Adjuvant Photothermal Therapy Inhibits Local Recurrences after

Dec 22, 2017 - Department of Medical Imaging, Jinling Hospital, School of Medicine, ... Imaging, Institute of Biomedical and Health Engineering, Shenz...
0 downloads 0 Views 6MB Size
Download PDF
www.acsnano.org

Adjuvant Photothermal Therapy Inhibits Local Recurrences after Breast-Conserving Surgery with Little Skin Damage Shouju Wang,*,†,‡,# Xingqun Ma,§,# Xuhao Hong,∥ Yingxia Cheng,§ Ying Tian,† Shuang Zhao,† Wenfei Liu,† Yuxia Tang,† Ruizhi Zhao,∥ Liang Song,⊥ Zhaogang Teng,†,‡ and Guangming Lu*,†,‡ Downloaded via KAOHSIUNG MEDICAL UNIV on July 21, 2018 at 20:06:10 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Department of Medical Imaging, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, P. R. China State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China § The Affiliated Bayi Hospital of Nanjing University of Chinese Medicine, Nanjing 210002, P. R. China ∥ Department of Physics, Nanjing University, Nanjing 210000, P. R. China ⊥ Research Laboratory for Biomedical Optics and Molecular Imaging, Shenzhen Key Laboratory for Molecular Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, P. R. China ‡

S Supporting Information *

ABSTRACT: Adjuvant treatments following breast-conserving surgery (BCS) are essential to reduce the risk of local recurrences in patients with breast cancer. However, current adjuvant treatments are based on ionizing radiation, which brings radiation-induced damage and amplifies the risk of death. Here we explore the feasibility of using non-ionizing light to induce photothermal therapy as an adjuvant treatment to BCS. In an orthotopic breast cancer mice model, we demonstrate that adjuvant photothermal therapy (aPTT) decreases the incidence of local recurrences after BCS with no expense of cosmetic outcome. In comparison with conventional photothermal therapy, the technique used in aPTT provides more uniformly distributed light energy and less risk of skin burns and local recurrences. Overall, this work represents a departure from the traditional concept of using PTT as an alternative to surgery and reveals the potential of using PTT as an alternative to adjuvant radiation therapy, which is valuable especially for patients susceptible to radiation damage. KEYWORDS: adjuvant photothermal therapy, breast-conserving surgery, breast cancer, local recurrence, cosmetic outcome

B

Since the vast majority of local recurrences that developed in patients who did not receive WBRT are in the vicinity of the primary tumor, WBRT is supposed to exert its primary effect on the residual malignant cells left in the tumor beds.8−10 Thus, it is reasonable to explore other modalities of treatment which are more localized to the tumor beds as alternatives to WBRT. Recently, serval phase II and III clinical trials show accelerated partial breast irradiation (APBI),7,11 a radiation therapy that focuses specifically on the part of the breast where the tumor is removed, is as effective as WBRT for patients with early stage breast cancer. The use of APBI also shortens the course of treatment and reduces the radiation dose to healthy

reast cancer is the most common cancer diagnosed in women, and 61% of patients are diagnosed at the early stage in the United States.1 For these patients, breastconserving surgery (BCS) is strongly recommended by the NCCN guidelines as a good and safe alternative to total mastectomy for its equivalent therapeutic effect and better cosmetic result.2 BCS is usually followed by whole-breast radiotherapy (WBRT) to lower the incidence of local recurrences after BCS and increase the survival of patients in the long term.3,4 However, the ionizing radiation used in WBRT amplifies the risk of death due to the radiation-induced heart disease and secondary malignant disease.4,5 For these concerns, up to 50% of patients in the United States who are clinically eligible for BCS choose to undergo total mastectomy with the goal to omit radiation therapy.6,7 © 2017 American Chemical Society

Received: November 1, 2017 Accepted: December 22, 2017 Published: December 22, 2017 662

DOI: 10.1021/acsnano.7b07757 ACS Nano 2018, 12, 662−670

Article

Cite This: ACS Nano 2018, 12, 662−670

Article

ACS Nano

Figure 1. Characterization of GPB-PEG. (a, b) TEM images of GBP-PEG at low and high magnification. (c) UV−vis absorbance of crude GBP and GBP-PEG after purification. (d, e) Heating curves and thermal images of various concentrations of GBP-PEG upon laser irradiation for 10 min (808 nm, 1 W·cm−2).

tissues.12−14 Nonetheless, APBI is still a technique based on ionizing radiation and cannot completely omit the damage to healthy tissues from high-energy radiation. Therefore, it is in great demand to develop adjuvant therapies based on nonionizing irradiation for patients qualified for the treatment with BCS. Photothermal therapy (PTT) is an emerging therapeutic modality utilizing the heat generated by certain kinds of nanoparticles upon near-infrared (NIR) light irradiation to kill cancers.15−21 As compared with radiation therapy, the advantages of PTT include: (1) free of ionizing radiation damage and (2) dualselectivity from the tumor-targeting accumulation of nanoparticles and the spatially confined delivery of light. It is noted that the penetration depth of the NIR light in tissues is about 1 cm,22 which is close to the margin width required irradiation in the APBI treatment.13,23 Thus, PTT may serve as an alternative to the adjuvant APBI treatment to control local recurrences postsurgery with no radiation damage and superior tumor selectivity. However, to the best of our knowledge, there are no previous reports to explore the feasibility of using PTT as an adjuvant treatment followed BCS. Herein, we report the application of PEGylated gold nanobipyramids (GBP-PEG) in adjuvant photothermal therapy (aPTT) followed BCS in an orthotopic breast cancer mice model. The production of gold nanobipyramids (GBPs) with high purity is realized by synthetic approaches very recently.24−26 Previous reports showed GBPs have stronger and narrower localized surface plasmonic resonance (LSPR) than other shapes of gold nanoparticles,27,28 thus they are supposed to convert light energy into heat more efficiently. Our results showed that the obtained GBP-PEG had superior photothermal conversion efficacy over that of nanorods. More important, we found the GBP-PEG-mediated aPTT significantly decreased the likelihood of local recurrences after BCS

with no expense of cosmetic outcomes. In contrast, BCS and conventional photothermal therapy (cPTT) alone failed to control the local recurrences. The risk of adverse cosmesis was even escalated in mice treated by cPTT because of the overheating of healthy tissues resulting from maldistributed light energy.

RESULTS First, PEGylated gold nanobipyramids (GBP-PEG) were prepared, purified, and characterized. Transmission electronic microscopy (TEM) images display GBP-PEG have a uniform length of 77.2 ± 3.3 nm and width of 23.0 ± 1.8 nm (Figure 1a,b). The selective area electronic diffraction (SAED) pattern of GBP-PEG additionally revealed their high crystallinity (Figure S1). UV−vis absorbance showed the LSPR of GBPPEG peaked at 808 nm. Successful purification was identified by the dramatically reduced absorbance in the spectral region from 500 to 600 nm (Figure 1c). Zeta potential measurement exhibited a decrease of surface charge from +39.0 ± 1.4 mV to −2.0 ± 2.1 mV after PEGylation, implying the attached surfactants on crude GBPs were replaced by mPEG-SH molecules. Dynamic light scattering (DLS) measurement showed the hydrodynamic diameter of GBP-PEG is 41.7 ± 1.0. This diameter is not consistent with the size measured on TEM images because of the anisotropic structure of nanobipyramids. The size of GBP-PEG remained stable in PBS for up to 1 week (Figure S2), suggesting the dense PEG layer protects GBP-PEG from aggregation. Thermal images show the temperature of GBP-PEG solutions increases rapidly upon 808 nm laser irradiation at 1 W·cm−2 and the maximum equilibrium temperature of solutions is correlated directly to the concentration of GBP-PEG. As for the ultrapure water itself, no significant change of temperature was observed during the irradiation (Figure 1d,e). It is noted that the photothermal conversion efficacy of GBP-PEG is higher than 663

DOI: 10.1021/acsnano.7b07757 ACS Nano 2018, 12, 662−670

Article

ACS Nano

Figure 2. GBP-PEG showed superior photothermal therapeutic efficacy and good biocompatibility in vitro. (a) Cell viability of MDA-MB-231 cells after incubation with various concentrations of GNR-PEG and GBP-PEG for 48 h and followed by laser irradiation for 5 min (808 nm, 1 W·cm−2). (b) Cell viability of MDA-MB-231 and MCF 10A cells after incubation with various concentrations of GBP-PEG for 48 h without laser irradiation. P values 50% of the intensity of the primary tumor. Conventional Photothermal Therapy Procedure. Tumorbearing mice were i.v. injected with 150 μL of GBP-PEG (3.75 mg/ kg) and anesthetized with isoflurane after 24 h. The tumor was then irradiated by an 808 nm laser at 2.5 W·cm−2 for 10 min. The laser was output from an optical fiber with a divergence angle of 16°. The temperature of mice during treatment was monitored by an IR camera. Breast-Conserving Surgical Procedure. Tumor-bearing mice were anesthetized by inhaling isoflurane. The skin over the tumors was sterilized by 70% alcohol. A 5−10 mm sagittal cut was performed medial to the skin−tumor interface, and the mammary fat pad was exposed. The exposed encapsulated tumor was carefully separated and removed. No skin or muscle was removed to mimic the breast-

the cosmetic outcome, aPTT might be particularly useful for patients who are susceptible to radiation damage, such as those with collagen vascular disease or that underwent radiation therapy before. To mimic the clinical situation, the surgical procedure we used in this study was established according to the standard for BCS in the management of invasive breast cancer.47 The incision was placed near the tumor with adequate size to remove the tumor in one piece. The tumors were removed with a rim of healthy tissue without excessive sacrifice of surrounding tissues. The muscles and skin were preserved. The success of gross tumor removal was defined as a resection with microscopically tumor-negative margin according to the consensus guideline on margins for BCS from the Society of Surgical Oncology and American Society for Radiation Oncology.23 All of the surgery was done by one operator under the guidance of an experienced surgeon to minimize the variations in the extent of breast resection. Compared to the rate of local recurrences in patients undergoing BCS, the likelihood of local recurrences was significantly higher in our animal model, which is probably due to the immune deficiency of the nude mice and the absence of adjuvant systematic treatment like chemotherapy.

CONCLUSIONS In summary, we reported the GBP-PEG-mediated PTT as an adjuvant therapy following breast-conserving surgery in an orthotopic breast cancer mice model. The GBP-PEG exhibited superior photothermal conversion efficacy and excellent biocompatibility. The GBP-PEG-mediated aPTT can decrease the incidence of local recurrences after surgery without worsening the cosmetic results. The strategy outlined here represents a departure from the traditional concept of using PTT as an alternative to surgery and reveals the potential of using PTT as an alternative to adjuvant radiation therapy, which is valuable especially for patients with collagen vascular disease or that underwent radiation therapy before. The comparison between adjuvant radiation therapy and aPTT on animal models is underway to fully understand the effect of aPTT in vivo. METHODS Materials. Gold(III) chloride trihydrate (HAuCl44·3H2O), silver nitrate (AgNO3), sodium borohydride (NaBH), ascorbic acid, trisodium citrate, and thiazolyl blue tetrazolium bromide (MTT) were purchased from Sigma-Aldrich. Cetyltrimethylammonium chloride (CTAC), cetyltrimethylammonium bromide (CTAB), hydrogen peroxide (H2O2), and ammonium hydroxide (NH3·H2O) were purchased from Aladdin Chemical. Methoxy-PEG-thiol (mPEGSH, MW = 5000 Da). MDA-MB-231/Luc (breast cancer cell lines expressing luciferase) was purchased from Shanghai Bioray Biotechnology, Co. Ltd. Synthesis of GBP-PEG. Crude GBP were obtained by a modified method reported in previous studies. Briefly, the gold seeds were synthesized by adding 150 μL of 0.01 M freshly prepared ice-cold NaBH4 in the mixture of 125 μL of 0.01 M HAuCl4, 250 μL of 0.01 M citrate sodium, and 9.625 mL of ultrapure water under stirring at 1400 rpm. After the mixture turned to pink, the gold seeds were aged for at least 2 h without stirring. The growth solution was prepared by adding 2000 μL of 0.01 M HAuCl4, 400 μL of 0.01 M AgNO3, 800 μL of 1 M HCl, and 320 μL of freshly prepared 0.1 M ascorbic acid to 40 mL of 0.1 M CTAB solution. Then 150 μL aged seed solution was gently mixed with the growth solution by inversion. The reaction solution was left in 30 °C water bath undisturbed overnight. 668

DOI: 10.1021/acsnano.7b07757 ACS Nano 2018, 12, 662−670

Article

ACS Nano conserving surgery. The incision was closed by clips. The removed tumors were fixed for hematoxylin and eosin (H&E) staining. Adjuvant Photothermal Therapy Procedure. Tumor-bearing mice were i.v. injected with 150 μL of GBP-PEG (3.75 mg/kg) 24 h prior surgery. When the incision was closed, the surgical area was irradiated by an 808 nm laser at 1 W·cm−2 for 5 min. The laser was transformed to plane wave by a homemade lens system to gain a uniform intensity distribution in the irradiated area (Figure S13). The size of irradiation field was controlled by an aperture stop. The temperature of mice during treatment was monitored by an IR camera. Biodistribution Studies in Vivo. Tumor-bearing mice were i.v. injected with 150 μL of GBP-PEG (3.75 mg/kg). The mice were sacrificed 6, 24, and 48 h postinjection (three mice per group). Tumors and major organs including heart, liver, spleen, lung, and kidney were collected. All of the samples were weighed and digested to estimate the gold concentration by inductively coupled plasma atomic emission spectroscopy (ICP-AES) measurement. Biocompatibility Studies in Vivo. Healthy female nude mice were randomly divided into two groups (six mice per group) and followed by i.v. injection of 150 μL of saline or GBP-PEG (3.75 mg/ kg). The mice were sacrificed 18 days later. The blood and major organs of mice were collected for biochemical examinations and H&E staining. Statistical Analysis. Data are expressed as mean ± SD. For the in vitro experiments and biocompatibility studies, the comparison between two groups was calculated by two-tailed Student’s t test. For the in vivo experiments, statistical significance was determined by one-way ANOVA for Gaussian distributed data followed by Tukey post hoc statistical test or by Kruskal−Wallis test for non-Gaussian distributed data followed by Dunn’s post hoc statistical test. To compare the trend of local tumor recurrences, a Kaplan−Meier survival curve statistical analysis was performed and followed by a logrank test. To compare the rate of skin scar formation, statistical significance was calculated by Fisher’s exact test. Differences between all groups were considered significant at a value below 0.05 except for the log-rank test, in which the significance threshold was adjusted to 0.0167 by Bonferroni correction.

REFERENCES (1) Howlader, N.; Noone, A. M.; Krapcho, M.; Garshell, J.; Miller, D.; Altekruse, S. F.; Kosary, C. L.; Yu, M.; Ruhl, J.; Tatalovich, Z.; Mariototto, A.; Lewis, D. R.; Chen, H. S.; Feuer, E. J.; Cronin, K. A. SEER Cancer Statistics Review, 1975−2012, http://seer.cancer.gov/ csr/1975_2012/ (accessed September 17, 2017). (2) National Comprehensive Cancer Network. Breast Cancer (Version 2.2017) https://www.nccn.org/professionals/physician_ gls/pdf/breast.pdf(accessed June 6, 2017). (3) Darby, S.; McGale, P.; Correa, C.; Taylor, C.; Arriagada, R.; Clarke, M.; Cutter, D.; Davies, C.; Ewertz, M.; Godwin, J.; Gray, R.; Pierce, L.; Whelan, T.; Wang, Y.; Peto, R. Effect of Radiotherapy After Breast-Conserving Surgery on 10-Year Recurrence and 15-Year Breast Cancer Death: Meta-Analysis of Individual Patient Data for 10,801 Women in 17 Randomised Trials. Lancet 2011, 378, 1707−1716. (4) Clarke, M.; Collins, R.; Darby, S.; Davies, C.; Elphinstone, P.; Evans, V.; Godwin, J.; Gray, R.; Hicks, C.; James, S.; Mackinnon, E.; McGale, P.; McHugh, T.; Peto, R.; Taylor, C.; Wang, Y. Effects of Radiotherapy and of Differences in the Extent of Surgery for Early Breast Cancer on Local Recurrence and 15-Year Survival: an Overview of the Randomised Trials. Lancet 2005, 366, 2087−2106. (5) Darby, S. C.; Ewertz, M.; Hall, P. Ischemic Heart Disease After Breast Cancer Radiotherapy. N. Engl. J. Med. 2013, 368, 2523−2527. (6) Showalter, S. L.; Grover, S.; Sharma, S.; Lin, L.; Czerniecki, B. J. Factors Influencing Surgical and Adjuvant Therapy in Stage I Breast Cancer: a SEER 18 Database Analysis. Ann. Surg. Oncol. 2013, 20, 1287−1294. (7) Strnad, V.; Ott, O. J.; Hildebrandt, G.; Kauer-Dorner, D.; Knauerhase, H.; Major, T.; Lyczek, J.; Guinot, J. L.; Dunst, J.; Gutierrez Miguelez, C.; Slampa, P.; Allgauer, M.; Lossl, K.; Polat, B.; Kovacs, G.; Fischedick, A.-R.; Wendt, T. G.; Fietkau, R.; Hindemith, M.; Resch, A.; et al. 5-Year Results of Accelerated Partial Breast Irradiation Using Sole Interstitial Multicatheter Brachytherapy Versus Whole-Breast Irradiation with Boost After Breast-Conserving Surgery for Low-Risk Invasive and in-Situ Carcinoma of the Female Breast: a Randomised, Phase 3, Non-Inferiority Trial. Lancet 2016, 387, 229− 238. (8) Clark, R. M.; Whelan, T.; Levine, M.; Roberts, R.; Willan, A.; McCulloch, P.; Lipa, M.; Wilkinson, R. H.; Mahoney, L. J. Randomized Clinical Trial of Breast Irradiation Following Lumpectomy and Axillary Dissection for Node-Negative Breast Cancer: an Update. Ontario Clinical Oncology Group. J. Natl. Cancer. Inst. 1996, 88, 1659−1664. (9) Fisher, B.; Jeong, J.-H.; Anderson, S.; Bryant, J.; Fisher, E. R.; Wolmark, N. Twenty-Five-Year Follow-Up of a Randomized Trial Comparing Radical Mastectomy, Total Mastectomy, and Total Mastectomy Followed by Irradiation. N. Engl. J. Med. 2002, 347, 567−575. (10) Fisher, B.; Anderson, S.; Bryant, J.; Margolese, R. G.; Deutsch, M.; Fisher, E. R.; Jeong, J.-H.; Wolmark, N. Twenty-Year Follow-Up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy Plus Irradiation for the Treatment of Invasive Breast Cancer. N. Engl. J. Med. 2002, 347, 1233−1241. (11) Olivotto, I. A.; Whelan, T. J.; Parpia, S.; Kim, D.-H.; Berrang, T.; Truong, P. T.; Kong, I.; Cochrane, B.; Nichol, A.; Roy, I.; Germain, I.; Akra, M.; Reed, M.; Fyles, A.; Trotter, T.; Perera, F.; Beckham, W.; Levine, M. N.; Julian, J. A. Interim Cosmetic and Toxicity Results From RAPID: a Randomized Trial of Accelerated Partial Breast Irradiation Using Three-Dimensional Conformal External Beam Radiation Therapy. J. Clin. Oncol. 2013, 31, 4038− 4045. (12) Vicini, F.; Kini, V. R.; Chen, P.; Horwitz, E.; Gustafson, G.; Benitez, P.; Edmundson, G.; Goldstein, N.; McCarthy, K.; Martinez, A. Irradiation of the Tumor Bed Alone After Lumpectomy in Selected Patients with Early-Stage Breast Cancer Treated with Breast Conserving Therapy. J. Surg. Oncol. 1999, 70, 33−40. (13) Krishnan, L.; Jewell, W. R.; Tawfik, O. W.; Krishnan, E. C. Breast Conservation Therapy with Tumor Bed Irradiation Alone in a

ASSOCIATED CONTENT S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.7b07757. Supplementary figures S1−S13 (PDF)

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Shouju Wang: 0000-0001-9213-6818 Guangming Lu: 0000-0003-4913-2314 Author Contributions #

These authors contributed equally.

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS This project is financially supported by the National Key Basic Research Program of the P.R. China (program no. 2014CB744504), the National Natural Science Foundation of China (program nos. 81501588 and 81601556), and the Natural Science Foundation of Jiangsu Province (program no. BK20140734). 669

DOI: 10.1021/acsnano.7b07757 ACS Nano 2018, 12, 662−670

Article

ACS Nano Selected Group of Patients with Stage I Breast Cancer. Breast J. 2001, 7, 91−96. (14) Polgár, C.; Sulyok, Z.; Fodor, J.; Orosz, Z.; Major, T.; TakácsiNagy, Z.; Mangel, L. C.; Somogyi, A.; Kásler, M.; Németh, G. Sole Brachytherapy of the Tumor Bed After Conservative Surgery for T1 Breast Cancer: Five-Year Results of a Phase I-II Study and Initial Findings of a Randomized Phase III Trial. J. Surg. Oncol. 2002, 80, 121. (15) Chen, Q.; Xu, L.; Liang, C.; Wang, C.; Peng, R.; Liu, Z. Photothermal Therapy with Immune-Adjuvant Nanoparticles Together with Checkpoint Blockade for Effective Cancer Immunotherapy. Nat. Commun. 2016, 7, 13193. (16) Wang, S.; Tian, Y.; Tian, W.; Sun, J.; Zhao, S.; Liu, Y.; Wang, C.; Tang, Y.; Ma, X.; Teng, Z.; Lu, G. Selectively Sensitizing Malignant Cells to Photothermal Therapy Using a CD44-Targeting Heat Shock Protein 72 Depletion Nanosystem. ACS Nano 2016, 10, 8578−8590. (17) Thakor, A. S.; Gambhir, S. S. Nanooncology: the Future of Cancer Diagnosis and Therapy. Ca-Cancer J. Clin. 2013, 63, 395−418. (18) Guo, Z.; Zou, Y.; He, H.; Rao, J.; Ji, S.; Cui, X.; Ke, H.; Deng, Y.; Yang, H.; Chen, C.; Zhao, Y.; Chen, H. Bifunctional Platinated Nanoparticles for Photoinduced Tumor Ablation. Adv. Mater. 2016, 28, 10155−10164. (19) Zhu, A.; Miao, K.; Deng, Y.; Ke, H.; He, H.; Yang, T.; Guo, M.; Li, Y.; Guo, Z.; Wang, Y.; Yang, X.; Zhao, Y.; Chen, H. Dually pH/ Reduction-Responsive Vesicles for Ultrahigh-Contrast Fluorescence Imaging and Thermo-Chemotherapy-Synergized Tumor Ablation. ACS Nano 2015, 9, 7874−7885. (20) He, H.; Ji, S.; He, Y.; Zhu, A.; Zou, Y.; Deng, Y.; Ke, H.; Yang, H.; Zhao, Y.; Guo, Z.; Chen, H. Photoconversion-Tunable Fluorophore Vesicles for Wavelength-Dependent Photoinduced Cancer Therapy. Adv. Mater. 2017, 29, 1606690. (21) Yang, T.; Tang, Y.; Liu, L.; Lv, X.; Wang, Q.; Ke, H.; Deng, Y.; Yang, H.; Yang, X.; Liu, G.; Zhao, Y.; Chen, H. Size-Dependent Ag2S Nanodots for Second Near-Infrared Fluorescence/Photoacoustics Imaging and Simultaneous Photothermal Therapy. ACS Nano 2017, 11, 1848−1857. (22) Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D.; Korbelik, M.; Moan, J.; Mroz, P.; Nowls, D.; Plette, J.; Wilson, B. C.; Golab, J. Photodynamic Therapy of Cancer: an Update. Ca-Cancer J. Clin. 2011, 61, 250−281. (23) Moran, M. S.; Schnitt, S. J.; Giuliano, A. E.; Harris, J. R.; Khan, S. A.; Horton, J.; Klimberg, S.; Chavez-MacGregor, M.; Freedman, G.; Houssami, N.; Johnson, P. L.; Morrow, M. Society of Surgical Oncology−American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery with WholeBreast Irradiation in Stages I and II Invasive Breast Cancer. J. Clin. Oncol. 2014, 32, 1507−1515. (24) Li, Q.; Zhuo, X.; Li, S.; Ruan, Q.; Xu, Q.-H.; Wang, J. Production of Monodisperse Gold Nanobipyramids with Number Percentages Approaching 100% and Evaluation of Their Plasmonic Properties. Adv. Opt. Mater. 2015, 3, 801−812. (25) Lee, J.-H.; Gibson, K. J.; Chen, G.; Weizmann, Y. BipyramidTemplated Synthesis of Monodisperse Anisotropic Gold Nanocrystals. Nat. Commun. 2015, 6, 7571. (26) Kou, X.; Ni, W.; Tsung, C.-K.; Chan, K.; Lin, H.-Q.; Stucky, G. D.; Wang, J. Growth of Gold Bipyramids with Improved Yield and Their Curvature-Directed Oxidation. Small 2007, 3, 2103−2113. (27) Feng, J.; Chen, L.; Xia, Y.; Xing, J.; Li, Z.; Qian, Q.; Wang, Y.; Wu, A.; Zeng, L.; Zhou, Y. Bioconjugation of Gold Nanobipyramids for SERS Detection and Targeted Photothermal Therapy in Breast Cancer. ACS Biomater. Sci. Eng. 2017, 3, 608−618. (28) Lv, J.; Wu, G.; He, Y.; Zhang, L.; Yi, Y. Methylene Blue-Loaded Gold Nanobipyramids @SiO_2 Enhanced Singlet Oxygen Generation for Phototherapy of Cancer Cells. Opt. Mater. Express 2017, 7, 409−6. (29) Roper, D. K.; Ahn, W.; Hoepfner, M. Microscale Heat Transfer Transduced by Surface Plasmon Resonant Gold Nanoparticles. J. Phys. Chem. C 2007, 111, 3636−3641.

(30) Ma, X.; Cheng, Y.; Huang, Y.; Tian, Y.; Wang, S.; Chen, Y. PEGylated Gold Nanoprisms for Photothermal Therapy at Low Laser Power Density. RSC Adv. 2015, 5, 81682−81688. (31) Zhu, T. C.; Finlay, J. C.; Hahn, S. M. Determination of the Distribution of Light, Optical Properties, Drug Concentration, and Tissue Oxygenation in-Vivo in Human Prostate During Motexafin Lutetium-Mediated Photodynamic Therapy. J. Photochem. Photobiol., B 2005, 79, 231−241. (32) Thecua, E.; Tylcz, J. B.; Betrouni, N.; Mordon, S. Latest Technologies of Homogeneous Light Distribution for Photodynamic Therapy of Non-Planar Anatomical Surfaces. Photodiagn. Photodyn. Ther. 2017, 17, A51. (33) Al-Ghazal, S. K.; Fallowfield, L.; Blamey, R. W. Comparison of Psychological Aspects and Patient Satisfaction Following Breast Conserving Surgery, Simple Mastectomy and Breast Reconstruction. Eur. J. Cancer 2000, 36, 1938−1943. (34) Al-Ghazal, S. K.; Fallowfield, L.; Blamey, R. W. Does Cosmetic Outcome From Treatment of Primary Breast Cancer Influence Psychosocial Morbidity? Eur. J. Surg. Oncol. 1999, 25, 571−573. (35) Murphy, C.; Anderson, P. R.; Li, T.; Bleicher, R. J.; Sigurdson, E. R.; Goldstein, L. J.; Swaby, R.; Denlinger, C.; Dushkin, H.; Nicolaou, N.; Freedman, G. M. Impact of the Radiation Boost on Outcomes After Breast-Conserving Surgery and Radiation. Int. J. Radiat. Oncol., Biol., Phys. 2011, 81, 69−76. (36) Wazer, D. E.; DiPetrillo, T.; Schmidt-Ullrich, R.; Weld, L.; Smith, T. J.; Marchant, D. J.; Robert, N. J. Factors Influencing Cosmetic Outcome and Complication Risk After Conservative Surgery and Radiotherapy for Early-Stage Breast Carcinoma. J. Clin. Oncol. 1992, 10, 356−363. (37) Huang, X.; Jain, P. K.; El-Sayed, I. H.; El-Sayed, M. A. Plasmonic Photothermal Therapy (PPTT) Using Gold Nanoparticles. Lasers. Med. Sci. 2008, 23, 217−228. (38) Abadeer, N. S.; Murphy, C. J. Recent Progress in Cancer Thermal Therapy Using Gold Nanoparticles. J. Phys. Chem. C 2016, 120, 4691−4716. (39) Chen, J.; Glaus, C.; Laforest, R.; Zhang, Q.; Yang, M.; Gidding, M.; Welch, M. J.; Xia, Y. Gold Nanocages as Photothermal Transducers for Cancer Treatment. Small 2010, 6, 811−817. (40) Kennedy, L. C.; Bickford, L. R.; Lewinski, N. A.; Coughlin, A. J.; Hu, Y.; Day, E. S.; West, J. L.; Drezek, R. A. A New Era for Cancer Treatment: Gold-Nanoparticle-Mediated Thermal Therapies. Small 2011, 7, 169−183. (41) Chen, Q.; Liang, C.; Wang, X.; He, J.; Li, Y.; Liu, Z. An Albumin-Based Theranostic Nano-Agent for Dual-Modal Imaging Guided Photothermal Therapy to Inhibit Lymphatic Metastasis of Cancer Post Surgery. Biomaterials 2014, 35, 9355−9362. (42) Liang, C.; Diao, S.; Wang, C.; Gong, H.; Liu, T.; Hong, G.; Shi, X.; Dai, H.; Liu, Z. Tumor Metastasis Inhibition by Imaging-Guided Photothermal Therapy with Single-Walled Carbon Nanotubes. Adv. Mater. 2014, 26, 5646−5652. (43) Burnet, N. G.; Thomas, S. J.; Burton, K. E.; Jefferies, S. J. Defining the Tumour and Target Volumes for Radiotherapy. Cancer Imaging 2004, 4, 153−161. (44) Nag, S.; Abdou, J. C.; Scruggs, G. Use of Gold Seeds as Tumor Bed Markers. J. Surg. Oncol. 2005, 92, 147−148. (45) Furet, E.; Peurien, D.; Fournier-Bidoz, N.; Servois, V.; Reyal, F.; Fourquet, A.; Rouzier, R.; Kirova, Y. M. Plastic Surgery for Breast Conservation Therapy: How to Define the Volume of the Tumor Bed for the Boost? Eur. J. Surg. Oncol. 2014, 40, 830−834. (46) Chen, A. M.; Obedian, E.; Haffty, B. G. Breast-Conserving Therapy in the Setting of Collagen Vascular Disease. Cancer J. 2001, 7, 480−491. (47) Morrow, M.; Strom, E. A.; Bassett, L. W.; Dershaw, D. D.; Fowble, B.; Giuliano, A.; Harris, J. R.; O’Malley, F.; Schnitt, S. J.; Singletary, S. E.; Winchester, D. P. American College of Radiology; American College of Surgeons; Society of Surgical Oncology; College of American Pathology. Standard for Breast Conservation Therapy in the Management of Invasive Breast Carcinoma. Ca-Cancer J. Clin. 2002, 52, 277−300. 670

DOI: 10.1021/acsnano.7b07757 ACS Nano 2018, 12, 662−670