Synthetic micro/nanomotors in drug delivery

Wei Gao and Joseph Wang

Nanomachines o

er considerable promise for the treatment of diseases. The ability of man-made

nanomotors to rapidly deliver therapeutic payloads to their target destination represents a novel

nanomedicine approach. Synthetic nanomotors, based on a multitude of propulsion mechanisms, have

been developed over the past decade toward diverse biomedical applications. In this review article, we

journey from the use of chemically powered drug-delivery nanovehicles to externally actuated (fuel-free)

drug-delivery nanomachine platforms, and conclude with future prospects and challenges for such

practical propelling drug-delivery systems. As future micro/nanomachines become more powerful and

functional, these tiny devices are expected to perform more demanding biomedical tasks and bene

erent drug delivery applications.

Introduction

Drug delivery needs

Drug delivery technology is an area of enormous importance to

health care, and aims at addressing the de



ciencies of

conventional means for administering drugs.

1,2

The need for the

development of innovative technologies to improve the delivery

of therapeutic agents in the body has been widely recognized.

Considerable research e

orts have thus been directed over the

past 15 years to the development of targeted drug delivery

systems aimed at preventing and treating debilitating diseases.

Such delivery platforms promise to address several key issues,

including low therapeutic e

ffi

cacy and signi



cant negative side

ects by delivering a drug where the medication is needed,

while sparing healthy parts of the body.

4,5

New technologies are

also needed for delivering therapeutic agents to areas of the

body that are currently inaccessible to current delivery methods

and for improving tissue penetration.

Towards nanomedicine

Nanotechnology-enabled drug delivery systems have received

considerable interest owing to their major impact on the

treatment of diseases.

6,7

The promise of such nanotechnology-

based systems is to deliver a drug selectively to the target tissues

and cells with increased e

ffi

cacy while reducing side e

ects.

Wei Gao received his PhD in

Chemical Engineering at

University of California, San

Diego in 2014, where he worked

under the supervision of

Professor Joseph Wang on

synthetic micro/nanomachines.

He has received Jacobs Fellow-

ship of UC San Diego, 2012

HHMI International Student

Research fellowship, 2012

Chinese Government Award for

Outstanding

Self-



nanced

Students Abroad and MRS Graduate Student Silver Award (2013

and 2014). He is currently a postdoctoral fellow at the University

of California, Berkeley. His research interests include nano-

materials, naonomachines, electrochemistry, MEMS/NEMS and

nanomedicine.

Joseph Wang is a Distinguished

Professor and Chair of Nano-

Engineering at University of

California San Diego (UCSD),

USA. A



er holding a Regents

Professor position at NMSU he

moved to ASU where he served

as the Director of the Center for

Bioelectronics and Biosensors

(Biodesign Institute). He joined

the UCSD NanoEngineering

Dept. in 2008. He also serves as

the Chief Editor of Electroanal-

ysis. The research interests of Dr Wang include the development of

nanomotors and nanoactuators, bioelectronics and biosensors,

and

“

smart

”

wearable sensor systems. He has authored over 900

research papers, 10 books, 12 patents, and 35 chapters

(H index 104).

Department of Nanoengineering, University of California, San Diego, La Jolla, CA,

92093, USA. E-mail: josephwang@ucsd.edu

Cite this:

Nanoscale

,2014,

, 10486

Received 6th June 2014

Accepted 30th June 2014

DOI: 10.1039/c4nr03124e

www.rsc.org/nanoscale

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wide range of nanomaterial-based systems have thus been

developed for drug delivery applications, including liposomes,

polymeric nanoparticles, dendrimers, polymersomes, nano-

emulsions.

1,2

Signi



cant progress has been made towards

improving the therapeutic e

ffi

cacy of drug-loaded nano-

particles, including extended drug systemic circulation lifetime,

improved the solubility of poorly water-soluble drugs, co-

delivery of two or more drugs or of therapeutic and imaging

agents within the same particle (

i.e.

“

theranostics

”

), and

controlled or triggered release of the encapsulated drugs. While

functionalizing the particle surface with targeting ligands can

result in accumulation around tumors, o

-targeting (and the

corresponding adverse e

ect) remains a major challenge.

Another challenge of common drug delivery vehicles is the lack

of power necessary for penetrating tissue and cellular barriers.

Deep tissue penetration and cellular interaction thus represents

another important goal. To achieve such active targeting and

deliver payloads to predetermined locations in the body, future

generation drug delivery vehicles may need to incorporate

propulsion and navigation capabilities. Nanoshuttles, precisely

guided by a physician, have the potential to transport thera-

peutic agents directly to diseased tissues, and to access nearly

every site of the human body through blood vessels, indepen-

dent of the blood



ow, thereby improving the therapeutic e

ffi

cacy and reducing systemic side e

ects of highly toxic drugs.

Nanomotors for drug delivery

The use of nanomotors to power nanomachines is currently a

research area of tremendous

activity due to a wide range of

potential applications.

–

Synthetic nanomotors, based on a

multitude of propulsion mechanisms, have thus been devel-

oped over the past decade.

–

10,18

Whilemostofthisattention

has been given to chemically powered catalytic micro-

motors,

–

many important applications (particularly

in vivo

biomedical ones) require the elimination of the fuel require-

ments toward biocompatible propulsion mechanisms. E

orts

in this direction have led to the fuel-free locomotion of

magnetically driven nanoswimmers,

–

or acoustically

propelled devices.

–

Major advances in nanomotor tech-

nology, including the design of powerful multifunctional

machines, advanced motion control and cargo towing capa-

bilities, have facilitated di

erent biomedical applications

ranging from cell sorting

to DNA hybridization.

The

substantial progress towards using functionalized nano-

motors for e

ffi

cient cargo transport and release paves the way

to their drug-delivery applications. The targeted delivery of

therapeutic cargoes represents a major future application of

synthetic micromotors.

Such nanomachine-based drug

delivery systems are highly at

tractive platforms for e

ffi

cient

delivery of therapeutic payloads to targeted sites, and could

address some of the obstacles o

f current drug delivery systems.

Unfortunately, there is no comprehensive review published on

using synthetic micro/nanomachines for drug delivery

platforms.

In this review we highlight recent research e

orts aimed at

developing man-made nanomachines for drug delivery

applications and give an outlook on current challenges and

emerging trends. Table 1 summarizes recent progress of drug

delivery based on diverse nanomotors powered by di

erent

mechanisms. These new drug-delivery nanoshuttles are dis-

cussed in the following sections, along with related opportu-

nities and challenges.

Catalytically powered micro/

nanomotors for targeted drug delivery

Catalytically powered micro/nanoscale motors rely on the

catalytic decomposition of a solution-borne fuel, usually

hydrogen peroxide, on a platinum surface.

–

Such fuel-driven

motors possess a relatively high power essential for performing

erent biomedical tasks involving cargo towing.

This force is



ected by a remarkable speed that can exceed 1000 body-

lengths s

Motion control is another important requirement

for targeted drug delivery. The directionality of catalytic micro/

nanoscale motors can be readily controlled (commonly

via

magnetic guidance) and their speed can be regulated using

erent stimuli.

Tremendous progress has been made on

cargo-carrying catalytic nanomotors based on di

erent loading

and unloading mechanisms.

These advances have facilitated

orts aimed at using a variety of catalytic nanomotors (based

on wire, sphere or open-tube con



gurations) for targeted drug

delivery.

Wang, Zhang and coworkers demonstrated the



rst

example of using man-made micromotors for the transport

and release of drugs.

This pioneering study

illustrated that

catalytic nanowire shuttles can readily pickup drug-loaded

poly

-lactic-

-glycolic acid (PLGA) particles and liposomes

and transport them over predetermined routes towards target

destinations. Powerful alloy or CNT-based nanowire motors

have been used to increase the force necessary to transport

‘

heavy

’

therapeutic cargos. These nickel-containing motors

captured the iron-oxide encapsulated PLGA and liposome drug

nanocarriers through magnetic interactions. The nanomotors

can thus pickup, transport and release varying sized drug

carriers towards predetermined destinations. Fig. 1 displays

scheme (A) and time-lapse

images (B) of such dynamic

capture, transport and release of doxorubicin (DOX)-loaded

PLGA nanoparticles using a catalytic Ni/(Au

/Ag

)/Ni/Pt

nanowire motor. In comparison with the PLGA particles,

transport of the drug-loaded liposome is relatively slower due

to its large size.

et al.

reported the preparation of a well-de



ned multi-

layer tubular polymeric nanomotor through the nanoporous

template-assisted layer-by-layer (LbL) assembly.

Platinum

nanoparticles (Pt NPs), assembled into the inner surface of LbL-

assembled nanotubes, provided the catalytic decomposition of

the hydrogen peroxide fuel essential for the bubble propulsion.

These nanorockets can serve as autonomous motors as well as

smart cargos, performing drug loading, targeted transportation

and remote-controlled release in the vicinity of cells and tissues.

The



uorescent anticancer drug doxorubicin was loaded onto

the nanorockets through encapsulation. An ultrasound (US)

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

eld was used to trigger the breakage of the outer shell of the

LbL assembled polyelectrolyte multilayer microcapsules and

release the encapsulated drugs. The images in Fig. 2 display

(alginate (ALG)/chitosan (CHI))

–

DOX

–

(ALG/CHI)

–

(CHI/

ALG)

–

Pt NP nanorockets attached to the outer surface of HeLa

Table 1

Recent progress on drug delivery using micro/nanomotors based on a multitude of propulsion mechanisms and designs

Types of motors

Type of drug/model drug

Attach/release

References

Catalytically powered

nanomotors

Ni/(Au

/Ag

)/Ni/Pt

Doxorubicin in PLGA and

liposome nanoparticles

Magnetic interaction

Kagan

et al.

LbL self-assembled

PSS/PAH capsule

FITC

–

dextran

Encapsulation by varying

solvent polarities

et al.

LbL polymer multilayer

CHI/ALG nanorockets

Doxorubicin

LbL encapsulation/

ultrasound triggered

release

et al.

Janus mesoporous silica

nanomotors

Doxorubicin

Adsorption of porous

silica/endocytosis

Xuan

et al.

LbL PSS/PAH catalase

based capsules

Doxorubicin

Encapsulation/NIR laser

triggered release

et al.

AgNP-decorated

polycaprolactone single

crystal

Fluorescent rhodamine B

isothiocyanate

Covalent link/disassembly Li

et al.

Micromotors-powered by

alternative fuels

Mg based microsphere

motors

FITC

Temperature-induced

“

breath-in

”

ect/

temperature triggered

release

Mou

et al.

Zinc based micromotors

Silica and gold particles

Plating encapsulation/

dissolution in an acidic

environment

Sattayasamitsathit

et al.

Magnetic nanomotors

Flexible nanowire motors Doxorubicin loaded in

PLGA nanoparticles

Magnetic interaction/

usion

Gao

et al.

Helical swimmer

Calcein loaded in

liposome particles

Electrostatic interaction/

fusion of the cationic

vesicles or endocytosis

Mhanna

et al.

Helical swimmer

Rhodamine B and calcein Electrostatic interaction/

temperature triggered

release

Qiu

et al.

Ultrasound nanomotors

Au/Ni/Au/PPy nanowire

motor

Brilliant green

Electrostatic interaction/

pH triggered release

Garcia-Gradilla

et al.

Porous Au

–

nanowire

Doxorubicin and brilliant

green

Electrostatic interaction/

NIR triggered release

Garcia-Gradilla

et al.

Fig. 1

Transport and release of PLGA drug carriers by catalytic

nanowire motors. Schematic (A) and microscopic time lapse-images

(B) depicting the dynamic pick-up (a), transport (b), and release (c) of

drug-loaded PLGA particles using a nanoshuttle. (Reproduced from

ref. 34, Wiley 2010.)

Fig. 2

(A) Self-assembled polymer multilayer nanorockets based on a

template-assisted layer-by-layer (LBL) technique can propel chemi-

cally in the presence of a hydrogen peroxide fuel. These motors can

perform drug loading, targeted transportation, and triggered drug

release by an external physical stimulus in a controlled manner. (B) The

DIC (a and d), the corresponding CLSM (b and e), and SEM images (c

and f) of a (CHI/ALG)

–

DOX

–

(ALG/CHI)

–

–

(CHI/ALG)

–

PtNP

nanorocket before (a

–

c) and after (d

–

f) ultrasound treatment

in vitro

and continuous cultivation of the HeLa cells for 3 h. (Reproduced from

ref. 35, Wiley 2013.)

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cancer cells. Di

erential interference contrast (DIC), confocal

laser scanning microscopy (CLSM), scanning electron micros-

copy (SEM), and atomic force microscopy (AFM) images show

the corresponding results before and a



er ultrasonic treatment.

In comparison with the image before ultrasonic treatment

(Fig. 2Bb), the red



uorescence from DOX in the CHI/ALG

multilayer nearly disappeared (Fig. 2Be), indicating that most of

DOX molecules have been released through the ultrasound

irradiation. Similar concepts were also demonstrated in LBL

capsule based micromotors. Wu

et al.

reported also the use of

dendritic Pt-nanoparticles or catalase-modi



ed polyelectrolyte

capsules as micromotors as well as carriers for drug delivery.

36,38

Fluorescein isothiocyanate

–

dextran (FITC

–

dextran) model

drugs or doxorubicin have been loaded onto these microcap-

sules by encapsulation.

Another recent work from the same Chinese group

described a new self-propelle

d Janus silica nanomotor which

can also serve as the drug carrier for intracellular drug

delivery.

As illustrated in Fig. 3, this peroxide-propelled

catalytic Janus nanomotor is based on mesoporous silica

nanoparticles (MSNs) with chromium/platinum metallic caps.

MSNs o

er an exceptionally high surface area, which enables

the loading of diverse cargoes. The DOX drug was loaded into

mesoporous pore channels of Janus MSN motors by physical

adsorption, and then covered with an egg phosphatidylcholine

(PC) bilayer. Intracellular l

ocalization and drug release

experiments

in vitro

have indicated that the amount of Janus

MSN nanomotors entering the cells is more than control MSNs

with the same culture time and particle concentrations,

meanwhile anticancer drug doxorubicin hydrochloride loaded

in Janus MSNs can be slowly released in the cells by biodeg-

radation of the lipid bilayers.

Other recent studies hold considerable promise for a variety

of biomedical applications. For example, Sanchez

et al.

reported

the use of self-propelled rolled-up microtubes to drill and

embed themselves into biomaterials such as cells which can be

potentially used to address the endosome escape challenge and

deliver the drug or gene inside the cell.

Another study by Wu

et al.

demonstrated that by taking advantages of photothermal

ects, PtNP-modi



ed polyelectrolyte multilayer microtube

engines can be used for targeted recognition and subsequent

killing of cancer cells.

Micromotors powered by alternative

fuels for drug delivery

Although major progress has been made on drug delivery based

on catalytic micro/nanomotors, current reliance on the

common hydrogen peroxide fuel greatly hinders practical

biomedical applications of catalytic micromotors. In particular,

in vivo

drug delivery applications would require the use of body



uids or their constituents as the powering fuel. Recent e

orts

have been directed at expanding the scope of fuels for synthetic

nanomotors by exploring the use of natural bio



uids as the fuel

source, thus obviating the need for external chemical fuels.

–

For example, Gao

et al.

described an acid-driven polyaniline/

zinc microtube rocket that can propel autonomously and e

ffi

ciently in gastric acid, and thus can be operated in the stomach

environment.

Reports of the use of glucose-powered enzyme-

based carbon swimmers are also promising in this respect,

although the propulsion mechanism is based on current



ow,

and was shown to diminish at high salt concentrations.

Of particular interest for practical drug delivery applications

are recently developed water-driven micromotors that utilize the

magnesium

–

water reaction for the propulsion.

55,56

These

magnesium-based Janus microsphere motors consist of biode-

gradable magnesium microparticles coated with a gold or

platinum patch. Such water-driven micromotors utilize macro-

galvanic corrosion and chloride pitting corrosion processes to

generate hydrogen bubbles that propel the microparticles. This

eliminates the need for external fuels and o

ers e

ffi

cient pro-

pulsion in untreated high-salt aquatic media which is particu-

larly attractive for

in vivo

drug delivery applications. Another

water-driven micromotor explores Janus particles based on the

–

Ga alloy for e

ffi

cient hydrogen bubble propulsion through a

process called

‘

liquid metal enbrittlement

’

but lacks the

biocompatibility of magnesium-based micromotors. Additional

orts should be devoted to extending the lifetime of these

water-powered micromotors, along with proper surface func-

tionalization, for addressing the requirements of practical drug

delivery.

Mou

et al.

described recently a biocompatible drug-loaded

magnesium-based Mg/Pt

–

poly(

-isopropylacrylamide) (PNI-

PAM) Janus micromotor (Fig. 4).

Such water-powered micro-

motors display an e

ffi

cient autonomous motion in simulated

body



uid (SBF) or blood plasma without any additives or fuels.

It o

ers also attractive capabilities of loading, transporting and

delivering drug molecules by taking advantages of the partial

surface-attached thermoresponsive PNIPAM hydrogel layers.

The drug releasing process from the micromotor can be

controlled by the environmental temperature due to the

‘

squeeze

’

ect. Hemolysis assay has suggested that such

micromotors and their autonomous motion have a negligible



uence on the red blood cells (RBCs, highly hemocompatible)

and are friendly to organisms.

Combination therapy o

ers several distinct advantages for

disease treatment (

e.g.

, high e

ffi

ciency, synergistic e

ects and

reversal of drug resistance) compared to normal single drug

therapy.

6,58

Such combinatorial drug delivery may require new

Fig. 3

(A) Synthetic procedure for the preparation of Janus MSN

nanomotors, as well as subsequent drug loading, lipid bilayer func-

tionalization, transportation, and drug release. (B) DOX release from

egg PC modi

ed Janus MSN nanomotors inside HeLa cells following:

(a) 0, (b) 1, (c) 2, and (d) 3 h. The images are overlays of

uorescence

and DIC channels. Scale bars, 10 mm. (Reproduced from ref. 37, Wiley

2014.)

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vehicles that enable co-encapsulation of di

erent drugs, active

targeting, and/or temporally controlled release. A recent work

from our laboratory illustrated a fully loaded multi-cargo zinc

based micromotor which can be potentially used for combina-

torial delivery (Fig. 5).

Such an acid-powered bubble-propelled

micromotor possesses several distinct functions for potential

biomedical use. These include remarkably high loading

capacity, combinatorial delivery of a multitude of cargoes,

autonomous release of encapsulated payloads, and self-

destruction. Such multifunctional zinc-based micromotors,

prepared by dual-templating nanofabrication, can move rapidly

in an acidic environment and transport the fully loaded cargoes

with a speed of 110

m

. As the zinc body is oxidized and

dissolved by the acid fuel, the di

erent cargoes are released

autonomously and the motors are self-destroyed, leaving

behind no harmful chemical agents. This attractive concept can

be readily expanded to simultaneous encapsulation of a wide

variety of payloads, possessing di

erent biomedical functions

such as therapy, diagnostics, and imaging, hence opening up

new drug delivery opportunities.

Magnetic micro/nanomotors for drug

delivery

To address the limitations of fuel-driven micromotors and

enhance biocompatibility, several groups have been exploring

fuel-free micro/nanomachine propulsion mechanisms,

including the utilization of magnetic,

–

electrical,

–

optical,

or ultrasound

–



elds. Magnetically driven nano-

motors, inspired by nature swimming microorganisms, are

particularly promising for use in a variety of

in vivo

biomedical

applications.

Such micromotors can swim under externally

applied magnetic



elds in various bio



uids, and perform

complex maneuvers while obviating fuel requirements.

Magnetic actuation is suitable for

in vivo

applications since the

required



eld-strengths are harmless to humans. Ghosh

et al.

reported recently the



rst successful

“

voyage

”

of magnetic

nanomotors, based on conformal ferrite coatings, in human

blood.

Such magnetic

“

nanovoyagers

”

were shown to be

cytocompatible with mouse myoblast cells. Magnetically actu-

ated micromachines are thus currently being explored exten-

sively as promising platforms for controlled

in vivo

drug delivery

applications.

Gao

et al.

reported the



rst example of directed delivery of

drug-loaded magnetic polymeric particles using magnetic

nanoswimmers.

The fundamental mechanism of the cargo-

towing ability and the hydrodynamic features of these



exible

nanowire motors have been discussed. The e

ect of the cargo

size on the swimming performance was evaluated experimen-

tally and compared to a theoretical model, emphasizing the

interplay between hydrodynamic drag forces and boundary

actuation. Potential applications of these cargo-towing nano-

swimmers were demonstrated using the directed delivery of

Fig. 4

(A) Schematic demonstration of the drug (a and b) loading, (c)

transporting, and (d) releasing behaviors of the Mg/Pt

–

PNIPAM Janus

micromotors. (B) Fluorescent images representing the drug release

from the Mg/Pt

–

PNIPAM Janus microsphere motor (a) and the

normalized average cumulative drug release pro

les (b) at 20 and

versus

time. Scale bars: 10

m

m. (Reproduced from ref. 40,

American Chemical Society 2014.)

Fig. 5

SEM images and energy-dispersive X-ray spectroscopy (EDX)

analysis of fully loaded dual-cargo Zn micromotors towards combi-

natorial therapy. (a

–

d) Zn micromotors encapsulated with 500 nm

SiO

particles. (e

–

h) control Zn micromotors without the SiO

parti-

cles. Scale bar, 0.5

m

m (b) and (f), 1

m

m (a) and (e), and 2

m

m (c), (d), (g)

and (h). (Reproduced from ref. 41, Wiley 2014.)

Fig. 6

Drug delivery to HeLa cells using

exible magnetic nano-

swimmers in cell-culture media. Scheme (A) and microscopic time-

lapsed images (B) depicting the process as a

exible magnetic Ni

–

nanowire motor (a) capturing the doxorubicin-loaded magnetic

poly(

-lactic-

-glycolic acid) (PLGA) particle in the loading reservoir

(b), transporting it through the microchannel (c), approaching the

target cell (d), sticking onto the target cell, and releasing the drug (e).

(Reproduced from ref. 42, Wiley 2014.)

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drug-loaded microparticles to HeLa cancer cells in biological

media. Fig. 6 illustrates the schematic and experimental results

of using the magnetic nanowire swimmers for transporting of

target iron oxide/doxorubicin-encapsulated PLGA particles

through a microchannel from the pick-up zone to the release

microwell.

As was illustrated by Nelson's group in ETH, magnetically

actuated helical micromachines hold considerable promise for

diverse biomedical applications.

64,65

The Swiss team developed

the arti



cial bacterial



agella (ABFs) which are capable of per-

forming precise 3D navigation in



uids under rotating magnetic



elds and are harmless to cells and tissues.

They reported the

successful functionalization of titanium-coated ABFs with

temperature-sensitive dipalmitoyl phosphatidylcholine (DPPC)-

based liposomes. The ability to load both hydrophilic and

hydrophobic drugs and to release the cargo was illustrated. The

functionalized ABFs (f-ABFs) can be used to incorporate both

hydrophilic and hydrophobic drugs. The preparation of lipo-

some-functionalized microdevices was demonstrated for

remotely controlled single-cell drug delivery. These liposome-

functionalized arti



cial bacterial



agella displayed corkscrew

swimming in 3D with micrometer positioning precision by

applying an external rotating magnetic



eld. The devices are

also capable of delivering water-soluble drugs to single cells

vitro

(Fig. 7A).

Thermally triggered release of calcein (a

common drug analog) from f-ABFs was demonstrated

(Fig. 7B).

The



uorescent signals on f-ABFs greatly decreased

upon increasing the temperature from 37 to 41

C and the



uorescence intensity of the background increased accordingly,

indicating the signi



cant release of entrapped calcein from the

DPPC/monostearoyl phosphatidylcholine (MSPC) liposomes at

C. These f-ABFs o

er considerable potential for drug

delivery.

Despite the signi



cant progress of the nanomotor design

and our new understanding of the ability of magnetic micro-

motors to transport cargo, several key challenges still exist for

their practical

in vivo

use. While eliminating the fuel require-

ments, attention must be given also to the preparation of more

biocompatible magnetic nanoswimmers. A protective coating

around a magnetic nanomotor is essential to prevent etching of

the magnetic material by blood components. Cleavable linkers,

responsive to tumor microenvironments, are desired to enable

an autonomous release of the therapeutic payload to the target

site. Signi



cant challenges remain for translating these initial

proof-of-concept studies into practical drug delivery applica-

tions. Eventually, such magnetically driven fuel-free nano-

shuttles are expected to provide an attractive approach for

delivering drug cargos to predetermined destinations in a target

speci



c manner.

Ultrasound-powered micro/

nanomotors for drug delivery

Ultrasound has found extensive applications in medicine, and

holds considerable promise for driving micromotors in bio-

logical



uids.

66,67

Recent e

orts by the teams of Mallouk's

group

29,68

and our team

30,31

have illustrated the use of possibility

of using ultrasound for propelling gold-nanowire and tubular

motors in biologically relevant environments.

Garcia-Gradilla

et al.

described recently the use of ultra-

sound-driven nanowire motors based on the nanoporous gold

segment for increasing the drug loading capacity.

The new

highly porous nanomotors, prepared by dealloying a Au

–

alloy segment, o

er a tunable pore size, high surface area, and

high capacity for the drug payload. The drug doxorubicin was

loaded within the nanopores

via

electrostatic interactions with

an anionic polymeric coating. Ultrasound-driven transport of

the loaded drug toward cancer cells was followed by near-

Fig. 7

Magnetically propelled helical microswimmer for drug delivery.

(A) f-ABF swimming and calcein delivery to single cells. (a) A repre-

sentative time-lapse follow-up of the swimming of functionalized

arti

cial bacterial

agella (f-ABF) coated with calcein-loaded lipo-

somes. (b) Representative calcein delivery from f-ABF to single cells at

low magni

cation (left), high magni

cation of calcein delivery (middle)

and calcein delivered to cells after removing the f-ABF (right).

(Reproduced from ref. 43, Wiley 2014.) (B) Calcein release from DPPC/

MSPC-functionalized ABFs at 33, 37 and 41

C, respectively. The upper

three pictures are

uorescence images, and the lower three pictures

are the combined images of

uorescence and bright

elds. (Repro-

duced from ref. 44, Elsevier 2014.)

Fig. 8

(A) Schematic of the ultrasound-driven movement of the drug-

loaded nanoporous Au nanowire motors and triggered release of the

drug around a cancer cell. (B) NIR-triggered anticancer drug DOX

release as a function of irradiation time using PSS-modi

ed PAu

nanomotors (a) and Au nanomotors (b). (Reproduced from ref. 45,

Wiley 2014.)

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infrared light (NIR) triggered release, as shown in Fig. 8. Such a

photothermal release has been facilitated by the nanoporous

gold structure. Directional movement was achieved by magnetic

guidance. The incorporation of the nanoporous gold segment

led to a nearly 20 fold increase in the active surface area

(compared to common gold nanowires) and to a high loading

capacity of 13.4

m

gmg

doxorubicin.

Recently developed ultrasound triggered tubular micro-

bullets are extremely promising for addressing the challenges of

limited tissue penetration of therapeutic particles,

i.e.

, directed

drug delivery into diseased tissue (Fig. 9A).

Such powerful

microbullets, developed by Esener and Wang,

rely on Acoustic

Droplet Vaporization (ADV) for propulsion of per



uorocarbon-

loaded conical-tube microbullets (MB) for penetration into

targeted tissue to provide a remarkable force su

ffi

cient for

penetrating and deforming cellular tissue for potential targeted

drug delivery and precision nanosurgery. This highly e

ffi

cient,

powerful and scalable propulsion technique utilizes ultrasound

to vaporize biocompatible fuels (

i.e.

, per



uorocarbon PFC

emulsions), con



ned within the interior of a micromachine, for

an ultrahigh velocity of over 6 m s

(

i.e.

, approximately 100

times faster than common micromachines). Such

‘

bullet-like

’

propulsion induces su

ffi

cient thrust for deep tissue penetration

and deformation for potential targeted drug delivery and

precision nanosurgery. By adjusting the level of propulsion

force, di

erent depths in the tissue can be reached. Such a

‘

bullet-like

’

carrier must also have the capability of carrying a

large therapeutic payload.

The US-triggered microbullet propulsion strategy is expected

to have a tremendous impact on diverse biomedical applica-

tions,

e.g.

, targeted drug delivery, circulating biolistics, micro-

tissue and artery-cleaning/removal schemes, precision nano-

surgery, or cancer surgery. Mallouk's group also demonstrated

recently the ultrasonic propulsion of rod-shaped nanomotors

inside living HeLa cells (Fig. 9B).

These nanomotors can

attach strongly to the external surface of the cells, and are

readily internalized by incubation with the cells for periods

longer than 24 h. The intracellular propulsion did not involve

any chemical fuel and the HeLa cells remained viable. Such

developments hold great promise for future

in vivo

studies of

the synthetic nanomotors.

Conclusions

This review has discussed recent advances in man-made

nanomotors towards controlled drug delivery applications.

Considerable progress has been made over the past decade in

designing a variety of micro/nanomotors for diverse biomedical

applications and strategies for the transport and release of

therapeutic agents. As our understanding of the design and

operation of nanomotors expands, it becomes feasible to utilize

the new capabilities of these machines for practical biomedical

applications. With increased power and functionality, future

micro/nanomachines are expected to perform more demanding

biomedical tasks and bene



tdi

erent drug delivery applica-

tions. While key challenges remain prior to applying these

nanomotors for

in vivo

targeted drug delivery, these recent

developments advance this objective one step closer to a

futuristic nanomachine suitable for improved delivery of ther-

apeutic agents in the body.

erent research teams are currently exploring several

routes for realizing future nanomotor-based drug delivery. In

order to improve the delivery e

ffi

ciency, it is essential to explore

the attachment of drug carriers to nanomotors through chem-

ical or biological linkers that are sensitive to the tumor micro-

environment (

e.g.

, protease enzyme and acidity). Such a

mechanism will allow for a more accurate localized drug

delivery to the target site using drug-loaded particles powered

by external magnetic or ultrasound



elds. Improved cellular

uptake could be achieved by the incorporation of an appropriate

ligand. The combination of multiple functions can lead to more

ective operation and this would require the assembly of

multiple nano-objects. In particular, incorporating therapeutic

or diagnostic entities in the same nanomachine would create

theranostic vehicles. Additional e

orts should be devoted

towards developing high-performance nanomotor locomotion

based on

in situ

fuel sources and alternate powering schemes,

ering signi



cant thrust for overcoming the large drag (asso-

ciated with the presence of the blood cells) and for improving

tissue penetration. Future e

orts will involve the development

of intelligent logic-controlled nanomachines

toward smart

Fig. 9

(A) Computer-aided graphic (graphics on the left) and the

corresponding experimental images of PFH-loaded MBs (a) pene-

trating, (b) cleaving, and (c) expanding tissue following an US pulse

signal. All images were taken sequentially at a frame rate of 10 000 fps

and 10

objective. US pulses of 44

m

s/1.6 MPa were used for (a) and (b)

and short pulses of 4.4

m

s/3.8 MPa were used for (c). Dotted circles and

solid arrows are used to indicate the MB's position, while curvilinear

dotted lines outline the tissue. (Reproduced from ref. 30, Wiley 2012.)

(B) Optical microscope image of a HeLa cell containing several gold

–

ruthenium nanomotors. Arrows indicate the trajectories of the nano-

motors, and the solid white line shows the propulsion. Near the center

of the image, a spindle of several nanomotors is spinning. Inset:

electron micrograph of a gold

–

ruthenium nanomotor. The scattering

of sound waves from the two ends results in propulsion. (Reproduced

from ref. 68, Wiley 2014).

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drug-delivery applications. Further attention should be given to

the biocompatibility of drug-delivery nanomotors, and partic-

ularly to common metallic constituents such as Ni, Ag, or Pt.

Lastly, the biodegradability (self-destruction) or removal of

nanomotors from the body a



er completing their delivery

mission needs further consideration.

The new generation of nanomachine platforms holds even

greater promise to improve the treatment of diseases. While the



eld of nanomachines has been moving at a very rapid pace,

such devices have translated gradually into clinical practice.

The potential biomedical applications of nanomotors,

e.g.

nanosurgery or biopsy, extend beyond those discussed in this

article and might be limited only by our collective imagination.

As research moves toward developing smaller and multifunc-

tional devices, larger multidisciplinary teams, and e

ective

communication between various disciplines, are needed for

success. With such collaborative e

orts we envision that

synthetic nanomotors would provide a new and unique

approach to rapidly delivering drug carriers to predetermined

destinations. Despite major challenges, the most exciting

prospect of nanomachines is the nearly limitless possibilities

for the treatment of diseases, towards the realization of Asi-

mov's 1966 microscopic submarine.

Acknowledgements

This project received support from the Defense Threat Reduc-

tion Agency-Joint Science and Technology O

ffi

ce for Chemical

and Biological Defense (Grant no. HDTRA1-13-1-0002). W.G. is a

HHMI International Student Research fellow.

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