Biodegradable and Multifunctional Microspheres for Treatment of

Article Cite This: ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

pubs.acs.org/journal/abseba

Biodegradable and Multifunctional Microspheres for Treatment of Hepatoma through Transarterial Embolization Ping-Fang Chiang,†,‡ Cheng-Liang Peng,†,‡ Ying-Hsia Shih,‡ Yung-Hung Cho,‡ Chun-Sheng Yu,‡ Yu-Min Kuo,‡ Ming-Jium Shieh,*,§ and Tsai-Yueh Luo*,‡ ‡

Isotope Application Division, Institute of Nuclear Energy Research, Longtan, Taoyuan 325, Taiwan Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, #1, Section 1, Jen-Ai Road, Taipei 100, Taiwan

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ABSTRACT: To improve the effectiveness of cancer treatment, this study aimed to develop biodegradable microspheres and to combine chemotherapy and radiotherapy via transcatheter arterial embolization/chemoembolization (TAE/TACE) with local radiation therapy for the slow release of chemotherapeutic agents. Microparticles were prepared by double emulsification using a biodegradable and biocompatible polymer Poly(D,L-lactideco-glycolide) (PLGA). Since the microspheres contain a watersoluble Poly(vinylsulfonic acid) (PVSA) solution, the functional groups of this polymer dissociate into −SO3− in water. The positively charged doxorubicin can be loaded into beads, ensuring slow release. After 188Retin colloids were added into the microspheres, TACE was performed in a rat hepatocellular carcinoma model. Single photon emission computed tomography/computed tomography imaging and biodistribution analyses showed that the microspheres were still in the liver after 72 h. During 4 weeks of observation, ultrasound images showed that the Re/DOX@MS treatment had the most significant inhibitory effect on tumor growth. Biodegradable PLGA microspheres have the advantage of enabling local embolization therapy with reduced adverse effects. In the future, microspheres could serve as a drug delivery system for cancer treatment by combining therapeutic radionuclides and chemotherapeutic drugs, thereby improving treatment effects for hepatocellular carcinoma. KEYWORDS: hepatocellular carcinoma, transcatheter arterial embolization, microsphere, doxorubicin, 188Re system serves as the main blood supply to normal liver tissues.6 TACE delivers cancer treatment directly to a tumor through minimally invasive means that afford significant reductions in systemic toxicity. Although the procedure is rarely a cure for liver cancer, the use of TACE as a locoregional therapy enables a complete local tumor control of 25−35% and increases patient survival.7 Traditional TACE includes the use of doxorubicin or doxorubicin mixed with Lipiodol followed by embolization using a gelatin sponge. Recent research has investigated the pharmacokinetics of TACE with Lipiodol and showed that plasma levels of adriamycin are identical for intraarterial administration with or without Lipiodol.8 To overcome the limitations of early generation TACE techniques, newer types of embolic agents (i.e., drug-eluting beads) such as Y-90 microspheres (TheraSphereH and SIR-SphereH)9−11 and DC beads12−14 have been developed for transcatheter delivery to HCC over a prolonged period of time. Microsphere drug delivery could potentially increase the efficacy of chemotherapy or radiotherapy for

1. INTRODUCTION The global incidence of liver cancer is increasing and has a poor prognosis, particularly when the tumor is unresectable or when orthotopic liver transplantation is contraindicated. More than 80% of cases of liver cancer are encountered in Asia and Africa.1 Hepatocellular carcinoma (HCC), a primary liver cancer, is ranked as the third most common lethal cancer.2−4 In the early stages, liver cancer does not cause signs and symptoms and so is difficult to detect. Despite the high prevalence of primary and metastatic liver tumors, they are among the most challenging situations that oncologists face, because of the complex arterial vessel morphology of the liver and the wide range of anatomic configurations. Only a minority of patients with HCC (25%) are found to be suited to the current curative treatment options, i.e., surgical resection, liver transplant, and percutaneous ablative therapies.5 Transcatheter chemoembolization (TACE) is used for some patients with liver cancer that cannot be treated surgically or by radiofrequency ablation. The liver is unique among organs in that it receives blood via two distinct circulatory routes: the portal vein (∼70% of blood flow) and the hepatic artery (∼30% of blood flow). HCC derives its blood supply mainly from the hepatic artery, whereas the portal venous © XXXX American Chemical Society

Received: May 31, 2018 Accepted: July 24, 2018

A

DOI: 10.1021/acsbiomaterials.8b00635 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Article

ACS Biomaterials Science & Engineering

half-life of 16.9 h. 188Re also provides useful radionuclides for therapy, emitting β(−) particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 keV, 15.1%).22 This study investigates a drug delivery system based on the effectiveness of PLGA microspheres containing negatively charged polymers produced by water/oil/water (w/o/w) emulsion. The PLGA microspheres absorb doxorubicin through an ionic exchange process and are embedded with 188Re-Tin colloid.23 The microspheres are combined with chemotherapy and radiotherapy for the treatment of the F344 rat HCC model via transcatheter arterial embolization (Figure 1).

2. MATERIALS AND METHODS 2.1. Materials. 50:50 Poly(D,L-lactide-co-glycolide) (PLGA RESOMER RG 503H, MW: 24 000−38 000) was purchased from Sigma-Aldrich. Poly(sodium 4-styrenesulfonate), poly(4-styrenesulfonic acid) ammonium salt solution, and poly(vinylsulfonic acid, sodium salt) solutions were used (Aldrich, St. Louis, MO). Dichloromethane (DCM) and dimethyl sulfoxide (DMSO) were purchased from Tedia Inc. (Fairfield, OH). Stannous chloride (SnCl2) was purchased from Sigma-Aldrich (Milwaukee, WI). Hydrophilic doxorubicin HCl (DOX) was purchased from TTY BioPharm Co., Ltd. (Taipei, Taiwan). All other chemicals were obtained from other commercial entities. The W-188/Re-188 generator was manufactured by the Institute of Nuclear Energy Research. 2.2. Microsphere Fabrication. The PLGA microspheres were prepared by a w/o/w double emulsion evaporation process. The four water-soluble polymers, including carboxymethylcellulose sodium salt, poly(sodium 4-styrenesulfonate), poly(4-styrenesulfonic acid)

Figure 1. Schematic depiction of the formation of Re/DOX@MS by entrapment of doxorubicin and 188Retin-colloid via embolization.

HCC via catheter-directed delivery while reducing adverse effects and morbidity compared with systemic treatments. Current studies have focused on the entrapments of drugs in microspheres or microcapsules prepared from a range of biomaterials, such as polysaccharides (e.g., hyaluronic acid and chitosan), proteins (e.g., gelatin and human serum albumin), or synthetic polymers (e.g., polymerspolylactide (PLA) and poly(L-lactide-co-glycolide) (PLGA)).15−17 Among them, PLGA is used in this study due to its biodegradability and biocompatibility.18 Doxorubicin is an anticancer chemotherapy drug effective against a wide range of cancers including hematological malignancies (e.g., blood cancers, such as leukemia and lymphoma), many types of carcinoma (e.g., solid tumors such as liver cancer) and soft-tissue sarcomas.19 The hydrochloride salt of doxorubicin has great therapeutic potential, but the use of doxorubicin is associated with many systemic effects (e.g., dosedependent cardiomyopathy), which limits its long-term use.20 Beta-emitting radiocolloids are widely used for treatment because of their sufficient energy and short radiation distance. Radioactive particles of 90Y microspheres are considered very promising and are increasingly being employed to treat patients with HCC.21 However, 90Y with 2.28 MeV beta emission and no gamma ray is unsuitable for imaging. 188Re is one of the most readily available generators and exhibits a physical

Figure 3. Loading profiles of PLGA microspheres containing PVSA, CMC, PSS, and PSSA.

Figure 2. Structures and scanning electron micrographs of water-soluble polymers, including (A) poly(vinylsulfonic acid, sodium salt) solution, (B) poly(4-styrenesulfonic acid) ammonium salt solution, (C) poly(sodium 4-styrenesulfonate), and (D) carboxymethylcellulose sodium salt. B


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Figure 4. Characterization of PVSA/PLGA microspheres. (a) Size distribution and circularity; (b) optical microscopy images. PBS (pH 7.4) in an incubator at 37 °C with gentle shaking at 120 rpm. At predetermined time intervals, the released media were collected, and the concentration of DOX was determined with a UV−vis spectrophotometer at 485 μm. After assaying, the collected media were returned to the tubes. 2.5. In Vitro Cytotoxicity Assay. A rat liver epithelial tumor cell line (GP7TB) was developed into HCC in syngeneic Fischer 344 (F344) rats. GP7TB cells were maintained in a humidified 5% CO2 incubator at 37 °C in Dulbecco’s modified Eagle’s medium (DMEM; Gibco BRL, Gaithersburg, MD) supplemented with 10% heatactivated fetal bovine serum (FBS; Gibco BRL) and 1% antibiotics (antibiotic-antimycotic; Gibco BRL). The cytotoxicity of Re/DOX@MS, Re@MS, DOX@MS, MS, Re, and DOX on GP7TB cells was evaluated by an MTT colorimetric procedure. GP7TB cells were plated at a density of 2 × 104 cells per well in 500 μL of prepared DMEM medium in 24-well plates and grown for 24 h. At 50% confluence, GP7TB cells were washed and exposed to different doses in six groups (Re/DOX@MS, Re@MS, DOX@MS, MS, Re, and DOX) at 37 °C for 24 and 48 h. Each experiment was repeated in quadruplicate. Cells were washed with PBS to eliminate the remaining drugs, and MTT solutions were treated for 4 h at 37 °C. After removing the supernatant, 200 μL of DMSO was added to each well for 30 min. The quantity of formazan dyes (directly proportional to the number of viable cells) was measured by the Synergy HT Multidetection reader in ultraviolent absorbance at 570 nm. Data were expressed as the percentages of viable cells compared to the survival of a control group. 2.6. TAE Technique. All animal studies were approved by the Animal Care Committee of the Institute of Nuclear Energy Research, and experiments were performed in accordance with institutional guidelines (number: 10178). The male F344 rats (13 weeks old) were purchased from the National Laboratory Animal Center in Taipei, Taiwan. F344 rats initially weighing 300−350 g were anesthetized with a mixture of air and Forane (isoflurane, USP, Baxter). Active tumor tissues were taken from the F344 rats inoculated with GP7TB tumors, washed with saline, and subdivided into small tissue pieces in suspension in saline. The other rats were fixed and the abdominal area was shaved and routinely disinfected. One tumor tissue (1 mm3) was inoculated into the left lateral liver lobe and gentle compression was applied for rapid and effective hemostasis. Abdominal incisions were closed by simple continuous suturing of the muscle layer, and animals were returned to storage facilities with periodic monitoring.

ammonium salt solution, and poly(vinylsulfonic acid, sodium salt) solution were dissolved in deionized water (25%, 200 μL) and added to CH3Cl dissolving PLGA (0.25% w/v) agents respectively to produce four kinds of formulations. The mixture was emulsified using an ultrasonic probe for 40 s. The resulting primary emulsion was poured into a poly(vinyl alcohol) (PVA) solution (15 mL, 1% w/v in ddH2O) and homogenized within 5 min at room temperature (25 °C) for the second emulsion. The double emulsion was placed in a rotary evaporator at 40 °C to evaporate the organic solvent. The hardened PLGA microspheres were rinsed with deionized water and filtered through a membrane filter before freezing and lyophilization. The PLGA microspheres absorbed DOX by soaking in the DOX solution (8 mg/mL) for 2 h and DOX was washed away with deionized water. After lyophilization, DOX@MS was immersed in 188Reperrhenate freshly eluted with saline from the alumina-based 188W/ 188Re-generator and incubated at 40 °C for 20 min. Stannous chloride (SnCl2) was added to the vial at 40 °C for 20 min. Re/DOX@ MS was collected through filtration. Labeling efficiency was checked by chromatography (ITLC-SG/normal saline) and radioactivity was monitored by a TLC scanner (AR-2000 radio-TLC Imaging Scanner, Bioscan). 2.3. Characterization of PLGA Microsphere Size and Morphology. A scanning electron microscope (SEM; HITACH S-4800) was employed to investigate the surface morphology and size of the prepared microspheres. Samples were coated with gold before observation. The voltage and current for measurement were 10 V and 2A, respectively. The size of the microspheres was also estimated with a particle size analyzer (Mastersizer 2000, Malvern). The diffraction scatting angle for the particle is proportionate to particle size when a bunch of micron particles pass through a beam of light with the Fraunhofer diffraction method. The dye, 3,3′-dioctadecyloxacarbocyanine perchlorate (DiO, 1 mg) mixed with CH3Cl dissolving PLGA (0.25% w/v) agents and a PVA solution was incorporated into the DiO-labeled PLGA microspheres using a double-emulsion evaporation process. The DiO-labeled PLGA microspheres absorbed DOX by immersion as described previously. The DiO/DOX loaded PLGA microspheres were observed under confocal fluorescence microscopy. 2.4. In Vitro Drug Release from PLGA Microspheres. In vitro release of DOX from DOX@MS was carried out in PBS (pH 7.4) and placed into a dialysis bag (molecular weight cutoff, 3.5 kDa). The dialysis bags were placed in 15 mL centrifuge tubes with 2.5 mL of C


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Figure 5. Chromatogram of radiochemical purity: (a)

188

Re and (b) Re@MS.

Figure 6. (a) Confocal fluorescence microscopy images of a DiO/DOX microsphere. (b) Optical microscopy image of a DiO/DOX microsphere. Hepatic artery catheterization was carried out according to Sheu et al.24 For each rat, the abdominal area was shaved and cleaned with an alcohol wipe. A 5 cm long incision was made, and cotton-tipped applicators were used to dissect through the mesentery to expose the portal triad. To separate and identify the components of the portal area, the gastroduodenal artery was ligated temporarily with silks to stop the arterial flow during catheterization, while the downstream end of the hepatic artery was ligated permanently to prevent retrograde bleeding. After perforation using micro scissors, a thin polyethylene tubing #10 (Clay Adams/Becton Dickinson and Company, NJ) connected with a syringe was placed inside the hepatic artery and 200 μL of experimental drugs was slowly injected with a tuberculin syringe, followed by 300 μL of saline solution. After injection, the upstream end of the hepatic artery was tied off and gastroduodenal flow was restored. 2.7. Biodistribution of Re/DOX@MS. Ten days after tumor implantation, the F344 rats received a hepatic artery injection of Re/DOX@MS. At selected time points (1, 24, and 48 h), groups of three rats were sacrificed and the uptake of radioactivity by the tumor and normal tissues was measured by a gamma counter. Tissue distribution data were expressed as the percentage of injected dose per gram of tissue (ID%/g). Single photon emission computed tomography/computed tomography (NanoSPECT/CT) was also performed to evaluate the distribution of Re/DOX@MS, Re@MS, and free Re/DOX in rats. SPECT images and X-ray CT images were taken at 1, 4, 24, 48, and 72 h after intraarterial injection, and the rats were immobilized by inhalation of anesthetic isoflurane and kept in the same position for image reconstruction. 2.8. Antitumor Efficacy. Although tumors were allowed to grow for 10 days after tumor inoculation, 24 male F344 rats were divided into six groups and screened by ultrasound imaging. The tumors reached an average diameter of 0.5 cm. The six groups were given different treatments including Re/DOX@MS, Re@MS, DOX@MS, MS, Re/DOX, and normal saline. A total dose of 3 mCi for Re/DOX@MS, Re@MS, and Re/DOX and a dose equivalent to

Figure 7. Release profile of DOX@MS. 0.8 mg/kg of doxorubicin for Re/DOX@MS, DOX@MS, and Re/ DOX were used as single hepatic arterial injections. During the 28th day of treatment, ultrasonic images were performed to confirm tumor growth once a week. After imaging, the rats were arterially embolized with different types of emboli. 2.9. Statistical Analysis. Comparison between two groups was analyzed by the one-tailed Student’s t test, and P < 0.05 was considered statistically significant. Data are presented as mean ± standard deviation (SD).

3. RESULTS AND DISCUSSION 3.1. Characterization of PLGA Microspheres. The morphology across all the sample groups was generally spherical, and the surface was covered with holes (Figure 2). Holes on the microsphere surface were used as channels to allow DOX and 188Re into the microspheres. Most holes on the surface D


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Figure 8. In vitro cytotoxicity of MS, DOX, DOX@MS, Re, Re@MS, and Re/DOX@MS.

taken from the solvent front part, where the sample of free Re carried up by the mobile phase accumulates. The other region in Figure 5b corresponds to the measurement taken from the origin of the strip, where the sample of Re@MS stayed in place. The percentage of regions of interest for the region was 100% (Figure 5b), indicating that the purity of 188Re presence in Re@MS was 100%. DiO (i.e., a type of lipophilic fluorescent stain for labeling cell membranes and other hydrophobic structures) was entrapped in the Dio-load microspheres. An issue regarding the distribution of doxorubicin was examined on recording the confocal fluorescence images of the microsphere at varied depths. Figure 6a showed vertical cross-sectional confocal fluorescence images of a Dio-load microsphere represented individual focal planes separated by a distance of 2 μm in an order from left to right and top to bottom; the field of view for each image is 60 × 60 μm2. Green fluorescence from Dio-load microspheres and red fluorescence from doxorubicin revealed the structure of microspheres where doxorubicin was distributed, which could be visualized by an arrangement of colored dots and provide a good indication of the internal structure.

were found in microspheres prepared with the Poly(vinylsulfonic acid, sodium salt) solution, and this micropshere showed the best absorption of DOX (Figure 3). PVSA/PLGA microspheres were selected in this study due to their high absorption of DOX. PVSA/PLGA microspheres were prepared with the w/o/w emulsion solvent evaporation method; the size of microsphere samples is shown in Figure 4. The mean diameter of PVSA/PLGA microspheres was 12.7 μm, and the particles were round. Our results corresponded to the SEM photographs and optical images. After radioembolization, radio-labeling efficiency of the microspheres (Re/Dox@MS and Re@MS) was analyzed. The radiochemical purities of free Re and Re@MS were assessed and detected with beta radioactive emissions from thin layer chromatography (TLC) plates with the radio-TLC Imaging Scanner. Figure 5 shows sample results for the radiochemical purity of free Re and Re@MS. The result provided the Rf value and the percentage of the region of interest directly. The two chromatograms showed two regions of interest, one from 67.7 to 87.0 mm and another from 10.5 to 29.8 mm. The measurement of the region in Figure 5a was E


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Figure 9. NanoSPECT/CT images of F344 rats carrying HCC 1, 4, 24, 48, and 72 h after the intraarterial injection of Re/DOX@MS.

Figure 10. NanoSPECT/CT images of F344 rats carrying HCC 1, 4, 24, 48, and 72 h after the intraarterial injection of Re@MS.

The optical image of DOX@MS loaded with doxorubicin is shown in Figure 6b. When the drug was sequestered into the microsphere structure, it changed color to red because doxorubicin is red (Figure 6b). 3.2. Kinetics of DOX Release. DOX@MS exhibited a two-phase release profile, i.e., a relatively rapid burst release of DOX of nearly 15% after 10 days, followed by a sustained and slower release for up to day 30 (Figure 7). This sustained release profile of DOX@MS highlights the potential applicability of microspheres as a drug delivery system for focusing therapeutic drugs in the tumor site while minimizing the exposure of healthy tissues. 3.3. Cytotoxicity of Drug-Loaded PLGA Microspheres. As expected, all groups showed inhibited growth of GP7TB cells in a dose-dependent manner through precise serial dilution (Figure 8). There was no significant difference between control and MS groups, but at high concentration of MS, too many particles were covered, which contributed to the down

growth of GP7TB cells. Compared to free DOX, DOX@MS had less cytotoxicity because the dosage was sustained for a prolonged period of time and drug release was slower. In contrast, Re@MS enhanced the inhibition of GP7TB cell growth compared with free 188Re. This result may be explained by the fact that free 188Re was diluted in the medium, but Re@MS containing radiation was deposited directly onto the cells. When the GP7TB cells were treated with the combination of 188 Re and DOX agent (Re/DOX@MS), cell viability was synergistically reduced. Re/DOX@MS also demonstrated highest cytotoxic activity compared to other groups, especially at 48 h. Combination therapy of chemotherapy and radiotherapy showed more efficacy than single-agent treatment. 3.4. Biodistribution of Re/DOX@MS. Images obtained by NanoSPECT/CT revealed that radioactivity accumulated in the hepatoma area, while some activity was distributed in the urinary bladder, especially in the Re/DOX group 1 h after injection. High radioactivity was observed in the liver 24 h after F


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Figure 11. NanoSPECT/CT images of F344 rats carrying HCC 1, 4, 24, 48, and 72 h after the intraarterial injection of free Re.

Figure 12. Biodistribution of Re/DOX@MS 1, 24, and 48 h after intraarterial injection in rats carrying GP7TB liver tumors. Figure 13. In vivo antitumor efficacy. Single stars (*) indicate P < 0.05 and double stars (**) indicate P < 0.01 compared with control.

the injection in Re/DOX@MS and Re@MS, but most Re/ DOX was metabolized through the urinary system. The Re/ DOX group showed almost no 188Re signal from 48 h after injection. NanoSPECT/CT images of the Re/DOX@MS and Re@MS groups showed radiation uptake of 188Re in the liver after 72 h (Figures 9−11). A similar phenomenon was also found in the biodistribution of Re/DOX@MS performed by γ-counting (Figure 12). Re/ DOX@MS was widely and rapidly distributed into the liver and the tumor, with the highest accumulation occurring in the tumor followed by the liver, urinary bladder, and stomach 1 h after injecting Re/DOX@MS. After 48 h, the accumulation of radioactivity in all tissues decreased, especially in the urinary bladder. The tumor and liver had the highest remaining radioactivity. This decreasing amplitude of radioactivity may be due to urine excretion removing most of the free 188Re or to the embolization of the hepatic artery. The percentage ID per gram of Re/ DOX@MS decreased slowly at the tumor site from 12.07% ID/g at 1 h after the injection to 7.57% ID/g at 48 h, and it was smaller in the blood and most tissues. Thus, Re/DOX@MS appears to be an ideal candidate carrier for long-term therapy. 3.5. Antitumor Efficacy of Drug-Loaded PLGA Microspheres. The antitumor effect of Re/DOX@MS was

compared with the effects of Re@MS, DOX@MS, MS, Re/ DOX, and normal saline (Figure 13). The tumor volumes of free Re/DOX were more inhibited than MS (Figure 14). Although the free Re/DOX could not be embolized for a long time, tumors remained in situ within 24 h. Compared to Re@ MS, DOX@MS had a smaller tumor-inhibition effect although the dosage was sustained for a prolonged period of time. But the 188Re of Re@MS had high beta-energy emission and deep tissue penetration to kill cancer cells before decaying. Compared with control or other treatments, the Re/DOX@MS treatment was responsible for significantly greater tumor growth inhibition and therapeutic response.

4. CONCLUSION The present study developed a novel biodegradable drug delivery system that investigates the feasibility of Re/DOX@ MS combined with chemotherapy and radiotherapy for transcatheter delivery to liver tumors. Doxorubicin is absorbed in microspheres by an ionic exchange process resulting in slow release. 188Retin-colloid is embedded to fill the pores of microspheres, leading to brachytherapy. In vitro and in vivo results G


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Figure 14. Serial changes in tumor size among treatments from 0 to 4 weeks measured by sonography. prevention and projections of future burden. Int. J. Cancer 1993, 55, 891−903. (2) Ferlay, J.; Shin, H. R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D. M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 2010, 127, 2893−2917. (3) El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 2011, 365, 1118−1127. (4) Liu, L. X.; Zhang, W. H.; Jiang, H. C. Current treatment for liver metastases from colorectal cancer. World J. Gastroenterol. 2003, 9, 193−200. (5) Kumar, A.; Srivastava, D. N.; Chau, T. T.; Long, H. D.; Bal, C.; Chandra, P.; Chien, le. T.; Hoa, N. V.; Thulkar, S.; Sharma, S.; Tam, L. H.; Xuan, T. Q.; Canh, N. X.; Pant, G. S.; Bandopadhyaya, G. P. Inoperable hepatocellular carcinoma: Transarterial 188Re HDDlabeled iodized oil for treatment-prospective multicenter clinical trial. Radiology 2007, 243, 509−519. (6) Ackerman, N. B. Experimental studies on the circulation dynamics of intrahepatic tumor blood supply. Cancer 1972, 29, 435− 439. (7) Biolato, M.; Marrone, G.; Racco, S.; Di Stasi, C.; Miele, L.; Gasbarrini, G.; Landolfi, R.; Grieco, A. Transarterial chemoembolization (TACE) for unresectable HCC: a new life begins? Eur. Rev. Med. Pharmacol. Sci. 2010, 14, 356−362. (8) Grosso, M.; Pedrazzini, F.; Balderi, A.; Antonietti, A.; Peano, E.; Ferro, L.; Sortino, D. Transarterial Chemoembolization for HCC with

demonstrated that Re/DOX@MS has excellent therapeutic effects, exemplified by significant tumor suppression in F344 rats with HCC. TAE of Re/DOX@MS is therefore a potential agent for treatment of liver cancer.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (T.-Y.L.). Tel: +886-3-82317717 ext. 7004. Fax: +886-3-4711416. *E-mail: [email protected]. Tel: +886-2-23123456 ext. 1444. Fax: +886-2-23940049 (M.-J.S.). ORCID

Ming-Jium Shieh: 0000-0003-2921-4443 Author Contributions †

P-F.C. and C.-L.P contributed equally and should be considered as co-first authors.

Notes

The authors declare no competing financial interest.

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REFERENCES

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Biodegradable and Multifunctional Microspheres for Treatment of

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