Hybrid poly(lactic-co-glycolic acid) nanoparticles: design and delivery prospectives

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Drug Discovery Today � Volume 00, Number 00 � July 2014 REVIEWS

Hybrid poly(lactic-co-glycolic acid)nanoparticles: design and deliveryprospectivesDeepti Pandita1, Sandeep Kumar1 and Viney Lather2

1Department of Pharmaceutics, Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa 125055, Haryana, India2Department of Pharmaceutical Chemistry, Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa 125055, Haryana, India

Poly(lactic-co-glycolic acid) (PLGA), a US Food and Drug Administration (FDA)-approved copolymer, has

been exploited widely in the design of nanoparticles because it is biodegradable, biocompatible, protects

the drug molecules from degradation, and aids in producing sustained and targeted delivery. However,

certain constraints associated with PLGA nanoparticles, such as poor drug encapsulation, polymer

degradation, and scale-up issues, have led to the development of emerging hybrid PLGA delivery

systems. These hybrid nanoparticles are core–shell nanostructures comprising either a PLGA core or a

PLGA shell combining multiple functionalities within one system and, thus, exhibiting the

complementary characteristics of two different platforms used for the delivery of a wide range of

therapeutics and imaging.

IntroductionNanotechnology has been extensively exploited in pharmaceuti-

cal and biomedical applications, with significant impact on the

therapeutics and diagnoses of diseases such as cancer and cardio-

vascular disease. The past two decades have seen a significant rise

in the commercialization of nanotechnology-based therapeutics,

with over 20 nanoparticle-based therapeutics now approved for

clinical use and several under clinical testing [1,2]. Among several

nanoparticulate systems, lipid-based nanocarriers, such as lipo-

somes, solid-lipid nanoparticles, and nanostructured lipid carriers,

and biodegradable polymeric nanoparticles are the most widely

adopted nanosystems for drug delivery [3].

PLGA has attracted great attention in the design of delivery

systems because of its excellent biocompatibility and biodegrad-

ability, which are the result of its ester linkages undergoing hy-

drolysis in the presence of water. This produces the original

monomers, lactic acid and glycolic acid, which are easily metabo-

lized in the body via the Krebs cycle without any systemic toxicity.

The attractive features of PLGA-based nanoparticles, such as small

size, high structural integrity, stability, ease of fabrication, tunable

properties, controlled release capability, and surface functionali-

zation characteristics, make them versatile therapeutic delivery

Please cite this article in press as: Pandita, D. et al. Hybrid poly(lactic-co-glycolic acid) nano10.1016/j.drudis.2014.09.018

Corresponding author: Pandita, D. ([email protected])

1359-6446/06/$ - see front matter � 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.

vehicles. However, the limitations of PLGA-based nanoparticles in

terms of their physicochemical and biological properties restrict-

ing their applications in nanomedicine include poor drug loading,

high burst release, uptake by the reticuloendothelial system (RES),

less circulation time in the body, aggregation, cost, and

manufacturing scale-up [4]. To resolve these constraints of PLGA

nanoparticles, the focus has now moved towards the development

of hybrid PLGA nanoparticles. To alleviate these limitations, sev-

eral attempts have also been made to modify the surface properties

of PLGA nanoparticles [5]. Hybridization enables the design of

novel nanoarchitecture, using two nanostructures, thus imbibing

the functionalities of both within one system.

To address the limitations of PLGA nanoparticles, a new integrat-

ed system based on hybrid nanoparticles using either organic or

inorganic materials is being explored for the improved delivery of

therapeutics and bioimaging. The PLGA–lipid hybrid nanostructure

is one such system, which combines the biomimetic characteristics

of lipids and architectural advantage of a polymeric core resulting in

a superior delivery system. Here, we briefly highlight the fundamen-

tal aspects related to the design and applications of various hybrid

PLGA nanosystems recently developed, with an emphasis on their

advantages in terms of surface functionality, tunable particle size

and drug release, and high drug loading, and emerging develop-

ments in drug delivery applications.

particles: design and delivery prospectives, Drug Discov Today (2014), http://dx.doi.org/

09.018 www.drugdiscoverytoday.com 1

http://dx.doi.org/10.1016/j.drudis.2014.09.018


mailto:[email protected]


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ybrid PLGA nanoparticles: designhe properties of the nanomaterials and the synthesis approach

pplied largely govern the physicochemical properties of the

esulting nanoparticles in terms of not only their size, stability,

rug encapsulation and release, but also their biological perfor-

ance as a drug carrier. Therefore, careful nanoparticle design is

ey to reaching the desired goals of safe and effective drug delivery.

igure 1 gives an overview of various hybrid PLGA nanoparticles

eviewed in this article.

LGA–lipid nanohybridshe PLGA–lipid hybrid nanocomposites provide a platform to

oalesce the properties of both lipids and polymeric nanoparticles

Please cite this article in press as: Pandita, D. et al. Hybrid poly(lactic-co-glycolic acid) na10.1016/j.drudis.2014.09.018

Lipid-PLGA-Lipid Hybridnanoparticle

Polymer-PLGA Hybridnanoparticle

Lipid-PLGnanopa

Typical nanopa

PLGA-Oil Hybridnanoparticle

PLGA

RBC membrane Lipid PEGylatedLipid

Liga

Drug A Drug B Gonanop

IGURE 1

n overview of major hybrid poly(lactic-co-glycolic acid) (PLGA) nanoparticles.

terfering RNA.

www.drugdiscoverytoday.com

in delivery systems. The release of a drug that is encapsulated in

the PLGA polymer matrix is controlled by its degradation as well

as by altering the properties of surrounding lipid layer. The lipid

layer acts as a barrier that protects the encapsulated drug from

undue leakage and helps in achieving controlled drug release,

where the PLGA polymer matrix aids in structural integrity of

lipid layer [6]. Such core –shell-type hybrids have a polymeric core

enveloped by single or multiple layers of lipids. Stearic acid,

lecithin, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),

1,2-dilauroylphosphatidylocholine (DLPC), 1,2-distearoyl-sn-

glycero-3-phosphoethanolamine-N-carboxy-(polyethylene gly-

col)-2000 (DSPE-PEG), or 1,2-dioleoyl-sn-glycero-3-phos-

phoethanolamine (DOPE) often comprise the lipid shell.

noparticles: design and delivery prospectives, Drug Discov Today (2014), http://dx.doi.org/

Lipid-PLGA-Polymer Hybridnanoparticle

A Hybridrticle

PLGArticle

RBC-PLGA Hybridnanoparticle

Inorganic-PLGA Hybridnanoparticle

nd siRNA Surfactant Other Polymer

ldarticle

Iron oxidenanoparticle

Quantum Dot Oil

Drug Discovery Today

Abbreviations: PEG, polyethylene glycol; RBC, red blood cells; siRNA, short-




DRUDIS 1504 1–10


Commonly, a two-step method and a one-step method are used in

preparation of hybrid core –shell nanoparticles. The two-step

method involves the incubation of drug-loaded PLGA nanopar-

ticles with preformed lipid vesicles, followed by extrusion

through a porous membrane to obtain the absorbed lipid vesicles

on polymeric nanostructures (i.e. a lipid-coated hybrid struc-

ture). Alternatively, the one-step method involves mixing a poly-

mer solution and a lipid solution followed by nanoprecipitation

and/or emulsification–solvent evaporation, which enables the

lipid to self assemble on the surface of polymeric nanoparticles

to form hybrid nanostructures [7].

Formulation issues in the preparation of PLGA–lipid nanohybridsThe particle size and colloidal stability of the final hybrid particles

are affected by several factors varying from the choice of method,

type of lipids used, mixing protocols of lipid vesicles and PLGA

nanoparticles, pH and ionic strengths of the buffer used, surface

charge of lipid vesicles, vesicle-to-particle ratio, and temperature

of incubation in case of two-step-method. By contrast, in the one-

step method, the characteristics of nanoparticles are influenced

mainly by the lipid:polymer mass ratio (i.e. L/P ratio). For instance,

Zhang et al. prepared lipid–polymer hybrid nanoparticles through

a simple synthesis process by self-assembly through a single-step

nanoprecipitation method [5]. The nanoparticles comprised a

hydrophobic PLGA core, a hydrophilic PEG shell, and a lipid

(lecithin) monolayer at the interface of the hydrophobic core

and the hydrophilic shell. The L/P ratio of 10–20% resulted in

nanoparticles with a favorable size and zeta potential of 70–80 nm

and 30–35 mV, respectively. In addition, an increase in polymer

viscosity resulted in decreased particle size (Fig. 2).

Liu et al. optimized the amount of the DLPC monolayer shell to

coat uniformly the PLGA core, because excess lipids can lead to the

formation of lipid vesicles, which would result in lower drug


PLGA

Drug

Lipid

Lipid-PEG

250 0

–10

–20

–30

–40

–50

200 SizeCharge

150

100

50

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op

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(n

m)

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(m

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(a)

(c)

FIGURE 2

Development of lipid–polymer hybrid nanoparticles. (a) Schematic illustration show

electron microscopy image demonstrating the structure of the hybrid nanoparticelectron contrast. (c) Effect of lipid:polymer weight ratio on nanoparticle size and su

molecular weight indicated as inherent viscosity on nanoparticle size and surface

encapsulation efficiency and intracellular delivery [8]. Amphiphi-

lic lipids, such as DLPC, stabilize the oil droplets in the oil–water

(O/W) emulsion to form a stable solid core with high drug encap-

sulation efficiency. In this study, it was also concluded that DLPC

was a more efficient emulsifier compared with the traditional

chemical emulsifier polyvinyl alcohol, and also had higher cellular

uptake efficiency. Recently, PLGA–lipid nanoparticles developed

with controlled size and uniformity were effective in sustained and

controlled release for the oral delivery of vaccines [9]. These

nanohybrids combine the advantages of both polymeric nanopar-

ticles and liposomes in terms of protection of payload from

degradation, higher affinity towards human microfold-cells, and

low inherent toxicity.

A crucial parameter controlling the formation of stable hybrid

nanostructure is the discrepancy in chemical composition and size

of hydrophobic segments between PLGA and lipids. The phospho-

lipids that constitute the shell of the lipid nanohybrid can act as

surfactants to stabilize the hybrid nanoparticles. However, addi-

tional surfactants are sometimes required with the lipid molecules

to obtain stable nanoparticles. For instance, Cheow et al., devel-

oped hybrid nanoparticles for three antibiotics of different solu-

bility, ionization, and lipophilicity using stearylamine and

phosphatidylcholine as lipids, where phosphatidylcholine also

worked as a surfactant molecule. The hybrid nanoparticles were

unstable when prepared with these lipids alone and addition of the

amphiphilic biocompatible surfactant D-a-tocopherol PEG 1000

succinate (10% (w/w) PLGA) during preparation of nanoparticles

imparted stability in phosphate buffer saline [10]. Moreover, the

synthesis of lipid–PLGA hybrid nanoparticles using PEGylated

lipids improved the colloidal stability of these hybrid nanostruc-

tures. Decorating the lipid PLGA nanohybrid surface with a hy-

drophilic stealth layer safeguarded the nanoparticles against

opsonization and subsequent phagocytosis and prolonged their


Polymer Lipid

100 nm

100

80

60

40

20

0 –40

–30

–20

–10

0

PLGA viscosity (g/dL)

Nan

op

arti

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size

(n

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Nan

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arti

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zeta

po

ten

tial

(m

V)

Size

Charge

(b)

(d)

0.0 0.2 0.4 0.6 0.8 1.0


ing the formulation of lipid–polymer hybrid nanoparticles, (b) Transmission

les proposed in (a). Uranyl acetate was used to stain lipids to enhance theirrface zeta potential. (d) Effect of poly(lactic-co-glycolic acid) (PLGA) polymer

zeta potential [5]. Abbreviation: PEG, polyethylene glycol.

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irculation in the blood [11]. Ling et al. designed hybrid nano-

articles comprising a PEG shell, a hybrid polymer core of dextran

ulfate–PLGA, and a monolayer of lecithin [12]. The drug-loading

nd encapsulation efficiency of vincristine sulfate 1% and 55.4%,

vincristine-loaded PLGA nanoparticles increased to 12.5% and

6%, respectively when incorporated in the dextran sulfate–PLGA

ore of hybrid nanoparticles. Moreover, these hybrid nanoparti-

les showed improved cellular uptake up to 12.4-fold when used

n MCF-7 and MCF-7/ADR cells. Later, the same group reported

igh encapsulation of vincristine into hybrid PLGA nanoparticles

eplacing dextran sulfate with another anionic small molecule of

hosphatidylserine; the resultant multifunctional nanoassembly

as investigated to overcome multidrug resistance [13]. A differ-

ntially charged lipid–polymer–lipid hybrid nanostructure was

eveloped by Shi et al. that comprised a hollow-core lipid layer

llowed by a layer of PLGA, an interlacing lipid layer, and outer

EG layer. The high encapsulation efficiency of small-interfering

NA (siRNA) showed greater potential in the design of the inner

ationic lipid layer, which is responsible for holding the siRNA

olecule. In vitro and in vivo studies further showed that this lipid–

olymer–lipid hybrid nanocarrier has promising potential in

iRNA delivery for inhibition of tumor growth [14].

LGA–lipid nanohybrids for drug targetingo achieve precise and targeted drug delivery, the use of molecular

robes on the surface of hybrid systems for active targeting has

een systematically investigated. For instance, the surface of the

ybrid nanoparticle can be modified with folic acid, transferrin,

onoclonal antibodies, peptide, therapeutic cytokines, DNA

equences, certain antibodies for immunotherapy, or fragments

f antibody. For example, transferrin-conjugated PLGA–lipid hy-

rid nanoparticles efficiently and selectively delivered the aroma-

ase inhibitor, 7a-(40-amino)phenylthio-1,4-androstadiene-3,17-

ione to breast cancer cells overexpressing the transferrin receptor

hrough receptor-mediated endocytosis [15]. Similarly, cancer

ells overexpressing various other receptors can be targeted by

onjugation with the corresponding probes or ligands, thus reach-

g and penetrating the malignant cells. Therefore, the decrease in

rug release from the PLGA core associated with a decrease in

LGA hydrolysis resulting from lipid coating can be overcome. In

nother study, folic acid-conjugated PLGA lipid nanoparticles for

argeted delivery of docetaxel were synthesized and the targeting

ffect was quantitatively controlled by adjusting the lipid compo-

ent ratio [16]. The in vitro cellular viability data revealed that the

late-modified polymer–lipid nanoparticles were 50.91% more

ffective than the unmodified nanoparticles and 93.65% more

ffective than Taxotere1. However, this proof-of-concept study

eeds further in vivo studies for clinical applications.

timuli-responsive PLGA–lipid nanohybrids stimuli-responsive drug delivery approach has also been success-

lly applied more recently in novel PLGA–lipid nanohybrids. This

trategy is fascinating in cancer chemotherapy because it improves

he therapeutic efficacy and minimizes the adverse effects of

hemotherapeutic agents by delivering them to the target tumor

ells and releasing them in the presence of certain external or

ternal stimuli. Triggering a stimuli-dependent phenomenon is

chieved using two main approaches: either by functionalization



of the outer surface of hybrid nanoparticles by using sheddable

and/or transformable coatings (upon environmental changes) or

by linking drugs to support through covalent bonds. For example,

Clawson et al. designed hybrid nanoparticles sensitive to a pH

stimulus by using a lipid–(succinate)–mPEG conjugate [17]. The

molar concentration of this conjugate in the lipid shell of the

nanoparticles could be used to tune the pH sensitivity of this

design. pH-triggered PEG shedding by acidic hydrolysis via a di-

ester succinate linker between the lipid and PEG moieties in this

type of nanoparticle would be useful for targeting tumor cells by

tuning the pH sensitivity, because intracellular organelles, such as

endosomes (pH 5.5–6.0), lysosomes (pH 4.5–5.0), and certain

tumor tissues, have mildly acidic pH compared with blood or

normal cells (pH 7.2–7.4). Later, in another study, reduction-

sensitive PLGA–lipid hybrid nanoparticles providing a sheddable

PEG shell showed more effective intracellular delivery of antican-

cer drug into tumor cells compared with reduction-insensitive

PLGA–lipid hybrid nanoparticles [7].

The rhamnolipid-triggered release Q2capability of hybrid nano-

particles has been shown to be a clinically feasible antibiotic

dosage formulation compared with liposomes [18]. Liposomes

on their own are not physically robust, whereas in polymer–lipid

hybrid nanoparticles, the polymer matrix core contributes to the

structural integrity of the lipid coat. The release characteristics of

the nanoparticles were evaluated in response to encountering

rhamnolipids present in biofilm colonies of bacterial pathogens.

To further advance the smart drug delivery, magnetic field-acti-

vated PLGA–lipid hybrid nanoparticles have been fabricated with

incorporated magnetic beads and camptothecin. The remote

radiofrequency magnetic field-activated drug release occurred

when the polymer matrices collapsed because of localized heating

by Fe3O4 inside the polymeric cores [19].

Other PLGA nanohybridsApart from lipids, other organic and inorganic materials are also

being explored with PLGA for the design of multifunctional

nanosystems. For instance, Nafee et al. cationically modified PLGA

nanoparticles utilizing chitosan and investigated their biomedical

application. In this study, various formulation parameters, such as

concentration and type of PLGA and chitosan, content of polyvi-

nyl alcohol, and the ratio of the organic to the aqueous phase of

the emulsion, were studied in designing chitosan-coated PLGA

nanoparticles for gene delivery. The nanoparticles of prominent

positive charge and smaller particle size efficiently encapsulated

DNA and were able to transfect A549 cells [20]. Furthermore, the

extent of mucus adhesion on the cell membrane of PLGA nano-

particles has been reported to be enhanced on modification with

chitosan, a mucoadhesive polymer [21]. The colloidal stability of

PLGA nanoparticles has also been achieved in the presence of

chitosan through strong electrostatic interactions between the

cationic chitosan and negative charge of the PLGA nanoparticle

surface [22].

In terms of PLGA nanocomposites using inorganic materials,

Kim et al. successfully incorporated antibody-coated quantum dots

within polymeric nanoparticles for the cytoplasmic delivery of

these dots with minimal toxicity to the cells [23]. Silica shells have

also been successfully introduced in PEG–PLGA nanoparticles

decorated with folic acid for the targeted delivery of capecitabine.




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The in vitro drug release behavior in both silica shell cross-linked

drug-loaded nanoparticles and nonsilica shell cross-linked nano-

particles was found to be a two-stage drug release that was more

sustained in the former. The comparable release rate values at the

same stage of the two systems (i.e. k/k0) were reported to be 1.78

and 1.96 for silica shell cross-linked and nonsilica shell cross-

linked nanoparticles, respectively, which suggested that the silica

shell was responsible for achieving the controlled release of the

drug [24].

Furthermore, polymer–metal hybrid nanoparticles have been

developed with the model drug paclitaxel that serve as a new class

of core–shell theranostics. The design involves fabrication of

paclitaxel-loaded PLGA nanoparticles followed by deposition of

silver in the presence of polyvinylpyrrolidone and then growing

silver-gold shells around the drug-loaded core to form a polymer

core and metallic shell hybrid nanoparticles [25]. More recently,

considering the application of gold nanoparticles in the field of

nanomedicine, Gajendiran et al. reported the novel synthesis of

citrate PEG hybrid dendron-stabilized gold nanoparticles with a

linearly linked PLGA–PEG–SA–PEG–PLGA multiblock copolymer

for the delivery of rifampicin, an antitubercular drug [26]. The

drug loading and drug content in gold nanoparticle-conjugated

multiblock copolymer nanoparticles were increased to 41–75%

and 11.7–17.7%, respectively, which was greater than reported in

the literature. In addition, pharmacokinetic studies in male Wistar

rats showed that these nanoparticles exhibited drug release for up

to 240 hours with a delayed tmax of 72 hours. The relative bioavail-

ability was enhanced to 107–190, whereas the concentrations of

metabolites of rifampicin were found to be <25 ng ml�1. Mont-

morillonite, a pharmaceutical-grade clay mineral with versatile

properties, such as good adsorption ability, highly dispersible in

water, drug-carrying capability, and controlled release system for

various therapeutic molecules, was utilized to synthesize mont-

morillonite–PLGA nanocomposites for the controlled release of

propranolol hydrochloride [27].

In addition, multifunctional PLGA nanocomposites with poly

(L-glutamic acid)-capped silver nanoparticles were prepared to-

gether with ascorbic acid within PLGA spheres for simultaneous

antioxidative and prolonged antimicrobial activity [28]. Silver

nanoparticles were more biocompatible and had better affinity

for the polymer matrix with poly(L-glutamic acid) caps. Further-

more, the researchers also explored surface modification of PLGA

with red blood cells by a unique and robust top-down approach, to

bypass macrophage uptake and systemic clearance [29]. The deg-

radation time of PLGA nanoparticles could be adjusted from hours

to months without any immunogenic response when coated with

natural erythrocyte membranes (i.e. both lipids and the corre-

sponding surface proteins). This design could be a promising

alternative for nanoparticle stealth coating in cases of anti-PEG

immunological responses [30].

In an interesting study with respect to novel hybrid nano-

systems, Narvekar et al. reported the integration of oil in PLGA

[i.e. a polymer–oil-nanostructured carrier in which the core (oil

encapsulating the drug molecule), is dispersed within a

polymer matrix of PLGA] [31]. This combination enabled the

efficient incorporation of a lipophilic drug, all-trans-retinoic

acid, in a dissolved state in oil and also resulted in controlled

drug release and decreased burst release effect during in vitro


drug release, which was attributed to the high amorphicity of

the carrier.

Delivery prospects of hybrid PLGA nanoparticlesDifferent groups are exploring proof-of-concept approaches for the

delivery of pharmaceutical drugs, therapeutic proteins, and genes

using hybrid PLGA nanoparticles (Table 1).

Small-molecule drug deliveryThe delivery of small-molecule therapeutics by hybrid PLGA nano-

particles has been reported in numerous recent studies to over-

come limitations related to drug delivery that are associated with

their components. As Qwith Eudragit1 RS100 or RL100/PLGA nano-

particles, PLGA–lecithin–PEG core–shell nanoparticles, PLGA–oil-

nanostructured carriers, and folate-decorated PEG–PLGA nanopar-

ticles with silica shells have been described for the controlled drug

delivery of ciprofloxacin, docetaxel, all-trans-retinoic acid, and

capecitabine, respectively [24,31–33]. The effect of the drug release

Qprofile on the efficacy and toxicity of drugs delivered via hybrid

PGLA nanoparticles was recently investigated by Sethi et al., who

used wortmannin and docetaxel as model drugs [34]. The authors

reported a decrease in the hepatotoxicity of the nanoparticles

with a concomitant decrease in the drug release kinetics. In

addition, in vivo studies of PLGA-based nanoconjugates demon-

strated an increase in the relative bioavailability of rifampicin

[26]. Stevanovic et al. reported simultaneous antioxidative and

prolonged antimicrobial activity of PLGA/poly(L-glutamic acid)-

capped silver nanoparticles/ascorbic acid particles [28]. In a

recent study, the premature release of short-chain ceramides

(which are cytotoxic to various types of cancer cell) was reduced

when encapsulated in PLGA/liposome hybrid nanoparticles [35].

The authors used fluorescence resonance energy transfer to

monitor the release of the ceramides.

Macromolecular deliveryThe prolonged release of macromolecules Qcan provide a more

effective delivery system, avoiding the risk of tolerance and reduc-

ing the need for repeat dosing.

Gene deliveryAmong the numerous vehicles developed, hybrid PLGA nanopar-

ticles have already made their mark as attractive novel nonviral

gene carriers. They offer several advantages, including no or low

immunogenicity, no risk of transmission of infectious diseases,

flexibility towards the molecular size of the loaded plasmid DNA,

siRNA or antisense oligonucleotides, and low production costs. Shi

et al. developed a differentially charged hollow core of a lipid layer

followed by a PLGA polymer layer and then a neutral lipid layer

that interlaced between the PLGA and outermost PEG layer to

form a lipid–polymer–lipid hybrid nanostructure (Fig. 3a) [14]. The

hybrid nanoparticles encapsulated siRNA by up to 78–82% com-

pared with PLGA and PLGA–PEG, which were able to encapsulate

only 4–8% of the applied siRNA, highlighting the highly efficient

holding of siRNA molecules by inner cationic lipids. In another

study, the PLGA–siRNA nanoparticles comprising a polymeric core

containing siRNA and a lipid shell of 1,2-dioleoyl-3-trimethylam-

monium-propane (DOTAP) and DOPE were fabricated using par-

ticle replication and nonwetting templates technology to avoid





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TABLE 1

Overview of hybrid PLGA nanoparticles and their significancea

Hybridization Encapsulate Physical

characteristics:

size (nm)/LE%/EE%

Therapeutic outcome Application Refs

Material Role

Hydrogenated phosphatidylcholine Ovalbumin 215/15.9/95.3 Higher loading capacity andhigher affinity to M cells

Oral vaccinedelivery

[9]

Dextran sulfate, DSPE-PEG Inhibit P-glycoprotein

efflux

Vincristine 128/12.5/93.6 P-glycoprotein efflux

inhibition by nanoparticles

remarkably enhanced oralbioavailability and cellular

uptake of vincristine

Drug delivery [12]

Chitosan Paclitaxel 386/nd/nd Cellular association and

cytotoxicity of paclitaxelsignificantly enhanced

Drug delivery [21]

Tetramethoxysilane Tuning release properties Capecitabine 200/7.9/69 Silica shell improved

controlled release behavior of

nanocarrier

Drug delivery [24]

Ag–Au Enhance biodetection Paclitaxel 200/3.7/95 Highly efficient biodetectionwith chemotherapeutics

delivery

Drug delivery andbioimaging

[25]

Montmorillonite Tuning release properties Propranolol 100/60.6/77.3 High drug-loading capacity

with well-controlled release

Drug delivery [27]

Propylene glycol dicaprylate(Captex)

Enhance Loading capacity All-trans retinoic acid1

or indomethacin2215/nd/711, 632 High drug-loading capacity

and higher anticancer activity

compared with conventional

PLGA nanoparticles

Drug delivery [31]

Magnetic silica Induce magnetic properties Paclitaxel1, doxorubicin2 150/nd/89.21, 222 Enhanced BBB penetrationwith very high tumor growth

inhibition ability

Drug deliverythrough BBB

[43]

Octadecyl-quaternized lysine

modified chitosan

Bind DNA Doxorubicin, pEGFP 435/nd/nd Good DNA-binding ability

with tumor-targeted delivery

Codelivery of

drug and gene

[44]

Lecithin, DMPE, DTPA/DSPE-PEG Enhance Loading capacity Docetaxel, indium111,yttrium90

65/9/60 Chemotherapeutics andradiotherapeutics co-

encapsulated efficiently and

delivered effectively

Codelivery oftwo drugs

[46]

Cyclic lipid, DSPE-PEG, DOPC Capsaicin1, anti-siTNFa2 163/nd/901, 692 Enhanced skin permeationand efficient intracellular

delivery

Codelivery ofdrug and gene

[47]

DSPE-PEG/GD-LIPID Improve bio-distribution Iron oxide nanoparticles 150/nd/40 Three times higher T2 MRI

behavior compared with theclinically used contrast agent

Bioimaging [53]

Polyethylenimine Bind DNA pDNA 270/nd/72.6 Higher as well as controlled

gene transfection efficiency

Gene delivery [54]

Bovine serum albumin Entraps hydrophilic drug Gemcitabine 243/8.5/40.5 Hydrophilic molecule is

efficiently loaded

Drug delivery [55]

6

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TABLE 1 (Continued )

Hybridization Encapsulate Physical

characteristics:

size (nm)/LE%/EE%

Therapeutic outcome Application Refs

Material Role

Hydrogenated castor oil Enhances loading capacity Insulin1, bovine serum

albumin 2146/3.61, 3.91/

72.61, 83.72Enhanced loading capacity of

hydrophilic peptide andprotein

Protein and peptide

delivery

[56]

Poly-lactic acid Controlled drug release Meropenem 321/nd/82 Extended drug release for up

to 30 days

Drug delivery [57]

Lectin Improves bioadhesion Hepatitis B surface

antigen

360/nd/45.8 Efficient delivery to intestinal

Peyer’s patches followed by Mcell targeting

Vaccine delivery [58]

Chitosan/polyethylene glycol Reduces microphage uptake Paclitaxel 286/nd/65.8 Prolonged circulation time

with enhanced cellular uptake

and cytotoxicity

Drug delivery [59]

Casein Entraps hydrophilic drug Paclitaxel1, epigallocatechingallate (EGCG)2

190/nd/96.31, 622 Hydrophilic drug EGCGeffectively encapsulated in

casein shell and released

before paclitaxel, resulting in

higher plasma concentrationof paclitaxel

Codelivery of twodrugs

[60]

Heparin-/chitosan-pluronic

conjugate

Enhances stability – 144/nd/nd Good stability in blood and

improved cellular uptake

Tumor targeting [61]

aAbbreviations: Ag–Au, silver–gold; DMPE, 1,2-ditetradecanoyl-sn-glycero-3-phosphoethanolamine; DOPC, 1,2-dioleoyl-sn-glycero-3-phosphocholine; DTPA, diethylenetriaminepentaacetate; EE%, percentage entrapment efficiency; GD,

gadolinium; LE%, percentage loading efficiency; nd, not defined.

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DRUDIS 1504 1–10

DSPE-PEGm

200 nm

Lecithin

Polymer

Cationic lipid

siRNA

Loading DOX

Modificationwith –NH2

500 nm

10 µm

MNP-MSN

(i) Blood vessel

(ii) BBB

(iii) Brain

Endothelial cell

Iron oxide

Mesopore of MSN

DOX

PTX

Transferrin (Tf)

TfR

Cancer cell

(b) target glioma cellsand release drugs

(a) transport across BBBvia Tf-Tfr-mediated endocytosis

DOX-MNP-MSN

Single emulsificationsolid-in-oil-in-water

Two-step EDC/NHS activationand surface grafting method

Coating PLGA& loading PTX

DOX-PTX-MNP-MSN-PLGA

Conjugation of transferrin

DOX-PTX-NPs-TfPLGA

Normal cell

(i)(a)

(b)(i)

(ii)

(ii)


FIGURE 3

(a) (i) Schematic representation of the lipid–poly(lactic-co-glycolic acid) (PLGA)–lipid hybrid nanostructure, (ii) representative transmission electron microscopy

image of the hybrid nanoparticles, and (iii) confocal laser scanning fluorescence image of the hybrid microparticles demonstrating the existence of an outer lipid–

PEG layer (green) and inner lipid layer (red), separated by a PLGA layer (blue) [14]. (b) Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with

doxorubicin (DOX) and paclitaxel (PTX). (i) Preparation and (ii) transport across blood–brain barrier (BBB) for brain glioma treatment [43]. Abbreviations: DSPE-PEG,1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy-(polyethylene glycol)-2000; MNP, magnetic nanoparticle; MSN, mesoporous silica nanoparticle; NPs,

nanoparticles; siRNA, short-interfering RNA; TfR, Tf receptors.

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he formation of polyplexes [36]. The lipid-coated PLGA–siRNA

anoformulation knocked down luciferase expression as well as

ausing significant mitotic arrest. More recently, the potential for

iRNA-encapsulated polyethylenimine–PLGA nanoparticles to

ross the blood–brain barrier (BBB) for use as cancer therapy has

lso been reported [37].

rotein delivery PLGA-based nanoplatform offers promising opportunities for

nhanced efficacy of protein and peptide therapeutics, as suggested

y various recent studies. For example, recombinant IFNg was

mobilized on silver nanoparticle-loaded PLGA composites, where



the fabricated platform provided stability to the protein and the

silver nanoparticles potentiated the anticancer activity of the re-

combinant IFNg [38]. In addition, insulin-loaded PLGA nanoparti-

cles entrapped in polyvinyl alcohol hydrogels exhibited a protein

encapsulation efficiency of 72.6% and controlled release protein

kinetics as a result of a reduction in the release rate [39]. Recently,

the optimization of human serum albumin-loaded magnetic PLGA

nanoparticles was carried out using the mathematical GAMSTM/

MINOS software; the resulting nanoparticles were found to achieve

an encapsulation efficiency of 92.3% for 155-nm nanoparticles [40].

Ma and coworkers demonstrated the potential of PLGA–lipid lipo-

spheres for oral bioavailability enhancement of proteins [41]. By





DRUDIS 1504 1–10


tuning the degradation behavior or molecular weight of the poly-

mer, the authors we able to report a prolonged circulation time,

controlled release of the model protein with reduced burst release,

and enhanced transcytotic efficiency across the in vitro M cell model.

Co-deliverySeveral exciting results have been obtained using hybrid PLGA

nanosystems as a dual-drug delivery system for safe and targeted

cancer therapy. An aptamer–lipid–PLGA core–shell nanosystem

successfully targeted doxorubicin and paclitaxel to CEM (human T

cell acute lymphocytic leukemia) cancer cells and resulted in

enhanced antitumor efficacy [42]. In previous study, Cui et al.

studied the same combination of chemotherapeutic drugs for

brain glioma treatment, wherein doxorubicin was loaded in the

core phase of magnetic silica and the shell phase of PLGA was used

to load paclitaxel [43]. Figure 3b illustrates the preparation and

transport of transferrin-conjugated magnetic silica PLGA nano-

particles loaded with doxorubicin and paclitaxel across the BBB

and the targeting of glioma cells for cancer treatment.

The co-delivery of therapeutics with molecules and/or inhibi-

tors targeting antiapoptotic or other mechanisms of resistance

using hybrid systems might also be beneficial. The possibility to

deliver drug and DNA has been evaluated to address the problem of

multidrug resistance. Doxorubicin and pEGFP were incorporated

into PLGA/folate-coated PEGylated polymeric liposome core–shell

nanoparticles and tested against MDA-MB-231 breast cancer cells

overexpressing folate receptors [44]. RGD peptide-mediated tumor

targeting was achieved with doxorubicin and verapamil in an

integrated treatment for cancer and drug-induced cardiomyopa-

thy [45]. In an interesting study, Wang et al. designed ChemoRad

nanoparticles as a novel class of therapeutics, using docetaxel,

indium111 and yttrium90 as model drugs. The concurrent admin-

istration of chemotherapeutics and radiotherapeutics incorporat-

ed in a PLGA–lipid multifunctional platform has great potential to

improve cancer treatment [46].

Novel biodegradable cationic lipid–polymer hybrid PLGA nano-

particles were formulated by Desai and coworkers for the topical

delivery of capsaicin and siRNA simultaneously [47]. These nano-

particles comprised an inner PLGA layer encapsulating the drug

surrounded by cationic lipids that contained a cyclic pyrrolidinium

head group, which was responsible for delivering siRNA to deeper

skin tissues and promoting drug retention in the polymer core and

the outer DSPE-PEG2000 layer. The cytotoxic studies demonstrated

this carrier to be superior to the siRNA transfection reagent Lipo-

fectamineTM RNAiMAX. Furthermore, the system showed the en-

hanced permeation of drug through skin and was found to be

effective against chronic inflammation when evaluated in a chronic

plaque-like mouse model. Moreover, transfection by cationic lipids


produced a low immunological response and efficiently delivered

nucleic acids in large amounts under systemic conditions.

ImagingNovel lipid-coated PLGA nanoparticles with tunable bioimaging

features have been realized by integration of metallic gold nano-

crystals and quantum dots for computed tomography and mag-

netic resonance imaging (MRI) [48]. However, systematic

evaluation of the in vitro and in vivo performance of PLGA nano-

particles is complicated. These obstacles could be mitigated by co-

loading quantum dots, iron oxide, or gold nanoparticles along

with the therapeutic agent within the PLGA nanoparticles.

Schleich et al. developed paclitaxel and superparamagnetic iron

oxide-loaded PLGA nanoparticles for theranostic purposes [49].

The fabrication of nanocomposites using a simple technique of

coating the silica nanospheres (50 nm) on surface-modified posi-

tively charged monodisperse PLGA particles resulted in long-term

fluorescence and exhibited controlled release of pyrene, which

improves the functionality of this composite over that of pyrene/

PLGA particles; thus, it could be used as an efficient device for bio-

imaging and drug delivery [50].

A novel core–shell nanomedicine for blocking cancer migration

followed by photodynamic killing was developed that comprised a

photosensitizer-loaded �80-nm PLGA nano-core and tyrosine

kinase inhibitor, Dasatinib loaded �20 nm size albumin nano-

shell, was rationally designed against cancer metastasis [51]. Bio-

degradable polymeric vesicles consisting of PLGA nanoparticles

encapsulating magnetic nanoparticles and manganese-doped zinc

sulfide quantum dots have been recently reported for simulta-

neous diagnosis and cancer therapy [2]. Additionally, for the first

time Qiu et al. fabricated hybrid multimodal PLGA nanoparticles

by incorporating quantum dots, superparamagnetic iron oxide

and gold nanoparticles, for neutrophil labeling, imaging and

tracking [52].

Concluding remarksWith tunable properties, PLGA hybrid nanoparticles have emerged

as significant delivery vehicles for widespread applications, as

pointed out by several recent investigations. Since their inception,

hybrid PLGA nanoparticles have undergone remarkable progress

based on their versatile applications. Their flexibility in addressing

the delivery of therapeutic and imaging moieties because of their

superior encapsulation, cellular uptake, and cytotoxicity com-

pared with nonhybrid counterparts has created an intense need

for the development of newer hybrid delivery systems. However,

further research related to the stability, in vivo studies and phar-

macokinetic profiles of hybrid PLGA nanocarriers is required to

determine fully their clinical impact.

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Hybrid poly(lactic-co-glycolic acid) nanoparticles: design and delivery prospectives