A pH-responsive magnetic mesoporous silica-based nanoplatform for

Subscriber access provided by BOSTON UNIV

Functional Nanostructured Materials (including low-D carbon)

A pH-responsive magnetic mesoporous silica-based nanoplatform for synergistic photodynamic/chemo therapy Xianglong Tang, Feng Jing, Benlan Lin, Sheng Cui, Rutong Yu, Xiaodong Shen, and Tingwei Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 12, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

A pH-responsive magnetic mesoporous silica-based nanoplatform for synergistic photodynamic/chemo therapy Xiang-long Tang a, Feng Jing a, Ben-lan Lin a, Sheng Cui *a, Ru-tong Yub, Xiao-dong Shen *a and Ting-wei Wang a a

College of Material Science and Engineering, Nanjing Tech University, Nanjing, 210009,

China b

Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

KEYWORDS: mesoporous silica, pH-responsive, polydopamine, magnetic targeting, photodynamic/chemo therapy ABSTRACT: By overcoming drug resistance and subsequently enhancing the treatment, the combination therapy of photodynamic therapy (PDT) and chemotherapy has promising potential for cancer treatment. However, the major challenge is how to establish an advanced nanoplatform that can be efficiently guided to tumor sites and can then stably release both chemotherapy drugs and a photosensitizer simultaneously and precisely. In this study, which considered the possibility and targeting efficiency of a magnetic targeting strategy, a novel Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform was successfully built; this platform could be employed as an efficient synergistic antitumor nanoplatform with magnetic guidance for highly

ACS Paragon Plus Environment

1

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 28

specific targeting and retention. Doxorubicin (DOX) molecules were loaded into mesoporous silica with high loading capability, and the mesoporous channels were blocked by a polydopamine (PDA) coating. Human serum albumin (HSA) was conjugated to the outer surface to increase the biocompatibility and blood circulation time, as well as to provide a vehicle for loading photosensitizer chlorin e6 (Ce6). The sustained release of DOX in an acidic condition and the PDT induced by red light exerted a synergistic inhibitory effect on glioma cells. Our experiments

demonstrated

that

the

pH-responsive

Fe3O4@mSiO2(DOX)@HSA(Ce6)

nanoplatform was guided to the tumor region by magnetic targeting and that the nanoplatform suppressed glioma tumor growth efficiently, implying that the system is a highly promising photodynamic/chemotherapy combination nanoplatform with synergistic effects for cancer treatment.

Figure 1. (A) A schematic representation of the Fe3O4@mSiO2(DOX)@HSA(Ce6) synthesis process. (B) The schematic illustration of the application of Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform in glioma therapy under a magnetic field.


2

Page 3 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


INTRODUCTION Cancer has been a serious threat to human health worldwide because of its increasing death rate.1-3 Currently, although many new antitumor techniques, such as immunotherapy4,5 and genebased therapy,6,7 have been developed, chemotherapy is still the most effective modality for clinic application. However, to increase the local effective concentration of pharmaceutics at the tumor site and decrease the serious side effects of chemotherapy caused by the difficulties in distinguishing normal cells from tumor cells, a variety of synthetic drug delivery systems, such as polymers,8 hydrogel,9 micelles10 and inorganic nanoparticles,11-13 have been investigated; these systems showed significant prospects in this regard. In particular, drug platforms based on inorganic nanoparticles have attracted much attention because of their convenient preparation, easy modification and specific functionality. For example, Khashab et al.14 developed a mesoporous silica nanoplatform that improved the Doxorubicin (DOX) and gemcitabine loading capacity. However, currently, cancer therapy with a single therapy, which has many problems and shortcomings, is still challenging. In addition, the most common problem is multiple drug resistance (MDR), which reduces the accumulation of the antitumor chemotherapy drug in tumor cells and subsequently produces a poor therapeutic outcome.15-18 Thus, many chemotherapy failures in patients are caused by MDR. To overcome significant drug resistance for chemotherapy, many researchers are trying to build a combination therapeutic platform based on the characteristics of an inorganic nanoparticle delivery system for simultaneously achieving photodynamic therapy (PDT) and chemotherapy.19-23 The combination of PDT and chemotherapy in one system to kill cancer cells could be realized by augmenting the local cytotoxicity of chemotherapeutic agents with the synergistic effects of PDT. PDT has drawn tremendous attention in synergistic cancer therapy on account of its being minimally invasive,


3


Page 4 of 28

having fewer side effects than other therapies, and having negligible drug resistance. In a typical PDT, photosensitizer drugs are stimulated to produce singlet oxygen and other reactive oxygen species (ROS) under irradiation at a specific wavelength.24-26 These intracellular ROS could easily damage cellular biomolecules by causing oxidative stress or by direct reaction with DNA molecules, leading to cell apoptosis.27 In this work, to achieve synergistic PDT and chemotherapy in tumor treatment, we built a novel and multifunctional antitumor nanoplatform (Fe3O4@mSiO2(DOX)@HSA(Ce6)) based on the unique characteristics of Fe3O4 nanoparticles and polydopamine (PDA) molecules. DOX molecules, which can induce DNA damage and produce reactive oxygen species, were loaded into a mesoporous silica structure. To block DOX leakage in physiological circulation conditions (pH 7.4), a PDA shell was used to coat the silica surface, and this structure showed a sustainedrelease behavior in a low pH condition (pH 5.0). To increase the biocompatibility and blood circulation time, Human serum albumin (HSA) was linked to the polydopamine gatekeeper, and Ce6 molecules were then loaded into the inner HSA structure to achieve PDT functionality. Furthermore, with magnetic field navigation, this nanoplatform could be guided to the tumor region and could perform synergistic photodynamic/chemotherapy. The physiochemical properties, drug loading capacity, ROS production capability and in vitro anticancer performance were investigated in detail. In vivo evaluations showed that the pH-responsive release of DOX and the combination of PDT with magnetic targeting for accumulation at the tumor site could remarkably suppress glioma tumor growth. RESULTS AND DISCUSSION Synthesis and characterization. The detailed synthesis process and bioapplication of our Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform were illustrated (Figure 1). Fe3O4 nanoparticles


4

Page 5 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


were first synthesized by a modified high-temperature protocol. Then, a mesoporous silica shell (mSiO2) was used to surround an Fe3O4 core via a sol-gel route. DOX was loaded into the mesoporous structure via diffusion in water, and a polydopamine coating layer was conjugated by immersing the Fe3O4@mSiO2(DOX) into a dopamine Tris-HCl buffer solution (pH 8.5). The self-polymerization of the dopamine coating on the outer mesoporous silica was achieved when the brown Fe3O4@mSiO2 suspension became dark. Finally, HSA molecules were conjugated to the polydopamine surface via the Michael addition reaction28 to improve the long-term blood circulation, and Ce6 was then loaded into the inner hydrophobic domains of HSA molecules for PDT functionality. The DOX and Ce6 contents in this nanoplatform were measured by a UV-vis spectrophotometer, and the optimized contents were ~22.8 % and ~9.6 % (W/W), respectively. Our nanoplatform had good biocompatibility and a long circulation time; thus, this nanoplatform could more easily aggregate at tumor sites after magnetic targeting than traditional drug delivery systems could. The morphologies were investigated by transmission electronic microscopy (TEM) images. Low-resolution images (Figure 2A) revealed that monodispersed uniform Fe3O4 nanoparticles were synthesized by the high-temperature pyrolysis method. High-resolution images (Figure 2B) further demonstrated that Fe3O4 had a narrow size distribution centered at 15 nm and that the clear lattice distance of 0.253 nm corresponded to the (311) plane.29 TEM images further revealed that 60 nm Fe3O4@mSiO2 nanoparticles with only an Fe3O4 core were uniform and separated from one another (Figure 2C). After removal of the CTAB agent, approximately 45 nm wormhole-like mesopores with diameters of around 2.42 nm (Figure S1) were obtained in the silica shells. The precisely controlled size of the Fe3O4@mSiO2 nanoparticles made it possible and easy to subsequently deposit a thin PDA film on Fe3O4@mSiO2(DOX), and the low


5


Page 6 of 28

resolution images of Fe3O4@mSiO2(DOX)@PDA (Figure 2D) with a uniform size and welldispersed characteristics supported this conclusion. The successfully controlled size of Fe3O4@mSiO2(DOX)@PDA was so important because this feature provided convenience and the possibility to subsequently perform HSA surface modification and load the photosensitizer Ce6.

Figure 2. TEM images of (A) Fe3O4 at low resolution, (B) Fe3O4 at high resolution, (C) Fe3O4@mSiO2

and

(D)

Fe3O4@mSiO2(DOX)@PDA.

DLS

size

distribution

of

(E)

Fe3O4@mSiO2(DOX)@HSA and (F) Fe3O4@mSiO2(DOX)@HSA(Ce6). The hydrodynamic size of all samples was measured via dynamic light scattering (DLS) technique (Table 1). The sizes of the fabricated Fe3O4@mSiO2, Fe3O4@mSiO2(DOX), Fe3O4@mSiO2(DOX)@PDA and Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles were 82 ± 6.2 nm, 125 ± 8.6 nm, 156 ± 9.3 nm and 162 ± 11.3 nm, respectively. The hydrodynamic diameters


6

Page 7 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of all prepared nanoparticles were larger than the diameters in TEM images. The size of Fe3O4@mSiO2(DOX)@HSA increased by approximately 35 nm compared to that of Fe3O4@mSiO2(DOX)@PDA, which could be regarded as successful coating with HSA. In addition,

after

Ce6

was

loaded

into

HSA

molecules,

the

size

of

Fe3O4@mSiO2(DOX)@HSA(Ce6) increased by approximately 6 nm (Figure 2E and 2F). The zeta potential of Fe3O4@mSiO2 nanoparticles was very important to the stability and DOX loading efficiency. The negative charge of the -Si-OH on silica surface made it easy to load positively charged DOX molecules due to the charge interaction. HSA molecules which had a zeta potential potential of -27.7 mV made the nanoplatform very stable because of the electrostatic repulsion between particles circulating in the bloodstream (Figure S2). The crystal structure of prepared Fe3O4 nanoparticles was evaluated by XRD pattern (Figure 3A), which showed characteristic peaks (220, 311, 400, 422, 511 and 440) with no difference from the standard Fe3O4 pattern (JCPDS No.19-0629). Compared with pure Fe3O4, Fe3O4@mSiO2 with the amorphous mesoporous silica coating had main peaks with lower intensity; these peaks were still observed in Fe3O4@mSiO2 nanoparticles.30 In addition, after the mesoporous silica coating was applied, a new absorption peak at 1050 cm-1 (Si-O vibration) appeared in the FTIR spectra (Figure 3B); In contrast, this peak was not observed in the spectra of the original Fe3O4 core. In addition, the C–C resonance vibration peaks of an aromatic ring at 1630 cm-1 could be evidence of the success of PDA coating. The broad peaks near 3400 cm-1 corresponded to N-H or O-H vibrations. To study the saturation magnetization, the magnetization curves of Fe3O4, Fe3O4@mSiO2(DOX)@PDA and Fe3O4@mSiO2(DOX)@HSA (Ce6) at room temperature from -5000 to 5000 Oe were obtained (Figure 3C). As shown, the superparamagnetic property of prepared samples was confirmed by the hysteresis loop. The


7


saturation

magnetization

(Ms)

values

of

Fe3O4,

Page 8 of 28

Fe3O4@mSiO2(DOX)@PDA

and

Fe3O4@mSiO2(DOX)@HSA(Ce6) were 78.1, 51.9 and 36.2 emu/g, respectively. These results suggested that our Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform still had superparamagnetic properties and retained the high Ms of Fe3O4 nanoparticles. Table. 1 Zeta potential and DLS results analysis Sample

Size (nm)

Zeta potential (mV)

Fe3O4@mSiO2

82 ± 6.2

-18.7 ± 5.2

Fe3O4@mSiO2(DOX)@PDA

125 ± 8.6

-12.3 ± 3.4

Fe3O4@mSiO2(DOX)@HSA

156 ± 9.3

-29.7 ± 7.6


162 ± 11.3

-27.5 ± 8.2

Figure 3. (A) XRD patterns of (a) Fe3O4 and (b) Fe3O4@mSiO2. (B) FTIR spectra of Fe3O4, Fe3O4@mSiO2 and Fe3O4@mSiO2@PDA. (C) Magnetization curves of (a) Fe3O4, (b) Fe3O4@mSiO2(DOX)@PDA and (c) Fe3O4@mSiO2(DOX)@HSA(Ce6). In vitro release. The drug release kinetics of DOX molecules from our nanoplatform and their pH dependence were investigated at room temperature in different aqueous solutions (pH 5.0, 6.0, and 7.4). As shown (Figure 4A), a burst release of the drug was observed for Fe3O4@mSiO2(DOX) in all media at all tested pH values. Approximately 80 % of preloaded


8

Page 9 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


DOX molecules were released from the Fe3O4@mSiO2(DOX) nanoplatform at 5 h. In contrast, a different release behavior of Fe3O4@mSiO2(DOX)@HSA occurred (Figure 4B). In general, compared with those of the Fe3O4@mSiO2(DOX) nanoplatform, the distinct release profiles suggested that the release of the inner DOX in the mesoporous pore could be blocked by the PDA coating and that this coating suppressed the DOX release. However, pH-responsive behavior of Fe3O4@mSiO2(DOX)@HSA was observed. In an acidic condition (pH 5.0), the cumulative release of DOX reached 70 % in 20 h, and this value in neutral medium was only 10 %. This difference in release behavior was mainly due to the characteristics of the PDA coating, which could be disrupted in acidic conditions to unblock the channels of the mesoporous pore. The results indicated that at physiological pH, Fe3O4@mSiO2(DOX)@HSA could be used as a DOX vehicle and provided sustained release in acidic medium when the nanoplatform entered tumor cells. In contrast, Ce6 molecules in HSA inner domain showed lower than 11.5 % release in all tested media with different pH values (Figure S3), which reduced the toxicity to normal tissue.

Figure 4. Release profiles of (A) Fe3O4@mSiO2(DOX) and (B) Fe3O4@mSiO2(DOX)@HSA in PBS buffer at different pH values.


9


Page 10 of 28

Figure 5. (A) U87 cell uptake of Fe3O4@mSiO2(DOX)@HSA(Ce6) at different times (2 h, 6 h and 12 h). (B) The in vitro generation of 1O2 was analyzed through the singlet oxygen sensor green (SOSG) assay under red light irradiation (5 mW/cm2). (C) CLSM images of U87 cells treated with Fe3O4@mSiO2(DOX)@HSA(Ce6) under red light irradiation (5 mW/cm2). DCFHDA was used to detect ROS generation. (D) Cell viability of Fe3O4@mSiO2@HSA incubated with U87 cells for 24 h and 48 h. (E) Antitumor effect on U87 cells incubated with different concentration for the various treatment groups. Cellular uptake, ROS detection and cancer cell inhibition. To evaluate the U87 cell uptake capability of the Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform, Fe3O4@mSiO2(DOX)@ HSA(Ce6) incubated with U87 cells for different times was investigated by confocal microscopy


10

Page 11 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Figure 5A). It was obvious that more and more Ce6 labeled Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles were internalized by U87 cells as the incubation time increased. Compared with the weak emission after 2 h, enhanced bright red emission of Ce6 was observed after 12 h of incubation. Although our nanoplatform had a large negative charge, which was not beneficial for cell uptake, it was internalized by U87 cells, probably by the gp60 receptor on tumor cells.31 In vitro ROS generation was evaluated by the SOSG probe. As the laser irradiation time increased, more ROS could be produced in solution by our nanoplatform (Figure 5B). The in vivo ROS in U87 cells were detected by DCFH-DA probe with high sensitivity to ROS. As the illumination time increased, more ROS production was examined in U87 cells (Figure 5C). These above results showed the high efficiency of extracellular and intracellular generation of ROS by our nanoplatform. The biocompatibility of this nanoplatform was evaluated by measuring cell viability (Figure 5D). The cell viabilities were close to 98 % even when the concentration reached 800 µg/ml after 48 h of incubation. The U87 cell inhibition effect was evaluated in a different group (Figure 5E). It was obvious that the synergistic PDT + Chemotherapy group had much greater inhibition than the groups treated with only PDT or chemotherapy. Magnetic tumor targeting, accumulation and retention. A magnetic targeting strategy for drug delivery systems is regarded as one promising method for tumor-targeting treatments. In our work, Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles and free Ce6 were injected into two different groups, and the fluorescence of Ce6 was used to evaluate the tumor accumulation and retention. The in vivo distributions of Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles at different

times

were

determined

(Figure

6).

The

Ce6

signal

of

Fe3O4@mSiO2(DOX)@HSA(Ce6), which was delivered by magnetic guidance, gradually increased in the tumor, and an obvious Ce6 signal was found after 4 h postinjection. No Ce6


11


Page 12 of 28

signal could be detected in other tissues after 12 h postinjection. The Ce6 fluorescence distribution in major organs and tumors (Figure S4) at 24 h was also used to demonstrate the accumulation and retention capacity of our nanoplatform, and quantitative analysis (Figure S5) also confirmed the superiority of using the Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform with magnetic targeting. Further, even at 36 h, Fe3O4@mSiO2(DOX)@HSA(Ce6) was still located at the tumor, which showed its longer retention capacity. However, free Ce6 molecules were distributed in the whole body and were cleared quickly from the bloodstream and major organs.

Figure 6. In vivo fluorescence imaging after intravenous injection of (A) free Ce6 and (B) Fe3O4@mSiO2(DOX)@HSA(Ce6) in tumor-bearing mice at 4 h, 12 h and 24 h and 36 h after magnetic targeting. (C) In vivo tumor accumulation and retention at 36 h postinjection. (a) PBS group, (b) free Ce6 group and (c) Fe3O4@mSiO2(DOX)@HSA(Ce6) group.


12

Page 13 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In addition, the Ce6 distribution in the tumor after 36 h postinjection was compared by observing frozen tumor tissue sections via fluorescence microscopy (Figure 6C). Compared with the free Ce6 group, the Fe3O4@mSiO2(DOX)@HSA(Ce6) group had marked Ce6 fluorescence, indicating that our nanoplatform with magnetic targeting could enhance the drug accumulation and tumor retention.

Figure 7. (A) T2-weighted MR images of Fe3O4@mSiO2(DOX)@HSA(Ce6) ([Fe] (mmol): 0, 0.1, 0.2, 0.4 and 0.6. (B) X-ray photos of mice implanted with magnets. (C) T2-MR images of the retention of the Fe3O4@mSiO2(DOX)@HSA(Ce6) guided by magnetic targeting to muscle tissue. Superparamagnetic Fe3O4 nanoparticles are usually used as MR negative contrast agent. 32 The T2-weighted

MRI

functionality

of

the

fabricated


nanoplatform was evaluated by a 7 T magnetic resonance (MR) scanner (Figure 7A). The nanoplatform exhibited an apparent iron concentration (0-0.6 mM)-dependent darkening effect, and the corresponding transverse relaxivity (r2) value was approximately 39.7 mM−1 s-1, demonstrating that the nanoplatform could be used for sensitive MRI T2 contrast agent. To


13


Page 14 of 28

further investigate the retention effect with a magnetic field, mice implanted with magnets (Figure 7B) were used. As shown (Figure 7C), Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles could mostly be attracted to the muscle tissues close to the implanted magnets, demonstrating that our magnetic nanoplatform could be guided by a specific magnetic field.

Figure 8. (A) Tumor growth curves of tumor-bearing mice after various treatments. (B) The tumor weights measured after various treatments. (C) Digital photographs of excised tumors from representative mice after various treatments. ((a) PDT + Chemotherapy group, (b) Chemotherapy group, (c) PDT group and (d) Control group). (D) Images of H&E-stained tumor sections from the various treatment groups (Day 14). In vivo synergistic antitumor efficacy. To investigate the antitumor activity of the magnetic field-guided Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform in vivo, U87 tumor-bearing nude model mice were selected to evaluate the synergistic antitumor efficacy. The tumor volume was recorded every other day for 14 days. As shown (Figure 8A), rapid tumor growth was observed


14

Page 15 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


in the control group. Both the PDT and Chemotherapy groups had some tumor inhibition. However, the Chemotherapy group exhibited a higher antitumor effect than did the PDT group. In contrast, compared with other three groups, the PDT + Chemotherapy group, which had synergistic photodynamic/chemo therapy, showed significantly suppressed tumor growth. With the magnetic active targeting effect of the Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform to the tumor site, a relatively high DOX and Ce6 concentration was attained, further improving the synergistic photodynamic/chemo therapy effect greatly. The tumor morphology (Figure 8C) and average

weights

of

each

group

(Figure

8B)

directly

demonstrated

that

our

Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform exerted an excellent tumor-inhibiting effect via magnetic targeting. In addition, hematoxylin and eosin (H&E) staining of tumor tissues was employed to evaluate the morphology of tumor cells and confirmed the therapeutic efficiency (Figure 8D). It was clear that compared with other groups the morphology of tumor tissue cells from PDT + Chemotherapy group were obviously destroyed. In contrast, the tumor cells from only PDT or Chemotherapy still retained the normal morphology.

Figure 9. The major organs stained with hematoxylin and eosin (H&E) after different treatments.


15


Page 16 of 28

Histology examination. In addition, to further assess the in vivo cytotoxicity of these samples, histological analysis of the major organs was employed (Figure 9). Hematoxylin and eosin (H&E) staining method was used in this experiment. Notably, histopathological examination revealed no significant tissue damage in the major organs, including the heart, liver, spleens, lung, and kidney, in the different treatment groups. These results indicated the good biocompatibility of our nanoplatform and its promising prospects for in vivo applications. CONCLUSION In summary, we successfully developed a multifunctional combination therapeutic platform (Fe3O4@mSiO2(DOX)@HSA(Ce6)) for synergistic photodynamic/chemo therapy based on magnetic field guidance. Monodispersed Fe3O4@mSiO2 nanoparticles were synthesized and DOX molecules were loaded into mesoporous silica. To control the DOX burst release and leakage, the mesoporous silica channel was gated by a polydopamine shell, which enabled pHresponsive, sustained release. HSA modification could not only make the nanoplatform stable and biocompatible but also offer a vehicle for photosensitizer Ce6 molecules. Under a magnetic field, our nanoplatform can be guided to tumor sites. Our animal experiments demonstrated that the


nanoplatform

was

an

effective

synergistic

photodynamic/chemo drug delivery system for treating glioma tumor. MATERIALS AND METHODS Materials. Ferric chloride hexahydrate (FeCl3.6H2O), oleic acid (C17H33COOH), 1-octadecene (C18H36), tetraethyl orthosilicate (TEOS), cetyltrimethyl ammonium bromide (CTAB) and dopamine hydrochloride (DA.HCl) were purchased from Aladdin. (Shanghai, China). Human serum albumin (HSA) was obtained by Beijing Biosynthesis Biotechnology Co., Ltd. (Beijing, China). Doxorubicin hydrochloride (DOX.HCl) was purchased from Sangong Biotech Co., Ltd.


16

Page 17 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Shanghai, China). Chlorin e6 (Ce6) was purchased from J&K Chemical Reagent Co., Ltd. (China). Synthesis of Fe3O4 nanoparticles. The Fe3O4 nanoparticles were synthesized according to our previous procedure. 33 Typically, the iron-oleate complex was first prepared in a mixture solution containing ethanol, distilled water and hexane. The obtained solid iron-oleate complex dissolved in 1-octadecene was slowly heated to 320 °C and stored at the reaction temperature for half an hour. Ethanol was added to deposit Fe3O4 nanoparticles when the hot solution was cooled down to room temperature, and black Fe3O4 nanoparticles were obtained by centrifugation and washed several times with an ethanol and hexane mixture solution. Synthesis of Fe3O4@mSiO2 core/shell nanoparticles. Fe3O4@mSiO2 core/shell nanoparticles were prepared by a modified procedure as previously described.

34

In brief, 2 ml of Fe3O4

nanoparticles in cyclohexane (10 mg/ml) was added to 20 ml of 0.01 M aqueous CTAB solution, and the obtained solution was stirred vigorously for 30 min. The turbid brown microemulsion was heated to 70 °C for 30 min to evaporate the organic cyclohexane. Then, 40 ml of water was added, and 300 µl of NaOH solution (2 M) was injected, followed by the slow addition of 400 µl of TEOS into this CTAB-stabilized Fe3O4 micelle solution for 30 min. The reaction mixture was continuously and slowly stirring at 480 r/min for 2 h. Finally, the solid products were centrifuged (12000 rpm, 10 min) and refluxed into 20 ml of ethanol containing 40 µl of HCl for 3 h to remove the surfactant CTAB. The Fe3O4@mSiO2 nanoparticles were obtained by centrifugation and washed with ethanol three times. Synthesis of Fe3O4@mSiO2(DOX)@PDA nanoparticles. For DOX loading, 100 mg of Fe3O4/mSiO2 nanoparticles was dispersed in 5 ml of pure water containing 100 mg of DOX, and the mixture was then stirred for 24 h in the dark. DOX-loaded Fe3O4/mSiO2 nanoparticles were


17


Page 18 of 28

obtained after centrifugation and washing with water to remove the residual DOX molecules on the mesoporous silica surface. The DOX loading capacity was determined by UV-Vis spectroscopy at 480 nm. For the PDA surface coating, the obtained Fe3O4/mSiO2(DOX) nanoparticles were dispersed in 10 ml of Tris-HCl (pH 8.5) buffer solution, and 20 mg of dopamine was then added to the solution, which was then slowly stirred for 4 h at room temperature. The obtained dark brown solution was centrifuged (12000 r/min) for 10 min, and the resulting black PDA-coated Fe3O4/mSiO2(DOX) nanoparticles were obtained after the solution was washed with water three times to remove unpolymerized dopamine. Synthesis of Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles. Fe3O4@mSiO2(DOX)@PDA nanoparticles were further modified with HSA molecules by the Michael addition reaction. Briefly, the obtained polydopamine-coated nanoparticles were added to 20 ml of HSA solution (10 mg/ml) and stirred at 300 r/min for 12 h. The resulting brown solution was centrifuged (12000 r/min) for 10 min, and the final Fe3O4@mSiO2(DOX)@HSA nanoparticles were collected and washed with water three times. The obtained Fe3O4@mSiO2(DOX)@HSA nanoparticles were redispersed in ultrapure water by sonication, and 30 mg of Ce6 dissolved in 100 µl of DMSO was added dropwise to the brown suspension and stirred slowly overnight. In addition, Ce6-loaded Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles were obtained after collection and washing. The Ce6 loading capacity was determined by UV-Vis spectroscopy at 660 nm. Characterization. Fourier transform infrared spectroscopy (Nexus 670, Nicolet, USA) was used to analyze the surface structure changes. The XRD patterns of the powders were acquired by means of a Rigaku Smart Lab 3000 diffractometer. The morphology of all samples was analyzed by transmission electron microscopy (TEM, JEOL JEM-2100). The zeta potential and hydrodynamic size of each nanoparticle were determined by using a Zetasizer Nano ZS (Malvern


18

Page 19 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Instrument, Malvern, UK). The superparamagnetic property and saturation magnetization values were investigated by a magnetometer (Zhengxian HH-15), which was operated under a circulating magnetic field (-5000 to 5000 Oe). In vitro drug release study. The DOX release behavior of Fe3O4@mSiO2(DOX) and Fe3O4@mSiO2(DOX)@HSA was studied in PBS buffer solutions with different pH values. At specific time points during the incubation, the fluorescence intensity of the free DOX in solution was

quantified

by

a

UV-vis

spectrophotometer.

The

Ce6

release

behavior

of

Fe3O4@mSiO2@HSA(Ce6) was carried out by the similar process. Cell uptake and ROS detection. Human glioma U87 cells were seeded in culture dishes. U87 cells were incubated with Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles (Ce6: 2.5 µg/ml)) for different times (2 h, 6 h, 12 h) to allow uptake. After fixing with 4 % paraformaldehyde, U87 cells were washed with PBS solution several times. The fluorescence emission spectrum of the Ce6 inside the HSA molecules was detected in the red channel of a fluorescence microscope. Singlet oxygen sensor green (SOSG) was employed to quantify the in vitro singlet oxygen production process according to a previously reported protocol.35 Firstly, SOSG was dissolved in methanol (5 mM), and then 10 µl of the above-prepared SOSG solution was added to different sample solutions (Ce6: 1 µM). Finally, after red light (5 mW/cm2) irradiation for different periods of time, fluorescence intensity was recorded. To confirm the in vivo ROS generation of Fe3O4@mSiO2(DOX)@HSA(Ce6), the single oxygen probe DCFH-DA was employed. Briefly, the U87 cells were incubated with Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles (Ce6: 2.5 µg/ml) for 12 h and then incubated with DCFH-DA (20 µM, 20 min). Finally, the U87 cells were exposed to a red light (5 mW/cm2) for 5 min and 12 min. The green fluorescence of the DCF into U87 cells was detected with


19


Page 20 of 28

excitation at 488 nm and emission at 525 nm by a fluorescence microscopy. Cell viability assays and antitumor effects. The cytotoxicity of Fe3O4@mSiO2@HSA nanoparticles was explored by the standard MTT assays. Generally, U87 cells were seeded and cultured with cell media into 96-well plates. After 12 h, the cells were treated with Fe3O4@mSiO2@HSA nanoparticles with different concentrations for 24 h and 48 h. Then, 20 µl of MTT PBS solutions (5 mg/ml) was added to each well. After the media was removed DMSO was added. The absorbance at a 570 nm test wave was detected on a microplate reader. For

U87

cell

therapy,

Fe3O4@mSiO2(DOX)@HSA

(Chemotherapy

group),

Fe3O4@mSiO2@HSA(Ce6) (PDT group), and Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles (PDT + Chemotherapy group) with various concentrations were incubated with U87 cells. After incubation with U87 cells for 12 h, the PDT and PDT + Chemotherapy groups were exposed to red light (660 nm, 5 mW/cm2) for 30 min and incubated for 24 h. Finally, the U87 cell viabilities of all groups were evaluated by the standard MTT assay in vitro. Tumor-targeting accumulation assessed by in vivo fluorescence imaging. The animal procedures were in accordance with the guidelines of the Institutional Animal Care and Use Committee. Fluorescence imaging exploration was performed when the tumors reached ~200300 mm3. Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles were intravenously injected into mice at an equivalent Ce6 dose of 5.6 mg/kg. After magnetic targeting for different periods, the Ce6 fluorescence distribution in vivo was recorded by a Maestro animal imaging system. Spectral unmixing was conducted by Maestro software to remove the auto-fluorescence background. In vitro T2 MRI and retention analysis under a magnetic field. A 7 T MRI instrument (PharmaScan, Bruker BioSpin MRI Co., Germany) was employed to investigate T2-weighted


20

Page 21 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


magnetic resonance (MR) images. For T2 in vitro imaging, Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoparticles with different iron concentrations (0, 0.1, 0.2, 0.4 and 0.6 mM) were dispersed in water. The parameters of T2 MRI in this operation were set as: TR = 5519.8 ms, TE = 27.9 ms, slice thickness = 3 mm, and field of view (FOV) = 4 cm. The Fe3O4@mSiO2(DOX)@HSA(Ce6) retention in tissue under a magnetic field was also explored by means of the 7 T MRI instrument. In vivo synergistic antitumor efficacy. U87 tumor-bearing mice were randomly divided into 4 groups (n=5) that received four different treatments via tail vein intravenous injection: (a) PBS group (Control group), (b) injection with 200 µl of Fe3O4@mSiO2(DOX)@HSA (Chemotherapy group), (c) injection with 200 µl of Fe3O4@mSiO2@HSA(Ce6) group (PDT group) and (d) injection with 200 µl of Fe3O4@mSiO2(DOX)@HSA(Ce6) (PDT + Chemotherapy group). All groups received guidance for targeting via a 0.5 T magnetic field. PDT performance was conducted under appropriate red light (5 mW/cm2, 0.5 h) after 12 h of magnetic targeting. Tumor size were recorded after calculating according to the following formula: Tumor volume (V) = length×width2/2. The value of V/V0 was used to monitor tumor volume. (V0: original tumor volume). Treatment was initiated as the tumor volume reached ~100 mm3. Histology examination. To evaluate the safety of the Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform for biomedical application and observe morphology change of tumor tissue cells after treatments, histological analysis of main organs and tumors was performed. Samples were excised and fixed in 4 % formalin for the following experiments. Hematoxylin and eosin (H&E) was applied to detect the changes in the features of each organ and tumor tissue after different treatments. ASSOCIATED CONTENT Supporting Information.


21


Page 22 of 28

The following files are available free of charge. Figures S1-S5 (PDF) AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was financially supported by the NSFC (81471183),

the clinical medical special

Program of Science and Technology Project of Jiangsu Province (BL2014074),the Industry Program of Science and Technology Support Project of Jiangsu Province (BE2014128), the Major Program of Natural Science Fund in Colleges and Universities of Jiangsu Province (15KJA430005), the Prospective Joint Research Program of Jiangsu Province (BY201500501), the Program for Changjiang Scholars and Innovative Research Team in Universiy (No.IRT_15R35), Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites and Priority Academic Program Development of Jiangsu Higher Education Institutions, the Natural Science Foundation of Jiangsu Province: ( BK2014377 ). REFERENCES (1) Zhu, R. R.; Wang, Z. Q.; Liang, P.; He, X. L.; Zhuang, X. Z.; Huang, R. Q.; Wang, M.; Wang, Q.; Qian, Y. C.; Wang, S. L. Efficient VEGF Targeting Delivery of DOX Using


22

Page 23 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Bevacizumab Conjugated SiO2@LDH for Anti-Neuroblastoma Therapy. Acta Biomater. 2017, 63, 163-180. (2) Jin, L. H.; Liu J. H.; Tang, Y.; Cao, L. Q.; Zhang, T. Q.; Yuan, Q. H.; Wang, Y. H.; Zhang, H. J. MnO2-Functionalized Co-P Nanocomposite: A New Theranostic Agent for pH-Triggered T1/T2 Dual-Modality Magnetic Resonance Imaging-Guided Chemo-Photothermal Synergistic Therapy. ACS Appl. Mater. Inter. 2017, 9, 41648-41658. (3)

Yang, G. B.; Gong, H.; Liu, T.; Sun, X. Q.; Cheng, L.; Liu, Z. Two-Dimensional

Magnetic WS2@Fe3O4 Nanocomposite with Mesoporous Silica Coating for Drug Delivery and Imaging-Guided Therapy of Cancer. Biomaterials 2015, 60, 62-71. (4) Luen, S. J., Savas, P.; Fox, S. B.; Salgado, R.; Loi, S. Tumour-Infiltrating Lymphocytes and the Emerging Role of Immunotherapy in Breast Cancer. Pathology 2017, 49, 141-155. (5) Sabado, R. L., Balan, S.; Bhardwaj, N. Dendritic Cell-Based Immunotherapy. Cell Res. 2017, 27, 74-95. (6) Karjoo, Z.; Chen, X. G.; Hatefi, A. Progress and Problems with the Use of Suicide Genes for Targeted Cancer Therapy. Adv. Drug Deliv. Rev. 2016, 99, 113-128. (7) Costa, P. M.; Cardoso, A. L.; Custodia, C.; Cunha, P.; Almeida, L. P.; Lima, M. P. miRNA-21 Silencing Mediated by Tumor-Targeted Nanoparticles Combined with Sunitinib: A New Multimodal Gene Therapy Approach for Glioblastoma. J. Control. Release 2015, 207, 3139. (8) Jiang, Y.; Cui, D.; Fang, Y.; Zhen, X.; Upputuri, P. K.; Pramanik, M.; Ding, D.; Pu, K. Amphiphilic

Semiconducting

Polymer

as

Multifunctional

Nanocarrier

for


23


Page 24 of 28

Fluorescence/Photoacoustic Imaging Guided Chemo-Photothermal Therapy. Biomaterials 2017, 145, 168-177. (9)

Liang, H. T.; Lai, X. S.; Wei, F. M.; Lu, S. H.; Wen, W. F.; Kuo, S. H.; Chen, C. M.;

Tseng, W. Y.; Lin, F. H. Intratumoral Injection of Thermogelling and Sustained-Release Carboplatin-Loaded Hydrogel Simplifies the Administration and Remains the Synergistic Effect with Radiotherapy for Mice Gliomas. Biomaterials 2018, 151, 38-52. (10)

Zhu, Y. Q.; Zhang, J.; Meng, F. H.; Deng, C.; Cheng, R.; Feijen, J.; Zhong, Z. Y.

cRGD-Functionalized Reduction-Sensitive Shell-Sheddable Biodegradable Micelles Mediate Enhanced Doxorubicin Delivery to Human Glioma Xenografts In Vivo. J. Control. Release 2016, 233, 29-38. (11)

Yang, G. B.; Sun, X. Q.; Liu, J. J.; Feng, L. Z.; Liu, Z. Light-Responsive, Singlet-

Oxygen-Triggered On-Demand Drug Release from Photosensitizer-Doped Mesoporous Silica Nanorods for Cancer Combination Therapy. Adv. Funct. Mater. 2016, 26, 4722-4732. (12)

Yang, C. Y.; Guo, W.; Cui, L.; An, N.; Zhang, T.; Guo, G.; Lin, H.; Qu, F. Y.

Fe3O4@mSiO2 Core–Shell Nanocomposite Capped with Disulfide Gatekeepers for EnzymeSensitive Controlled Release of Anti-Cancer Drugs. J. Mater. Chem. B 2015, 3, 1010-1019. (13)

Ruan, S. B.; Yuan, M. Q.; Zhang, L.; Hu, G. L.; Chen, J. T.; Cun, X. L.; Zhang, Q. Y.;

Yang, Y. T.; He, Q.; Gao, H. L. Tumor Microenvironment Sensitive Doxorubicin Delivery and Release to Glioma Using Angiopep-2 Decorated Gold Nanoparticles. Biomaterials 2015, 37, 425-435.


24

Page 25 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(14) Croissant, J. G.; Zhang, D. Y.; Alsaiari, S.; Lu, J.; Deng, L.; Tamanoi, F.; AlMalik, A. M.; Zink, J.; Khashab, N. Protein-Gold Clusters-Capped Mesoporous Silica Nanoparticles for High Drug Loading, Autonomous Gemcitabine/Doxorubicin Co-Delivery, and In-Vivo Tumor Imaging. J. Control. Release 2016, 229, 183-191. (15)

Fletcher, J. I.; Williams, R. T.; Henderson, M. J.; Norris, M. D.; Haber, M. ABC

Transporters as Mediators of Drug Resistance and Contributors to Cancer Cell Biology. Drug Resist. Updat. 2016, 26, 1-9. (16) Ramirez, M. R.; Rajaram, S.; Steininger, R. J.; Osipchuk, D.; Roth, M. A.; Morinishi, L. S.; Evans, L.; Ji, W. Y.; Hsu, C. H.; Thurkley, K.; Wei, S. G.; Zhou, A.; Koduru, P. R.; Posner, B. A.; Wu, L. F.; Altschuler, S. Diverse Drug-Resistance Mechanisms Can Emerge from DrugTolerant Cancer Persister Cells. Nat. Commun. 2016, 7, 10690. (17)

Cheng, W.; Liang, C. L.; Liu, L. X.; Gao, N.; Tao, W.; Luo, L. Y.; Zuo, Y. X.; Wang,

X. S.; Zhang, X. D.; Zeng, X. W.; Mei, L. TPGS-Functionalized Polydopamine-Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance. Small 2017, 13, 1700623. (18) Huang, Y. Y.; He, L. Z.; Song, Z. H.; Chan, L.; Huang, W.; Zhou, B. Z.; Chen, T. F. Phycocyanin-Based Nanocarrier as A New Nanoplatform for Efficient Overcoming of Cancer Drug Resistance. J. Mater. Chem. B 2017, 5, 3300-3314. (19)

Chen, W. H.; Luo, G. F.; Qiu, W. X.; Lei, Q.; Liu, L. H.; Wang, S. B.; Zhang, X. Z.

Mesoporous Silica-Based Versatile Theranostic Nanoplatform Constructed by Layer-by-Layer Assembly for Excellent Photodynamic/Chemo Therapy. Biomaterials 2017, 117, 54-65.


25


(20)

Page 26 of 28

Feng, X. Y.; Kang, T.; Yao, J. H.; Jing, Y. X.; Jiang, T. Z.; Feng, J. X.; Zhu, Q. Q.;

Song, Q. X.; Dong, N.; Gao, X. L.; Chen, J. Tumor-Homing and Penetrating PeptideFunctionalized Photosensitizer-Conjugated PEG-PLA Nanoparticles for Chemo-Photodynamic Combination Therapy of Drug-Resistant Cancer. ACS Appl. Mater. Inter. 2016, 8, 17817-17832. (21) Hu, J. J.; Lei, Q.; Peng, M. Y.; Zheng, D. W.; Chen, Y. X.; Zhang, X. Z. A Positive Feedback Strategy for Enhanced Chemotherapy Based on ROS-Triggered Self-Accelerating Drug Release Nanosystem. Biomaterials 2017, 128, 136-146. (22) Kankala, R. K.; Liu, C. G.; Chen, A. Z.; Wang, S. B.; Xu, P. Y.; Mende, L. K.; Liu, C. L.; Hu, Y. F. Overcoming Multidrug Resistance through the Synergistic Effects of Hierarchical pH-Sensitive, ROS-Generating Nanoreactors. ACS Biomater. Sci. Eng. 2017, 3, 2431-2442. (23)

Wan, H.; Zhang, Y.; Zhang, W. B.; Zou, H. F. Robust Two-Photon Visualized

Nanocarrier with Dual Targeting Ability for Controlled Chemo-Photodynamic Synergistic Treatment of Cancer. ACS Appl. Mater. Inter. 2015, 7, 9608-9618. (24) Agostinis, A.; Berg, K.; Cengel, K. A.; Foster, T. H.; Griotti, A. W.; Gollnick, S. O.; Hahn,S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D.; Korbelik, M.; Moan, J.; MD, P. M.; MD, D. N.; Piette, J.; Wilson, B. C.; MD, J. G. Photodynamic Therapy of Cancer: An Update. CA Cancer J. Clin. 2011, 61, 250-281. (25) Zhang, D.; Zheng, A. X.; Wu, M.; Cai, Z. X.; Wu, L. J.; Wei, Z. W.; Yang, H. H.; Liu, X. L.; Liu, J. F. Tumor Microenvironment Activable Self-Assembled DNA Hybrids for pH and Redox Dual-Responsive Chemotherapy/PDT Treatment of Hepatocellular Carcinoma. Adv. Sci. 2017, 4, 1600460.


26

Page 27 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(26) Zhang, D.; Wu, M.; Zeng, Y. Y.; Wu, L. J.; Wang, Q. T.; Han, X.; Liu, X. L.; Liu, J. F. Chlorin e6 Conjugated Poly(dopamine) Nanospheres as PDT/PTT Dual-Modal Therapeutic Agents for Enhanced Cancer Therapy. ACS Appl. Mater. Inter. 2015, 7, 8176-8187. (27) Zhang, Y.; Huang, F.; Ren, C. H.; Yang, L. J.; Liu, J. F.; Cheng, Z.; Chu, L. P.; Liu, J. J. Targeted Chemo-Photodynamic Combination Platform Based on the DOX Prodrug Nanoparticles for Enhanced Cancer Therapy. ACS Appl. Mater. Inter. 2017, 9, 13016-13028. (28) Wei, Y.; Wang, L.; Shi, L.; Wei, E. D.; Zhou, B. T.; Zhou, L.; Ge, B. Polydopamine and Peptide Decorated Doxorubicin-Loaded Mesoporous Silica Nanoparticles as A Targeted Drug Delivery System for Bladder Cancer Therapy. Drug Deliv. 2017, 24, 681-691. (29)

Hao, B. Y.; Xing, R. J.; Xu, Z. C.; Hou, Y. L.; Gao, S.; Sun, S. H. Synthesis,

Functionalization, and Biomedical Applications of Multifunctional Magnetic Nanoparticles. Adv. Mater. 2010, 22, 2729-2742. (30) Gao, L. P.; Yu, J.; Zhou, J. G.; Sun, L.; Wang, J.; Zhu, J. Z.; Peng, H.; Lu, W. Y.; Yan, Z. Q.; Wang, Y. T. Tumor-Penetrating Peptide Conjugated and Doxorubicin Loaded T1-T2 Dual Mode MRI Contrast Agents Nanoparticles for Tumor Theranostics. Theranostics 2018, 8, 92108. (31) Lin, T. T.; Zhao, P. F.; Jiang, Y. F.; Tang, Y. S.; Jin, H. Y.; Pan, Z. Z; He, H. N.; Yang, V. C.; Huang, Y. Z. Blood-Brain-Barrier-Penetrating Albumin Nanoparticles for Biomimetic Drug Delivery via Albumin-Binding Protein Pathways for Antiglioma Therapy. ACS Nano 2016, 10, 9999-10012.


27


Page 28 of 28

(32) Peng, Y. K.; Lui, C. N.; Chen, Y. W.; Chou, S. W.; Raine, E.; Chou, P. T.; Yung, K.; Tsang, S. C. E. Engineering of Single Magnetic Particle Carrier for Living Brain Cell Imaging: A Tunable T1-/T2-/Dual-Modal Contrast Agent for Magnetic Resonance Imaging Application. Chem. Mater. 2017, 29, 4411-4417. (33) Tang, X. L.; Lin, B. L.; Cui, S.; Zhang, X.; Zhong, Y.; Wu, Q.; Zhang, X.; Shen, X. D.; Wang, T. W. Paclitaxel Modified Fe3O4 Loaded Albumin Nanoparticles as Drug Delivery Vehicles by Self-Assembly. RSC Adv. 2016, 6, 43284-43292. (34) Cheng, W.; Nie, J. P.; Xu, L.; Liang, C. Y.; Peng, Y. M.; Wang, T.; Mei, L.; Huang, L. Q.; Zeng, X. W. pH-Sensitive Delivery Vehicle Based on Folic Acid-Conjugated PolydopamineModified Mesoporous Silica Nanoparticles for Targeted Cancer Therapy. ACS Appl. Mater. Inter. 2017, 9, 18462-18473. (35) Li, Z. W.; Wang, C.; Cheng, L.; Gong, H.; Yin, S. N.; Gong, Q. F.; Li, Y. G.; Liu, Z. PEG Functionalized Iron Oxide Nanoclusters Loaded with Chlorin e6 for Targeted, NIR Light Induced, Photodynamic Therapy. Biomaterials 2013, 34, 9160-9170.

For Table of Contents Only


28

A pH-responsive magnetic mesoporous silica-based nanoplatform for

Recommend Documents