www.nanoadv.org

Research Article

Nano Adv., 2017, 2, 29−35.

2016, 1, X−X. Nano Advances

http://dx.doi.org/10.22180/na200 Volume 2, Issue 2, 2017

Fe3O4/Polycaprolactone Microneedles with Controlled Drug Delivery and Magnetic Hyperthermia

Jiwei Cheng, a Gang Chen, b* and Yufang Zhu a*

a School of Materials Science and Engineering, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai

200093, China

b National Laboratory for Infrared Physics, Shanghai Institute of Technical Physics, Chinese Academy of Sciences, 500 Yutian Road,

Shanghai 200083, China

*Corresponding author. Email: zjf2412@163.com (Y. Zhu); gchen@mail.sitp.ac.cn (G. Chen)

Received February 24, 2017; Revised March 29, 2017

Citation: J. Cheng, G. Chen, and Y. Zhu, Nano Adv., 2017, 2 (2), 29−35.

In this study, we have developed biodegradable Fe3O4/polycaprolactone (Fe3O4/PCL) microneedles with controlled

drug delivery and magnetic hyperthermia, which consist of biodegradable PCL and the encapsulated Fe3O4

nanoparticles, drugs and low-melting-point monomer (trimethylene carbonate, TMC). The structure, mechanical

strength, magnetic heating ability and drug release behavior of the Fe3O4/PCL microneedles were characterized. Each

microneedle patch shows well-structured microneedle arrays comprised of 100 (10 × 10) pyramidal needles with a

tip-to-tip distance of 500 μm, and the microneedles have enough mechanical strength to penetrate skin. Interestingly,

the Fe3O4/PCL microneedles could generate heat to increase the temperature under an alternating magnetic field.

Also, the Fe3O4/PCL microneedles exhibit the temperature-controlled drug release behavior through adjusting the

encapsulated TMC amount. Hence, the developed Fe3O4/PCL microneedles show potential synergistic chemotherapy

and magnetic hyperthermia in skin cancer treatment.

KEYWORDS: Microneedles; Fe3O4 nanoparticles; Polycaprolactone; Controlled drug release; Magnetic hyperthermia

1. Introduction

Skin cancers are indeed the most common malignancy in

humans. Chemotherapy is a common therapeutic modality for

the treatment of skin cancers, but associated with

multidrug-resistance of cancer cells and serious side effects,1–2

which result in poor prognoses for the patients.

To enhance therapeutic efficacy, multimodal treatments with

chemotherapy and other therapeutic modalities including

magnetic hyperthermia, photothermal therapy, and

immunotherapy have been intensively studied.3–6 Among these

studies, the combination of chemotherapy with magnetic

hyperthermia shows a powerful potency.7–15 Magnetic

hyperthermia could treat the localized or deeply existing tumors

without side effect by raising the temperature to 43-48 °C.16–17

Heat also increases the efficacy of different chemotherapeutic

drugs at the hyperthermia temperature.18 For example, Kim et al.

reported magnetic iron oxide nanoparticles-conjugated

polymeric micelles (MNP-PMs) as nanocarriers for combined

chemotherapy and hyperthermia.7 When the anticancer drug

(doxorubicin, DOX) loaded MNP-PMs were used to treat human

lung adenocarcinoma A549 cells in combination with

hyperthermia under an alternating magnetic field (AMF), 78% of

the cells were killed by the synergistic effect of heat and

anticancer drugs, which was more effective than either

chemotherapy or magnetic hyperthermia treatment alone.7 Ren et

al. investigated the efficiency of multifunctional Fe3O4 magnetic

nanoparticles (Fe3O4-MNP) with chemotherapy and

hyperthermia for overcoming multidrug resistance in an in vivo

model of leukemia.8 The results showed that the anticancer

drug-loaded Fe3O4-MNP not only increased tumor temperature

during hyperthermia under an AMF, but also noticeably

decreased P-glycoprotein and Bcl-2 expression and markedly

increased Bax and caspase-3 expression.8 Our group prepared

magnetic mesoporous silica nanoparticles (MMSNs) for

potential chemotherapy and magnetic hyperthermia.9–12 After

capping with DNA on the DOX-loaded MMSNs, the

DOX-MMSNs/DNA nanoparticles could efficiently generate

heat to increase the temperature under an AMF, and thereby

triggered the DOX release, which induced a higher efficacy to

kill cancer cells.10 However, treatments with nanoparticle-system

are often repeated because cancer cells survive and continue to

grow after the initial treatment. Furthermore, therapeutic

nanosystems should be reinjected to achieve an adequate

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Research Article Nano Advances

Nano Adv., 2017, 2, 29−35.016, 1, X−X.

doi: 10.22180/na200

concentration in the tumor tissues for the following treatment

due to rapid clearance of nanosystems from the tumor tissues.

Multiple and frequent injections of therapeutic nanosystems

could lead to patient pain or cause adverse side effects.

Microneedles are microscale projections with the capability of

delivering drugs to skin painlessly.19–21 Also, microneedles can

be designed to target specific layer of skin. For the treatment of

skin cancers, microneedles are possible to arrive at tumor tissues,

allowing for enhancing efficacy of therapeutic delivery.22–26 For

example, Wang et al. reported the microneedle patch-assisted

immunotherapy that delivers anti-PD-1 (aPD1) for the enhanced

treatment of the skin cancer.22 The microneedle patch with

biocompatible hyaluronic acid and pH-sensitive dextran

nanoparticles can painlessly penetrate the epidermis and become

submerged in the interstitial fluid to efficiently deliver aPD1 to

the tumor microenvironment, which inhibited tumor growth

superior to those obtained with intratumor injection of the same

dose.20 Donnelly et al. used silicon microneedle arrays to

enhance skin penetration of porphyrin precursor

5-aminolevulinic acid (ALA) for photodynamic therapy, and in

vivo experiments showed that microneedle puncture could

reduce application time and ALA dose for high levels of the

photosensitizer in skin.23 Recently, Chen et al. developed a

multifunctional microneedle system with the combination of

chemotherapy and photothermal therapy,24–25 which consists of

embeddable polycaprolactone (PCL) microneedles containing a

photosensitive lanthanum hexaboride nanoparticles and an

anticancer drug DOX. When applying microneedle system to

treat mice bearing 4T1 breast tumors, the near-infrared

light-activated heating and the DOX releasing behavior can be

precisely controlled, and the microneedle-mediated synergistic

therapy completely eradicated 4T1 tumors within 1 week.25

Therefore, it can be speculated that the development of

microneedles with the combination of chemotherapy and

magnetic hyperthermia would achieve synergistic effect in the

treatment of skin cancer. However, to the best of our knowledge,

there are no previous reports describing the fabrication of

magnetic microneedle systems with controlled drug delivery and

magnetic hyperthermia for potential skin cancer therapy.

In this study, we developed biodegradable

Fe3O4/polycaprolactone (Fe3O4/PCL) transdermal microneedles

that could controllably release the encapsulated drugs into the

tumor tissues and simultaneously generate heat under an AMF.

The microneedles consist of biodegradable PCL and the

encapsulated Fe3O4 nanoparticles, drugs and low-melting-point

monomer (trmethylene carbonate, TMC). Here, Fe3O4

nanoparticles could generate heat under an AMF due to the

hysteresis loss and/or Néel and Brownian relaxations.27 TMC is

a biocompatible low-melting-point monomer (melting

temperature (Tm): 43-47 °C), which acts as an additive to adjust

the drug release rate by changing the TMC amount and/or

release temperature. When treated under AMF, Fe3O4

nanoparticles generate heat to induce the TMC and PCL melting

(Tm PCL is about 60 °C),24–25 thus accelerating drug release

from the Fe3O4/PCL microneedles. Once stopping the treatment

under AMF, the temperature quickly decreased and the drug

release slowed dramatically. Therefore, the Fe3O4/PCL

microneedles could produce a synergistic effect of chemotherapy

and magnetic hyperthermia in treating skin cancers. Furthermore,

magnetic hyperthermia ability of the Fe3O4/PCL microneedles

could be controlled by the encapsulation of Fe3O4 amount.

Painless microneedles minimize the uncomfortable feeling by

injection and realize the localized treatment of skin cancers.

2. Experimental section

2.1 Materials and chemicals

Polycaprolactone (PCL, Mw: 70000-90000), trimethylene

carbonate (TMC), rhodamine B (RhB), and phosphate buffered

saline (PBS) were purchased from Sigma-Aldrich. Ferric

chloride (FeCl3·6H2O), ferrous chloride (FeCl2·4H2O),

hydrochloride acid (HCl, 36–38%), and sodium hydroxide

(NaOH) were obtained from Sinopharm Chemical Reagent Co.

Ltd. Ultrapure water was obtained from a Millipore pure water

system. All chemicals were of analytical-reagent grade and used

without further purification.

2.2 Fabrication of Fe3O4/PCL microneedles

Magnetic Fe3O4 nanoparticles were synthesized according to the

previously reported co-precipitation method.9 All of the

Fe3O4/PCL microneedle systems were fabricated using

polydimethylsiloxane (PDMS) molds from Micropoint

Technologies Pte, Ltd. Singapore. Each microneedle is of

pyramidal shape, with 200 μm in width at the base, 600 μm in

height, and a sharp tip tapering to 10 μm. The microneedles are

arranged in a 10×10 array with 500 μm tip-to-tip spacing.

First, a 20% (w/v) PCL+TMC solution was prepared by

dissolving PCL and TMC in chloroform. Subsequently, a certain

amount of Fe3O4 nanoparticles and a model drug rhodamine B

(RhB) were added to the PCL+TMC solution and then well

mixed to obtain a homogeneous solution. The final amounts of

different components in the microneedles and the sample names

are listed in Table 1.

After preparation of the mixture solution, a two-step casting

process was used to fabricate the Fe3O4/PCL microneedles.

Table 1. Weight ratio of the components in different microneedles.

Sample

names

PCL

(wt%)

Fe3O4

(wt%)

TMC

(wt%)

RhB

(wt%)

MNs-1 100 0 0 0.5

MNs-2 90 10 0 0.5

MNs-3 80 20 0 0.5

MNs-4 70 30 0 0.5

MNs-5 70 20 10 0.5

MNs-6 60 20 20 0.5

MNs-7 50 20 30 0.5

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Research Article Nano Advances

Nano Adv., 2017, 2, 29−35.016, 1, X−X.

doi: 10.22180/na200

Typically, 1.0 mL of the RhB/Fe3O4/(PCL+TMC) mixture

solution was injected into each PDMS mold, followed by

vacuum condition for 5 min to allow the mixture solution flow

into the microneedle cavities. Afterward, the PDMS molds were

centrifuged at rpm = 4000 for 20 min to compact the mixture

into microneedle cavities, and the excess amounts of the mixture

solution on the mold surface were removed for reuse.

To form a patch without the drug and Fe3O4 nanoparticles,

pure 20% (w/v) PCL solution was poured onto the filled mold,

followed by further centrifugation at rpm=4000 and pressed with

a piece of copper adhesive tape. Finally, the fully filled mold

was dried at 25 °C for 24 h, and the drug-loaded Fe3O4/PCL

microneedles were gently taken from the PDMS mold.

2.3 Mechanical strength test

Mechanical compression tests were performed using a universal

testing machine (Zwick static materials testing machine (5 KN)).

A microneedle array was placed on the flat rigid surface of a

stainless steel base plate. An axial force was applied by a mount

of a moving sensor, perpendicular to the axis of the microneedle

array, at a constant speed of 5 μm s–1. The initial distance from

the tips of the microneedle arrays to the mount was set at 500 μm.

The force was measured when the moving sensor touched the

uppermost point of the microneedle array. The testing machine

subsequently recorded the force required to move the mount as a

function of microneedle displacement.

2.4 Magnetic heating ability of the Fe3O4/PCL microneedles

Magnetic heating abilities of the Fe3O4/PCL microneedles were

evaluated using a DM100 System (NanoScale Biomagnetics,

Spain) and the temperature was monitored with an optical fiber

temperature sensor.

To evaluate magnetic heating abilities of the microneedles,

we fabricated the microneedles containing a patch with drug and

Fe3O4 nanoparticles. Typically, 0.5 g of microneedles was

placed in a testing vial with 1 mL water, and testing vial was

heated under an AMF of 180 Gauss strength at 409 kHz

frequency for 20 min. The upper limit of temperature was set to

be 80 °C. The water temperature in testing vial was recorded and

plotted as a function of the exposed time.

2.5 In vitro drug release from the Fe3O4/PCL microneedles

Rhodmine B (RhB) was used as a model drug, and the RhB

loading amount was set to be 0.5 wt% to the weight of the

PCL+TMC+Fe3O4 mixture in this study. In vitro release of RhB

from microneedles was evaluated through soaking microneedle

system in PBS (pH = 7.4) at different temperature on an orbital

shaker. The detailed process as follows: 1.0 g of microneedles

was soaked in 4 mL of PBS at 37, 43 and 50 °C, respectively. At

time intervals (10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h

and 24 h), 50 μL of the released solution was withdrawn for

analysis and replaced with 50 μL fresh PBS. The RhB

concentrations in the released solutions were analyzed using a

NanoDrop 2000C UV–Vis spectrophotometer. The percentages

of the released RhB were calculated from the total RhB amount

in the microneedles.

3. Results and discussion

Magnetic Fe3O4 nanoparticles were synthesized by a

co-precipitation method, and the crystalline structure can be

easily indexed to Fe3O4 according to the reflection peak

positions and relative intensities on the wile-angle XRD pattern

(Figure 1A). As depicted in TEM image, the particle size of

Figure 1. (A) Wide-angle XRD pattern and (B) TEM image of Fe3O4

nanoparticles.

Figure 2. SEM images of the Fe3O4/PCL microneedles with different percentages of Fe3O4 nanoparticles (A1, A2: MNs-1; B1, B2: MNs-2;

C1, C2: MNs-3; D1, D2: MNs-4).

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Research Article Nano Advances

Nano Adv., 2017, 2, 29−35.016, 1, X−X.

doi: 10.22180/na200

Fe3O4 nanoparticles was estimated to be 15~20 nm (Figure 1B),

which is similar to the results in previous study,9 endowing them

with magnetic heating ability. In this study, magnetic Fe3O4 nanoparticles were

encapsulated in the PCL-based solution, and a two-step casting

process was used to fabricate Fe3O4/PCL microneedles. Figure 2

shows SEM images of Fe3O4/PCL microneedles with different

percentages of Fe3O4 nanoparticles (MNs-1, MNs-2, MNs-3 and

MNs-4 microneedles). It can be observed that each type of

microneedles showed well-structured microneedle arrays

comprised 100 (10 × 10) pyramidal needles with a tip-to-tip

distance of 500 µm. The base width, height and tip size of the

microneedles were 200, 600, and 10 µm, respectively. The

encapsulation of magnetic Fe3O4 nanoparticles did not influence

the formation ability of microneedle arrays even up to 30 wt%.

Furthermore, the encapsulated Fe3O4 nanoparticles could be

observed on the surface of each microneedle, suggesting that

magnetic Fe3O4 nanoparticles could uniformly distribute in the

PCL matrix due to small particle size and good dispersity of

Fe3O4 nanoparticles.

Figure 3 shows SEM images of Fe3O4/PCL microneedles

with 20 wt% Fe3O4 nanoparticles and different percentages of

TMC (MNs-5, MNs-6 and MNs-7 microneedles). Compared to

the Fe3O4/PCL microneedles without TMC encapsulation, the

Fe3O4/PCL microneedles with different percentages of TMC still

maintained regular microneedle arrays, indicating that the TMC

encapsulation did not change the casting ability of the

Fe3O4/PCL microneedles. From viewpoint of the microneedle

structure and needle size, the Fe3O4/PCL microneedles with or

without TMC encapsulation are potential for intradermal drug

delivery.

For intradermal delivery of drugs from microneedles to

specific sites, the Fe3O4/PCL microneedles must be strong

enough to effectively penetrate the skin. In this study,

mechanical compression tests were performed using a universal

testing machine. Figure 4 shows mechanical compressive

properties of the Fe3O4/PCL microneedles with or without TMC

encapsulation. The increase in axial forces caused a progressive

reduction in the height of microneedles. For the Fe3O4/PCL

microneedles without TMC encapsulation (MNs-1, MNs-2,

MNs-3 and MNs-4 microneedles), when the height of

microneedles reduced 0.3 mm, the applied force on the

microneedles was estimated to be 0.18-0.23 N/needle, and the

encapsulation of 10-30 wt% Fe3O4 nanoparticles in the PCL

microneedles increased the mechanical strength of microneedles.

On the other hand, the Fe3O4/PCL microneedles with TMC

encapsulation (MNs-5, MNs-6 and MNs-7 microneedles)

showed a little decrease in the applied force to be 0.12-0.15

N/needle when the height of microneedles reduced 0.3 mm,

suggesting the TMC encapsulation would decrease the

mechanical strength of the Fe3O4/PCL microneedles. It might be

attributed to the weak strength of the TMC monomer. However,

Figure 3. SEM images of the Fe3O4/PCL microneedles with 20 wt% Fe3O4 nanoparticles and different percentages of TMC (A1, A2:

MNs-5; B1, B2: MNs-6; C1, C2: MNs-7).

Figure 4. (A) mechanical copressive properties of the Fe3O4/PCL

microneedles with different percentages of Fe3O4 nanoparticles, and (B)

mechanical copressive properties of the Fe3O4/PCL microneedles with 20

wt% Fe3O4 nanoparticles and different percentages of TMC.

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Research Article Nano Advances

Nano Adv., 2017, 2, 29−35.016, 1, X−X.

doi: 10.22180/na200

previous studies demonstrated that the insertion force as low as

0.03 N/needle could result in 100% of microneedle penetrating

the stratum corneum of skin in vitro.28 Thus, the fabricated

Fe3O4/PCL microneedles might enable complete insertion into

the skin.

To evaluate whether the Fe3O4/PCL microneedles have

enough magnetic heating ability for hyperthermia therapy, the

microneedles were placed in a testing vial with water and treated

under an AMF with a magnetic field strength of 180 Gauss and a

frequency of 409 kHz. Figure 5 shows magnetic heating curves

of the water containing the Fe3O4/PCL microneedles with

different percentages of Fe3O4 nanoparticles and TMC. It can be

seen that the PCL microneedles without Fe3O4 nanoparticles

(MNs-1 microneedles) cannot generate heat to increase the water

temperature, but the temperatures of the water containing the

Fe3O4/PCL microneedles increased rapidly, and the temperature

increase rate enhanced with increasing the Fe3O4 percentage in

the Fe3O4/PCL microneedles. For example, the temperature of

the water containing the Fe3O4/PCL microneedles with 10 wt%

Fe3O4 nanoparticles (MNs-2 microneedles) can be increased

from 37 to 47.6 °C within 20 min, while that containing the

Fe3O4/PCL microneedles with 20 wt% Fe3O4 nanoparticles

(MNs-3 microneedles) can be increased from 37 to 55.6 °C

within 20 min.

When we fixed the 20 wt% Fe3O4 nanoparticles in the

microneedles, and changed the TMC from 10 to 30 wt% in the

microneedles (MNs-3, MNs-5, MNs-6 and MNs-7 microneedles),

the temperature increases for all types of microneedles were

close to each other, which indicated that the heat generation was

attributed to the encapsulated Fe3O4 nanoparticles, and the TMC

encapsulation did not influence the magnetic heating ability of

the Fe3O4/PCL microneedles. On the other hand, the melting

temperatures of TMC and PCL are 43-47 °C and 60 °C,

respectively. That is to say, TMC and PCL can undergo rapid

thermal transitions from a solid to liquid state when the

Fe3O4/PCL microneedles are treated under an AMF. Therefore,

it is possible to control the drug release rate through adjusting

the percentages of Fe3O4 nanoparticles and TMC.

To evaluate the feasibility of controlled drug release from the

Fe3O4/PCL microneedles, rhodamine B (RhB) was used as a

model drug and encapsulated with 0.5 wt% in each type of

microneedles. Figure 6 shows the RhB release profiles from the

Fe3O4/PCL microneedles without and with different Fe3O4

nanoparticles and TMC in PBS at 37, 43 and 50 °C, respectively.

It can be observed that all types of microneedles exhibited

increased RhB release rate with increasing temperature. For

Figure 5. (A) magnetic heating abilities of the Fe3O4/PCL microneedles with different percentages of Fe3O4 nanoparticles, and (B)

magnetic heating abilities of the Fe3O4/PCL microneedles with 20wt% Fe3O4 nanoparticles and different percentages of TMC.

Figure 6. (A) Rhodamine B release profiles from the MNs-1, MNs-3 and MNs-6 microneedles at different temperatures, and (B)

Rhodamine B release profiles from the Fe3O4/PCL microneedles with different components at 43 °C.

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Research Article Nano Advances

Nano Adv., 2017, 2, 29−35.016, 1, X−X.

doi: 10.22180/na200

example, MNs-6 microneedles released 36%, 45% and 49% of

RhB within 24 h at 37, 43 and 50 °C, respectively (Figure 6A). It

might be that the temperature increase could lead to thermal

transitions of TMC and PCL due to their low melting

temperatures, thus increasing the mobility of the polymer chains

and monomers, and thereby accelerating the RhB diffusion.

On the other hand, at the same temperature, PCL

microneedles (MNs-1) showed the lowest release rate and the

encapsulation of Fe3O4 nanoparticles and TMC in the

microneedles could accelerate the RhB release rate. For example,

the released percentages of RhB from the MNs-1, MNs-3 and

MNs-6 microneedles at 50 °C were about 20%, 32% and 49%,

respectively (Figure 6A). Furthermore, the encapsulation

percentages of Fe3O4 nanoparticles and TMC in the

microneedles influenced the RhB release rate. The RhB release

from the Fe3O4/PCL microneedles was slightly accelerated with

increasing the encapsulation percentages of Fe3O4 nanoparticles

in the microneedles, but the increase of TMC percentages in the

Fe3O4/PCL microneedles resulted in the significant increase for

the RhB release rate (Figure 6B). The encapsulation of Fe3O4

nanoparticles in the PCL microneedles could slightly increase

the porosity of the microneedles, and thereby accelerate RhB

release rate. While for the Fe3O4/PCL microneedles with TMC

encapsulation, TMC is easy to melt due to the low melting

temperature, and the TMC melting could increase the mobility of

TMC, and accelerate the RhB release. More Fe3O4 nanoparticles

and TMC in the microneedles could induce higher porosity and

mobility for RhB release. Thus, the encapsulation of Fe3O4

nanoparticles and TMC with different percentages could control

the RhB release rate.

4. Conclusions

In this study, biodegradable Fe3O4/PCL microneedles were

developed for potential skin cancer treatment with transdermal

controlled drug delivery and magnetic hyperthermia. The

Fe3O4/PCL microneedles had enough mechanical strength to

penetrate skin, and could generate heat to increase the

temperature through adjusting the encapsulation amount of

Fe3O4 nanoparticles in the microneedles. Interestingly, the

encapsulation of TMC in the Fe3O4/PCL microneedles enabled

them with temperature-controlled drug release behavior and

magnetic hyperthermia simultaneously. Therefore, the

Fe3O4/PCL microneedles would be promising for skin cancer

treatment with the potential combination of chemotherapy and

magnetic hyperthermia.

Acknowledgements

The authors gratefully acknowledge the financial support by the

National Natural Science Foundation of China (No. 51572172

and No. 61474130), the Scientific Development Project of

University of Shanghai for Science and Technology

(16KJFZ011), and Chinese Academy of Sciences via Hundred

Talents Program.

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