“Nanoencapsulation II. Biomedical Applications and

Current Status of Peptide and Protein Nanoparticulate

Delivery Systems,” Nanomedicine: Nanotechnology, Bi-

ology and Medicine, Vol. 2, No. 2, 2006, pp. 53-65.

doi:10.1016/j.nano.2006.04.009

[70] R. Alvarez-Roman, A. Naik, Y. N. Kalia, R. H. Guy and

H. Fessi, “Enhancement of Topical Delivery from Biode-

Recent Advances in Drug Delivery Systems

524

gradable Nanoparticles,” Pharmaceutical Research, Vol.

21, No. 10, 2004, pp. 1818-1825.

doi:10.1023/B:PHAM.0000045235.86197.ef

[71] N. Nafee, M. Schneider, U. F. Schaefer and C. M. Lehr,

“Relevance of the Colloidal Stability of Chitosan/PLGA

Nanoparticles on Their Cytotoxicity Profile,” Interna-

tional Journal of Pharmaceutics, Vol. 381, No. 2, 2009,

pp. 130-139. doi:10.1016/j.ijpharm.2009.04.049

[72] A. C. B. P. Reis, “Encapsulação de Fármacos Peptídicos

Pelo Método de Emulsificação/Gelificação Interna,” Ph.D.

Thesis, Faculdade Farmácia Universidade de Coimbra,

2007.

[73] T. Y. Lim, C. K. Poh and W. Wang, “Poly(lactic-co-

glycolic acid) as a Controlled Release Delivery Device,”

Journal of Materials Science: Materials in Medicine, Vol.

20, No. 8, 2009, pp. 1669-1675.

doi:10.1007/s10856-009-3727-z

[74] J. K. Park, J. Yeom, E. J. Oh, M. Reddy and J. Y. Kim,

“Guided Bone Regeneration by Poly(lactic-co-glycolic

acid) Grafted Hyaluronic Acid Bi-Layer Films for Perio-

dontal Barrier Applications,” Acta Biomaterialia, Vol. 5,

No. 9, 2009, pp. 3394-3403.

doi:10.1016/j.actbio.2009.05.019

[75] N. Vij, T. Min, R. Marasigan, C. N. Belcher and S. Mazur,

“Development of PEGylated PLGA Nanoparticle for

Controlled and Sustained Drug Delivery in Cystic Fibro-

sis,” Journal of Nanobiotechnology, Vol. 8, 2010, p. 22.

doi:10.1186/1477-3155-8-22

[76] N. Csaba, A. Sanchez and M. J. Alonso, “PLGA: Polox-

amer and PLGA: Poloxamine Blend Nanostructures as

Carriers for Nasal Gene Delivery,” Journal of Controlled

Release, Vol. 113, No. 2, 2006, pp. 164-172.

doi:10.1016/j.jconrel.2006.03.017

[77] S. R. Little, D. M. Lynn, Q. Ge, D. G. Anderson and S. V.

Puram, “Poly-Beta Amino Ester-Containing Microparti-

cles Enhance the Activity of Nonviral Genetic Vaccines,”

Proceedings of the National Academy of Sciences, Vol.

101, No. 26, 2004, pp. 9534-9539.

doi:10.1073/pnas.0403549101

[78] D. Shenoy, S. Little, R. Langer and M. Amiji, “Poly(eth-

ylene oxide)-Modified Poly(beta-amino ester) Nanoparti-

cles as a pH-Sensitive System for Tumor-Targeted Deliv-

ery of Hydrophobic Drugs. 1. In Vitro Evaluations,” Mo-

lecular Pharmaceutics, Vol. 2, No. 5, 2005, pp. 357-366.

doi:10.1021/mp0500420

[79] T. M. Allen, “Ligand-Targeted Therapeutics in Antican-

cer Therapy,” Nature Reviews Cancer, Vol. 2, No. 10,

2002, pp. 750-763. doi:10.1038/nrc903

[80] R. Gabathuler, “Development of New Peptide Vectors for

the Transport of Therapeutic across the Blood-Brain Bar-

rier,” Therapeutic Delivery, Vol. 1, No. 4, 2010, pp.

571-586. doi:10.4155/tde.10.35

[81] M. F. Bennewitz and W. M. Saltzman, “Nanotechnology

for Delivery of Drugs to the Brain for Epilepsy,” Neu-

rotherapeutics, Vol. 6, No. 2, 2009, pp. 323-336.

doi:10.1016/j.nurt.2009.01.018

[82] J. Park, P. M. Fong, J. Lu, K. S. Russell and C. J. Booth,

“PEGylated PLGA Nanoparticles for the Improved De-

livery of Doxorubicin,” Nanomedicine, Vol. 5, No. 4,

2009, pp. 410-418. doi:10.1016/j.nano.2009.02.002

[83] P. J. Gaillard, “Crossing Barriers from Blood-to-Brain

and Academia-to-Industry,” Therapeutic Delivery, Vol. 1,

No. 4, 2010, pp. 495-500. doi:10.4155/tde.10.43

[84] M. Habgood and J. Ek, “Delivering Drugs into the Brain:

Barriers and Possibilities,” Therapeutic Delivery, Vol. 1,

No. 4, 2010, pp. 483-488. doi:10.4155/tde.10.58

[85] E. Garcia-Garcia, K. Andrieux, S. Gil and P. Couvreur,

“Colloidal Carriers and Blood-Brain Barrier (BBB)

Translocation: A Way to Deliver Drugs to the Brain?”

International Journal of Pharmaceutics, Vol. 298, No. 2,

2005, pp. 274-292. doi:10.1016/j.ijpharm.2005.03.031

[86] D. Chen, W. Liu, Y. Shen, H. Mu and Y. Zhang, “Effects

of a Novel pH-Sensitive Liposome with Cleavable Es-

terase-Catalyzed and pH-Responsive Double Smart

mPEG Lipid Derivative on ABC Phenomenon,” Interna-

tional Journal of Nanomedicine, Vol. 6, 2011, pp. 2053-

2061.

[87] D. Shenoy, S. Little, R. Langer and M. Amiji, “Poly(eth-

ylene oxide)-Modified Poly(beta-amino ester) Nanoparti-

cles as a pH-Sensitive System for Tumor-Targeted Deliv-

ery of Hydrophobic Drugs: Part 2. In Vivo Distribution

and Tumor Localization Studies,” Pharmaceutical Re-

search, Vol. 22, No. 12, 2005, pp. 2107-2114.

doi:10.1007/s11095-005-8343-0

[88] B. C. Tang, M. Dawson, S. K. Lai, Y. Y. Wang and J. S.

Suk, “Biodegradable Polymer Nanoparticles That Rapidly

Penetrate the Human Mucus Barrier,” Proceedings of the

National Academy of Sciences, Vol. 106, No. 46, 2009,

pp. 19268-19273. doi:10.1073/pnas.0905998106

[89] R. Yang, W. S. Shim, F. D. Cui, G. Cheng and X. Han,

“Enhanced Electrostatic Interaction between Chitosan-

Modified PLGA Nanoparticle and Tumor,” International

Journal of Pharmaceutics, Vol. 371, No. 1-2, 2009, pp.

142-147. doi:10.1016/j.ijpharm.2008.12.007

[90] T. Dos Santos, J. Varela, I. Lynch, A. Salvati and K. A.

Dawson, “Effects of Transport Inhibitors on the Cellular

Uptake of Carboxylated Polystyrene Nanoparticles in

Different Cell Lines,” PLoS One, Vol. 6, No. 9, 2011, p.

e24438. doi:10.1371/journal.pone.0024438

[91] A. S. Hasan, M. Socha, A. Lamprecht, F. E. Ghazouani

and A. Sapin, “Effect of the Microencapsulation of Nano-

particles on the Reduction of Burst Release,” Interna-

tional Journal of Pharmaceutics, Vol. 344, No. 1-2, 2007,

pp. 53-61. doi:10.1016/j.ijpharm.2007.05.066

[92] S. S. Feng, G. Ruan and Q. T. Li, “Fabrication and Char-

acterizations of a Novel Drug Delivery Device Lipo-

somes-in-Microsphere (LIM),” Biomaterials, Vol. 25, No.

21, 2004, pp. 5181-5189.

doi:10.1016/j.biomaterials.2003.12.013

[93] R. K. Das, N. Kasoju and U. Bora, “Encapsulation of

Curcumin in Alginate-Chitosan-Pluronic Composite

Nanoparticles for Delivery to Cancer Cells,” Nanomedi-

cine, Vol. 6, No. 1, 2010, pp. 153-160.

doi:10.1016/j.nano.2009.05.009

Recent Advances in Drug Delivery Systems525

[94] A. S. Hassan, “Prolonged Release Microparticles Able to

Reduce the Initial Burst Effect,” Ph.D. Thesis, Universite

Henri Poincare, Nancy 1, 2008.

[95] T. Hammady, A. El-Gindy, E. Lejmi, R. S. Dhanikula and

P. Moreau, “Characteristics and Properties of Nano-

spheres Co-Loaded with Lipophilic and Hydrophilic Drug

Models,” International Journal of Pharmaceutics, Vol.

369, No. 1-2, 2009, pp. 185-195.

doi:10.1016/j.ijpharm.2008.10.034

[96] A. Budhian, S. J. Siegel and K. I. Winey, “Controlling the

in Vitro Release Profiles for a System of Haloperidol-

Loaded PLGA Nanoparticles,” International Journal of

Pharmaceutics, Vol. 346, No. 1-2, 2008, pp. 151-159.

doi:10.1016/j.ijpharm.2007.06.011

[97] R. M. Mainardes and R. C. Evangelista, “PLGA

Nanoparticles Containing Praziquantel: Effect of Formu-

lation Variables on Size Distribution,” International Jour-

nal of Pharmaceutics, Vol. 290, No. 1-2, 2005, pp. 137-

144. doi:10.1016/j.ijpharm.2004.11.027

[98] X. Song, Y. Zhao, W. Wu, Y. Bi and Z. Cai, “PLGA

Nanoparticles Simultaneously Loaded with Vincristine

Sulfate and Verapamil Hydrochloride: Systematic Study

of Particle Size and Drug Entrapment Efficiency,” Inter-

national Journal of Pharmaceutics, Vol. 350, No. 1-2,

2008, pp. 320-329. doi:10.1016/j.ijpharm.2007.08.034

[99] W. Ke, Y. Zhao, R. Huang, C. Jiang and Y. Pei, “En-

hanced Oral Bioavailability of Doxorubicin in a Den-

drimer Drug Delivery System,” Journal of Pharmaceuti-

cal Sciences, Vol. 97, No. 6, 2008, pp. 2208-2216.

doi:10.1002/jps.21155

[100] W. A. Banks and A. J. Kastin, “Aluminum Alters the

Permeability of the Blood-Brain Barrier to Some Non-

Peptides,” Neuropharmacology, Vol. 24, No. 5, 1985, pp.

407-412. doi:10.1016/0028-3908(85)90025-5

[101] P. Vlieghe and M. Khrestchatisky, “Peptide-Based Vec-

tors for Blood-Brain Barrier Targeting and Delivery of

Drugs to the Central Nervous System,” Therapeutic De-

livery, Vol. 1, No. 4, 2010, pp. 489-494.

doi:10.4155/tde.10.44

[102] B. Wilson, “Brain Targeting PBCA Nanoparticles and the

Blood-Brain Barrier,” Nanomedicine, Vol. 4, No. 5, 2009,

pp. 499-502. doi:10.2217/nnm.09.29

[103] V. Mangas-Sanjuan, M. González-Alvarez, I. Gonzalez-

Alvarez and M. Bermejo, “Drug Penetration across the

Blood-Brain Barrier: An Overview,” Therapeutic Deliv-

ery, Vol. 1, No. 4, 2010, pp. 535-562.

doi:10.4155/tde.10.37

[104] A. Misra, S. Ganesh, A. Shahiwala and S. P. Sha h, “Drug

Delivery to the Central Nervous System: A Review,”

Journal of Pharmaceutical Sciences, Vol. 6, No. 2, 2003,

pp. 252-273.

[105] S. J. Gray, K. T. Woodard and R. J. Samulski, “Viral

Vectors and Delivery Strategies for CNS Gene Therapy,”

Therapeutic Delivery, Vol. 1, No. 4, 2010, pp. 517-534.

doi:10.4155/tde.10.50

[106] R. N. Alyautdin, V. E. Petrov, K. Langer, A. Berthold and

D. A. Kharkevich, “Delivery of Loperamide across the

Blood-Brain Barrier with Polysorbate 80-Coated Polybu-

tylcyanoacrylate Nanoparticles,” Pharmaceutical Re-

search, Vol. 14, No. 3, 1997, pp. 325-328.

doi:10.1023/A:1012098005098

[107] J. Kreuter, D. Shamenkov, V. Petrov, P. Ramge and K.

Cychutek, “Apolipoprotein-Mediated Transport of Nano-

particle-Bound Drugs across the Blood-Brain Barrier,”

Journal of Drug Targeting, Vol. 10, No. 4, 2002, pp. 317-

325. doi:10.1080/10611860290031877

[108] J. Kreuter and S. Gelperina, “Use of Nanoparticles for

Cerebral Cancer,” Tumori, Vol. 94, No. 2008, pp. 270-

276.

[109] F. C. Thomas, K. Taskar, V. Rudraraju, S. Goda and H. R.

Thorsheim, “Uptake of ANG1005, a Novel Paclitaxel

Derivative, through the Blood-Brain Barrier into Brain

and Experimental Brain Metastases of Breast Cancer,”

Pharmaceutical Research, Vol. 26, No. 11, 2009, pp.

2486-2494. doi:10.1007/s11095-009-9964-5

[110] S. Bhaskar, F. Tian, T. Stoeger, W. Krey ling and J. M. de

la Fuente, “Multifunctional Nanocarriers for Diagnostics,

Drug Delivery and Targeted Treatment across Blood-

Brain Barrier: Perspectives on Tracking and Neuroimag-

ing,” Particle and Fibre Toxicology, Vol. 7, 2010, p. 3.

doi:10.1186/1743-8977-7-3

[111] H. Xin, X. Jiang, J. Gu, X. Sha and L. Chen, “Angiopep-

Conjugated Poly(ethylene glycol)-co-poly(epsilon-capro-

lactone) Nanoparticles as Dual-Targeting Drug Delivery

System for Brain Glioma,” Biomaterials, Vol. 32, No. 18,

2011, pp. 4293-4305.

doi:10.1016/j.biomaterials.2011.02.044

[112] EMA, “Glutathione-Pegylated Liposomal Doxorubicin

Hydrochloride for the Treatment of Glioma,” 2010.

http://www.ema.europa.eu/docs/en_GB/document_library

/Orphan_designation/2010/10/WC500097951.pdf

[113] H.-L. Zhang, S.-H. Wu, Y. Tao, L.-Q. Zang and Z.-Q. Su,

“Preparation and Characterization of Water-Soluble Chi-

tosan Nanoparticles as Protein Delivery System,” Journal

of Nanomaterials, Vol. 2010, 2010, Article ID 898910, 5

Pages.

[114] M. Garinot, V. Fievez, V. Pourcelle, F. Stoffelbach and A.

des Rieux, “PEGylated PLGA-Based Nanoparticles Tar-

geting M Cells for Oral Vaccination,” Journal of Con-

trolled Release, Vol. 120, No. 3, 2007, pp. 195-204.

doi:10.1016/j.jconrel.2007.04.021

[115] V. Fievez, L. Plapied, A. des Rieux, V. Pourcelle and H.

Freichels, “Targeting Nanoparticles to M Cells with Non-

Peptidic Ligands for Oral Vaccination,” European Jour-

nal of Pharmaceutics and Biopharmaceutics, Vol. 73, No.

1, 2009, pp. 16-24. doi:10.1016/j.ejpb.2009.04.009

[116] Y. Pan, Y. J. Li, H. Y. Zhao, J. M. Zheng and H. Xu,

“Bioadhesive Polysaccharide in Protein Delivery System:

Chitosan Nanoparticles Improve the Intestinal Absorption

of Insulin in Vivo,” International Journal of Pharmaceu-

tics, Vol. 249, No. 1-2, 2002, pp. 139-147.

doi:10.1016/S0378-5173(02)00486-6

[117] W. S. Shalaby, “Development of Oral Vaccines to Stimu-

late Mucosal and Systemic Immunity: Barriers and Novel

Recent Advances in Drug Delivery Systems

526

Strategies,” Clinical Immunology and Immunopathology,

Vol. 74, No. 2, 1995, pp. 127-134.

doi:10.1006/clin.1995.1019

[118] C. O. Tacket, M. B. Sztein, S. S. Wasserman, G. Loson-

sky and K. L. Kotloff, “Phase 2 Clinical Trial of Attenu-

ated Salmonella Enterica Serovar Typhi Oral Live Vector

Vaccine CVD 908-htrA in U.S. Volunteers,” Infection

and Immunity, Vol. 68, No. 3, 2000, pp. 1196-1201.

doi:10.1128/IAI.68.3.1196-1201.2000

[119] G. P. Li, Z. G. Liu, B. Liao and N. S. Zhong, “Induction

of Th1-Type Immune Response by Chitosan Nanoparti-

cles Containing Plasmid DNA Encoding House Dust Mite

Allergen Der p 2 for Oral Vaccination in Mice,” Cellular

& Molecular Immunology, Vol. 6, No. 1, 2009, pp. 45-50.

doi:10.1038/cmi.2009.6

[120] I. S. Kim, S. K. Lee, Y. M. Park, Y. B. Lee and S. C. Shin,

“Physicochemical Characterization of Poly(L-lactic acid)

and Poly(D,L-lactide-co-glycolide) Nanoparticles with

Polyethylenimine as Gene Delivery Carrier,” Interna-

tional Journal of Pharmaceutics, Vol. 298, No. 1, 2005,

pp. 255-262. doi:10.1016/j.ijpharm.2005.04.017

[121] ANGELINI, “EPAXAL®—Vaccine for Active Immuni-

sation against Hepatitis A,” 2011.

http://www.angelini.it/public/schedepharma/epaxal.htm

[122] PEVION, “Virosomes Are the Only VLP Assembled in

Vitro, Not by Host Cell,”

http://www.pevion.com/index.php?page=723

[123] M. R. Kumar, U. Bakowsky and C. M. Lehr, “Preparation

and Characterization of Cationic PLGA Nanospheres as

DNA Carriers,” Biomaterials, Vol. 25, No. 10, 2004, pp.

1771-1777. doi:10.1016/j.biomaterials.2003.08.069

[124] Y. Yue, F. Jin, R. Deng, J. Cai and Z. Dai, “Revisit Com-

plexation between DNA and Polyethylenimine—Effect of

Length of Free Polycationic Chains on Gene Transfec-

tion,” Journal of Controlled Release, Vol. 152, No. 1,

2011, pp. 143-151. doi:10.1016/j.jconrel.2011.03.020

[125] J. L. Italia, A. Sharp, K. C. Carter, P. Warn and M. N. V.

R. Kumar, “Peroral Amphotericin B Polymer Nanoparti-

cles Lead to Comparable or Superior in Vivo Antifungal

Activity to That of Intravenous Ambisome® or

Fungizone™,” PLoS One, Vol. 6, No. 10, 2011, p. 8.

doi:10.1371/journal.pone.0025744

[126] R. Rupp, S. L. Rosenthal and L. R. Stanberry, “VivaGel

(SPL7013 Gel): A Candidate Dendrimer—Microbicide

for the Prevention of HIV and HSV Infection,” Interna-

tional Journal of Nanomedicine, Vol. 2, No. 4, 2007, pp.

561-566.

[127] C. S. Maia, W. Mehnert and M. Schäfer-Korting, “Solid

lipid Nanoparticles as Drug Carriers for Topical Gluco-

corticoids,” International Journal of Pharmaceutics, Vol.

196, No. 2, 2000, pp. 165-167.

doi:10.1016/S0378-5173(99)00413-5

[128] H. Chen, X. Chang, D. Du, W. Liu and J. Liu, “Podo-

phyllotoxin-Loaded Solid Lipid Nanoparticles for Epi-

dermal Targeting,” Journal of Controlled Release, Vol.

110, No. 2, 2006, pp. 296-306.

doi:10.1016/j.jconrel.2005.09.052

[129] M. Rother, E. J. Seidel, P. M. Clarkson, S. Mazgareanu

and U. Vierl, “Efficacy of Epicutaneous Diractin (keto-

profen in Transfersome gel) for the Treatment of Pain

Related to Eccentric Muscle Contractions,” Journal of

Drug Design, Development and Therapy, Vol. 3, 2009, pp.

143-149.

[130] A. Rolland, N. Wagner, A. Chatelus, B. Shroot and H.

Schaefer, “Site-Specific Drug Delivery to Pilosebaceous

Structures Using Polymeric Microspheres,” Pharmaceu-

tical Research, Vol. 10, No. 12, 1993, pp. 1738-1744.

doi:10.1023/A:1018922114398

[131] B. Mahe, A. Vogt, C. Liard, D. Duffy and V. Abadie,

“Nanoparticle-Based Targeting of Vaccine Compounds to

Skin Antigen-Presenting Cells by Hair Follicles and Their

Transport in Mice,” Journal of Investigative Dermatology,

Vol. 129, No. 5, 2009, pp. 1156-1164.

doi:10.1038/jid.2008.356

[132] A. Vogt, B. Combadiere, S. Hadam, K. M. Stieler and J.

Lademann, “40 nm, but not 750 or 1500 nm, Nanoparti-

cles Enter Epidermal CD1a+ Cells after Transcutaneous

Application on Human Skin,” Journal of Investigative

Dermatology, Vol. 126, No. 6, 2006, pp. 1316-1322.

doi:10.1038/sj.jid.5700226

[133] F. F. Larese, F. D'Agostin, M. Crosera, G. Adami and N.

Renzi, “Human Skin Penetration of Silver Nanoparticles

through Intact and Damaged Skin,” Toxicology, Vol. 255,

No. 1-2, 2009, pp. 33-37.

doi:10.1016/j.tox.2008.09.025

[134] H. Maeda, J. Wu, T. Sawa, Y. Matsumura and K. Hori,

“Tumor Vascular Permeability and the EPR Effect in

Macromolecular Therapeutics: A Review,” Journal of

Controlled Release, Vol. 65, No. 1-2, 2000, pp. 271-284.

doi:10.1016/S0168-3659(99)00248-5

[135] H. Sarin, “Recent Progress towards Development of Ef-

fective Systemic Chemotherapy for the Treatment of Ma-

lignant Brain Tumors,” Journal of Translational Medi-

cine, Vol. 7, 2009, p. 77. doi:10.1186/1479-5876-7-77