with in 2hrs

1.Introduction According to the American Cancer Society's 2010 statistical data, almost 1.5 million new cases of cancer were diagnosed in the United States and more than one third as many people were projected to succumb to their disease [1]. The data also lists cancer as the second leading cause of death behind heart disease with an expected total annual healthcare cost of $263.8 billion. Even though many advances have been made in cancer diagnosis and treat- ment, many of the current treatments still cause considerable harm and discomfort to the pa- tient. A common treatment, chemotherapy, attempts to systemically deliver anticancer agents to pa- tients in order to eradicate the uncontrolled proliferation of cancer cells. Unfortunately, be- cause of nonspecific targeting, healthy cells can also be damaged during the treatment. This systemic approach results in hair loss, pain, anemia, and other side effects [2, 3]. In addition to the toxicity problems associated with nonspe- cific systemic treatments, up to 50% of ap- proved active molecules for cancer therapy have poor solubility in physiological conditions [4].

Another common treatment, radiation therapy, provides a more narrow treatment region, but still has side effects due to its indiscriminate nature. Moreover, this treatment modality has limited applications due to site specificity [5, 6]. However, using more direct methods such as the surgical removal of cancerous tissue may cause permanent disfigurement, is also location dependent, and may cause post operational infection or complications [3]. In an attempt to eliminate or reduce the disadvantages associ- ated with traditional techniques, minimally inva- sive energy-based therapies are being investi- gated, with many clinical trials currently under- way [7-11]. The purpose of this paper is to re- view nanotechnology enhancements to energy- based cancer therapies and discuss results that may be applicable for combined therapies. 2. Energy-based therapies Some promising focus areas in energy-based therapy research are photodynamic, alternating magnetic field, microwave, radio frequency (RF), high intensity focused ultrasound (HIFU), and cryoablation therapies, each with their own ad- vantages and disadvantages [8, 12-14]. An ad- vantage of these methods over systemic treat- ments or surgical resection is a more localized

Am J Cancer Res 2011;1(4):508-520 www.ajcr.us /ISSN:2156-6976/ajcr0000046

Review Article Nanotechnology for energy-based cancer therapies Kyle Gilstrap1,2, Xiaoxiao Hu3, Xiongbin Lu3, Xiaoming He1,2 1Department of Mechanical Engineering, and 2Biomedical Engineering Program, University of South Carolina, Columbia, SC 29208; 3Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Received February 16, 2011; Accepted March 5, 2011; Epub March 11; Published April 1, 2011

Abstract: To overcome problems of systemic toxicity associated with chemotherapy and enhance treatment resolution of cancer therapies, nanotechnology is increasingly providing many novel approaches, especially to energy-based cancer therapies. Enhancements to treatment targeting, the ability to facilitate combined therapies, and treatment imaging are but a few of the ongoing investigations in this ever growing field. This review briefly explores the modali- ties of energy-based cancer therapies, how nanotechnology has been allowed for improvements within them, and discusses potential future applications of combined therapies. Keywords: Nanotechnology, energy-based therapies, nanoencapsulation, thermal ablation, combined modality ther- apy, drug delivery, chemotherapy, cryosurgery, tumor targeting, cancer treatment

Nanotechnology in energy-based therapies

509 Am J Cancer Res 2011;1(4):508-520

destruction of diseased tissue while minimizing possible side effects such as systemic toxicity or infection. Also, these methods are considered minimally invasive and are primarily investi- gated as outpatient procedures. Energy-based therapies destroy tumor cells by causing a local temperature excursion within the designated treatment area. Commonly, this procedure is applied through a minimally invasive probe in- sertion technique or the focusing of external high energy sources. Although the individual implementation of these thermal ablation meth- odologies are different depending on the energy source, the fundamental therapeutic mecha- nisms for these therapies can be divided into two categories, damage from heating to hyper- thermic temperatures (usually > 43°C) or dam- age from cooling or freezing to cryothermic tem- peratures (usually < -20°C). The therapeutic benefit from both of these types of treatment are strongly temperature and time dependent with differing degrees of damage existing throughout a given treatment gradient, as shown in Figure 1 (left). In the complete kill zone, hyperthermic damage has been characterized by protein denaturation, cellular membrane damage, and vascular injury [12]. Alternatively, cryothermic damage has

been characterized by mechanical damage from ice formation, cellular dehydration, ischemia from vascular damage, and post treatment im- munological response [15]. Of the energy sources mentioned, all induce hyperthermic damage with the exception of cryoablation, which induces cryothermic damage. Although these methodologies have promising potential applications, they have problems that cannot be overlooked. Thermal ablation treatments are susceptible to uneven distribution of tempera- ture profiles, and in the case of hyperthermic treatments, the treated area is not readily visi- ble during the procedure and must be esti- mated from models or experimentation. Further- more, the methods of implementation for the delivery of the thermal energy required for these treatments cause unintended damage to sur- rounding healthy tissue. In contrast, the iceball formed during cryothermic ablation treatment is visible through ultrasound or CT and easily tracked, but the determination of effectively treated area with temperature < -20 C within the iceball is uncertain and must either be di- rectly measured or estimated through models and experimentation [16-18]. The fluctuation in temperature gradient and uncertainty in treated area causes ablation treatments to be less spe- cific than intended and in some cases possibly

Figure 1. Illustration of nanotechnology mediated enhancements that can improve energy-based cancer therapies. Classical energy-based treatments have limitations in treatment area visualization causing the total treated area to overlap with healthy tissue. Also, unquantified thermal distribution causes an uncertainty in the complete kill zone (left). By using nanotechnology mediated combined modality treatments, the total treatment area can be visualized to minimize healthy tissue overlap, and the complete kill zone can be expanded to the treated area edge.

Nanotechnology in energy-based therapies

510 Am J Cancer Res 2011;1(4):508-520

incomplete, as shown in Figure 1 (left) [7, 12, 19]. 3. Adjuvants for energy-based therapy To investigate enhancements to energy-based therapies, chemotherapeutic agents have been used as treatment adjuvants. It has been shown that both types of thermal ablation therapies, hyperthermic and cryothermic, have the poten- tial to enhance the uptake of chemotherapeutic agents as well as induce a secondary immu- nological response that can enhance the extent of the removal of diseased tissue [15, 20-31]. Additionally, various salts, chemotherapeutic agents, and immunological factors have been tested for enhanced cryoablation treatment outcomes [15, 32-37]. While promising results and discoveries have been elucidated using adjuvants to enhance thermal ablation therapy, there are significant drawbacks associated with this treatment meth- odology that warrant further investigation. In particular, unquantified systemic toxicity, tumor specific targeting, and intratumoral drug distri- bution have left areas for improvements and research [38-55]. The focus of further research in this field has been to improve the treated area versus non-treated area by using nanotechnology as a resolution enhancing mechanism to expand the complete kill zone into the incomplete kill zone, sharply define treatment boundaries, and reduce the total treated area, as shown in Figure 1 (right). 4. Nanotechnology mediated enhancements to energy-based therapies Over the past decade, nanotechnology has be- gun to be explored as a tool to increase the resolution of thermal ablation treatment area, tumor visualization, and improve treatment ef- fectiveness [13, 14, 19]. The most direct method used for the enhancement of thermal therapy has been the systemic or local introduc- tion of nanoparticles given concurrently with energy-based ablation treatments [56, 57]. For hyperthermic therapies, carbon nanotubes, gold nanoshells, and iron oxide nanoparticles have proven extremely useful for enhancing heating effects due to energy absorption by the nanoparticles during treatment [13, 19, 58]. Previous research has shown that the nanopar- ticles preferentially associate with tumors when

given systemically or locally under the premise of the enhanced permeability and retention ef- fect (EPR), which is often found in tumor vascu- lature [52, 53, 59-61]. Furthermore, the use of metallic or carbon nanoparticles as treatment adjuvants enables the treated region to be visu- alized through noninvasive means such as MRI and CT, as shown in Figure 2 [56]. To overcome problems with systemic toxicity and enable target specificity, nanocapsule carri- ers with targeting moieties have been investi- gated to preferentially deliver therapeutics to diseased tissue via cell surface receptors, as shown in Figure 3. Some cell surface receptors help transmit messages from the extracellular environment to the intracellular environment, and in many cancerous cells are overexpressed. Overexpression of these surface receptors and other similar hallmarks specific to cancer can serve as potential target areas due to their in-

Figure 2. Imaging results from a preliminary study of locally delivered metallic nanoparticles in hyperther- mic treatment of brain cancer: (A,B), pre-treatment brain MRI; (C,D), post nanoparticle delivery CT scan showing magnetic nanoparticle deposits as hyper- dense areas with the colored lines indicating calcu- lated treatment temperatures between 40°C (blue) and 50°C (red) and the brown line representing the tumor area; and (E,F), 3-D reconstruction of fused MRI and CT showing the tumor (brown), magnetic fluid (blue) and thermometry catheter (green) [144].

Nanotechnology in energy-based therapies

511 Am J Cancer Res 2011;1(4):508-520

creased concentration in diseased tissue. Spe- cifically, receptors to estrogen, folic acid, epider- mal growth factor and others have been ex- plored for potential treatment targets. Using the various cellular targeting moieties, preferential uptake of nanoparticles into target expressing cancer cells has been shown [23, 62-67]. In addition to small molecular compound drugs, a Nobel-prize winning discovery of RNA interfer- ence (RNAi) has been extensively applied with the progress of delivery systems in several dif- ferent experimental models and more recently in treatment of numerous diseases, including neurodegenerative disorders and cancer [68- 72]. Small interfering RNAs (siRNAs) promote the cleavage of complementary mRNA to reduce protein production in mammalian cells and play a pivotal role in triggering RNAi [73, 74]. SiRNAs have short plasma half-life, fast degradation times in the physiological milieu, inefficient translocation into the cytoplasm, and lack of targeting ability. Therefore, successful siRNA- based gene targeting relies on the following conditions: improvement on stability and pre- vention of degradation by serum RNAses, effi- cient cellular uptake and subsequent intracellu- lar release into the cytoplasm, as well as avoid- ance of intracellular immune responses, in vivo toxicity or rapid elimination in the liver or

kidneys [73, 75-77]. SiRNA, similar to DNA, carries a net negative charge on the sugar phosphate which prevents its contact and entrance to the lipid bilayer of the cell membrane, whose head groups are also negatively charged. In the early 1970s, Calcium phosphate (CaP) precipitates were used as transfection reagents of viral DNA as they are believed to be non-toxic [78]. CaP effectively protects the nucleic acids from enzymatic deg- radation and aided cellular delivery, but uncon- trollable rapid growth of calcium phosphate crystals greatly reduced the transfection effi- ciency [79, 80]. To facilitate higher genocom- patibility and lower toxicity, non-viral delivery vectors became a good choice for gene-based therapies and in drug development. Non-viral delivery vectors include cationic lipids (e.g. DO- TAP and Oligofectamine), cationic polymers (e.g. PEI and DAB dendrimers) and non-ionic (uncharged) polymers (e.g. poly HPMA and PEG) [81-87]. Nanoparticles (NPs) such as the cati- onic polymer, polyethyleneimine (PEI), can act as envelopes to protect the siRNA from metabo- lism and excretion, but can also carry specific molecules designed to target the siRNA to spe- cific tissue types. For example, hydrophobic DOX obtained by deprotonation accumulated in the PCL core of the cationic micelle assembled from PEI-PCL, as shown in Figure 4 [88]. More re- cently, gold nanoparticles were directly conju- gated to siRNA, increasing the serum half-life more than six fold compared to free RNA du- plexes [89]. Also, biodegradable nanoparticles have been developed and have shown good potential as carriers for anticancer drugs with a spherical structure [90]. Within the past decade, the use of siRNA for RNAi has proven to be an effective nanomedi- cine for gene silencing therapy [91-96]. How- ever, research into the delivery of siRNA via nanoparticles to target cells is still in its infancy. In cancer therapy, siRNA delivery via nanoparti- cles needs to satisfy two major concerns: to improve the therapeutic range by including more than one siRNA which acts on specific targets, but keep minimal toxicity and maximum patient safety; and to develop novel or modify established carrier systems to induce gene changes on siRNA mediated gene silencing, but avoid enhancing the off-target gene changes [97-99]. These emerging different new types of nanoparticles (biodegradable, gold, etc.) will

Figure 3. Illustration of nanocapsule containing thera- peutic agents for targeted delivery to tumor cells. Nanoencapsulation technology has the potential to offer many combined modality approaches for treat- ment enhancements and personalized treatment targeting.

Nanotechnology in energy-based therapies

512 Am J Cancer Res 2011;1(4):508-520

facilitate the brilliance of RNAi and promote its application in clinical trials targeting specific tissues and diseases. Recently, thermally responsive nanoencapsula- tion systems have been developed using tem- perature sensitive carriers designed to deliver chemotherapeutic agents preferentially to tu- mor sites. During the temperature change asso- ciated with energy-based treatment, a confor- mational or structural change in the delivery vehicle causes the release of chemotherapeu- tics from the carrier. Once released, therapeutic agents are free to diffuse away from their car- rier and act on nearby targets with promising results [64, 100-114]. Additionally, as previ- ously mentioned, the solubility of many chemo- therapeutic substances in physiological condi- tions is very poor. Therefore, an added benefit of nanoencapsulation is the expansion of avail- able chemotherapeutic agents that can be used for treatment. Moreover, an effect of energy- based treatments is enhanced uptake of chemotherapeutics possibly due to permeability

changes. Utilizing the nanoparticle aided target delivery approach allows drugs released via a tem- perature controlled mecha- nism to be preferentially distributed at the tumor location with an increased uptake caused from the energy-based treatment. Use of nanoencapsulation technology also has the potential to reduce sys- temic toxicity because of localized delivery of agents to the treatment area for controlled release. Conse- quently, this combined treatment has the potential benefit of reducing the overall treatment area by allowing for an increase in the complete kill zone aided by chemotherapeutic agents [115, 116]. Prelimi- nary results in animal stud- ies for temperature sensi- tive carriers (liposomes) have prompted several currently ongoing clinical trials in various phases, I-III

[117-121]. To provide additional improvements to the nanoparticle aided delivery methodology, facili- tated drug release and treatment visualization, some experimental systems have co- encapsulated metallic nanoparticles alongside c h e m o t h e r a p e u t i c a g e n t s . T h i s c o - encapsulation paradigm allows metallic nanoparticles to act as agents for imaging and controlled release of chemotherapeutics through their energy absorbing properties [100, 101, 122-124]. Moreover, the delivery of metal- lic nanoparticles and chemotherapeutic agents simultaneously provide an approximated visuali- zation of drug delivery localization and treat- ment area [125-129]. Therefore, this combined approach has the potential to reduce the total treatment area due to the energy absorbing properties of metallic nanoparticles, provide an increase to the complete kill zone from both targeted heating and chemotherapeutic agent delivery, and visual definition of treatment boundaries. However, more research into the

Figure 4: Formation of hierarchical nano-assemblies for combinatorial delivery of siRNA and anticancer drugs [88].

Nanotechnology in energy-based therapies

513 Am J Cancer Res 2011;1(4):508-520

development of this approach is necessary for clinical application to be realized, especially in the area of intratumoral nanoparticle distribu- tion. Exploration into immune response to enhance treatment has also been studied by conjugating TNF-α onto the surface of gold nanoparticles [130-135]. Results from animal model studies have shown a preferential biodistribution of gold -TNF-α within tumor locations with less systemic toxicity than free TNF-α. Furthermore, hyperther- mic and cryothermic ablation treatment given after gold-TNF-α nanoparticle delivery increased the complete kill zone in animal models, as shown in Figure 5. From these initial studies, further tumor model applications and combina- tions with chemotherapeutic and co- encapsulation treatments are warranted [115]. In addition to the nanoparticle mediated com- bined modality treatments, recent develop- ments such as nanoscissor technology in con- junction with gene and gene product specific targeting and manipulation may bring about

new areas of research focus for even more combined mo- dality therapies with patient specific cancer targeting treatments [136-140]. Spe- cifically, targeted DNA se- quences have been manipu- lated through localized dis- ruption by the utilization of the energy absorption proper- ties of gold nanoparticles [136]. Furthermore, gold and polymeric nanoparticles have also been used for DNA/ oligonucleotide conjugation to regulate transcription and translation in cell models [137, 140]. Considering that this research has used en- ergy absorption, metallic nanoparticles, and targeted delivery techniques similar to that used in previously men- tioned research areas, it is not a far stretch to imagine that combined therapy appli- cations with the correction or elimination of damaged DNA or initiation of apoptotic sig- naling through nanomanipu-

lation techniques may be of future relevance. These techniques are still in their infancy and much more research and technical advance- ment is needed in order for this to become a practical and economic reality. However, the pace of advancement toward affordable and accessible gene research technology for poten- tial treatment personalization applications is increasing rapidly [141]. While the majority of the advances made for nanotechnology derived delivery vehicles have been in the area of hyperthermic treatment, recent studies in our laboratories have focused on advancing cryoablation treatment using hy- pothermically responsive nanocapsules [142, 143]. The goal of this research has been to im- prove the effectiveness of cryoablation treat- ment by moving the complete kill zone closer to the edge of the ice ball (the total treated area) by releasing drugs from a nanocapsule carrier within the incomplete kill zone. If successful, the subsequent outcome of this treatment en- hancement would yield a smaller ice ball needed to achieve a greater clinical response

Figure 5. 30 day observation of tumor size in mice treated with cryosurgery, TNF-α with cryosurgery, or gold-TNF-α nanoparticles (CYT-6091) with cryosur- gery. CYT-6091 was found to have less systemic toxicity than free TNF-α and provided a similar benefit in tumor size reduction as the more toxic free TNF-α [135].

Nanotechnology in energy-based therapies

514 Am J Cancer Res 2011;1(4):508-520

and thus less peripheral damage to adjacent tissues. As shown in Figure 6, our initial studies have shown that a thermally responsive nano- capsule system for delivery of chemotherapeu- tic agents during cryothermic ablation treatment is theoretically possible and further research in this area is warranted and ongoing. The potential benefits offered by nanotechnol- ogy (target specificity, reduction of systemic toxicity for chemotherapeutics, and coencapsu- lation of adjuvants), bring nanoparticle medi- ated combined therapies to the forefront of po- tential enhancements to energy-based cancer therapies. Coupled with further understanding of host immune response and the possibility of patient specific treatments, nanoparticle medi- ated therapies can also provide the basis for many more interesting and novel treatment op- tions previously not investigated. Further re- search into the nanoparticle mediated enhance-

ments to energy-based therapies mentioned in this review should result in the final goal of ex- panding the complete kill zone while minimizing the total treatment area (or incomplete kill zone) and providing visualization of boundary zones needed to give energy-based therapies more clinical relevance and certainty, as shown in Figure 1 (right). 5. Summary and Conclusion Through advanced understanding and applica- tion of functional nanomaterials, cellular target- ing, and immune response, improvements in energy-based therapy have seen promising re- sults. Furthermore, as gene sequencing technol- ogy advances to a much more affordable level, the personalization of nanotechnology derived delivery vehicles and therapeutics will make nanoparticle mediated combined therapies a much more focused and patient specific treat- ment option. Through further investigation and clinical trials, energy-based therapy assisted by nanotechnology may bring about a paradigm shift in primary cancer treatment in the not so distant future Acknowledgments This work was partially supported by a grant (to X.H.) from the Wendy Will Case Cancer Fund and a grant (to X.L.) from the American Cancer Society (119135-RSG-10-185-01-TBE). Please address correspondence to: Xiaoming He, PhD, Department of Mechanical Engineering, and Biomedical Engineering Program, University of South C a r o l i n a , C o l u m b i a , S C , U S A . E - m a i l : [email protected] References [1] Jemal A, Siegel R, Xu J and Ward E. Cancer

Statistics, 2010. CA Cancer J Clin 60: 277-300. [2] Schwartzberg LS. Chemotherapy-induced nau-

sea and vomiting: Which antiemetic for which therapy? Oncology-New York 2007; 21: 946- 953.

[3] American Cancer Society. Treatments and Side Effects. Accessed from: http://www.cancer.org/ Treatment/TreatmentsandSideEffects/index on Jan. 27, 2011.

[4] Chiappetta DA and Sosnik A. Poly(ethylene ox- ide)-poly(propylene oxide) block copolymer mi- celles as drug delivery agents: improved hydro- solubility, stability and bioavailability of drugs. Eur J Pharm Biopharm 2007; 66: 303-317.

Figure 6. Cumulative release of ethidium bromide(EB) encapsulated in hypothermic temperature sensitive nanocapsules during dialysis. Before cold treatment, the nanocapsule solution was kept at 37°C to keep the encapsulated EB trapped within the capsule core to prevent release. After 3 hours, a cold treatment was given for 15 minutes to expand the nanocap- sules and increase the wall permeability to allow the encapsulated EB to be liberated (released) out of the nanocapsule. As a result, a burst release of EB dur- ing dialysis is observable after the cold treatment [143].

Nanotechnology in energy-based therapies

515 Am J Cancer Res 2011;1(4):508-520

[5] McDonald MW and Fitzek MM. Proton Therapy. Current Problems in Cancer 34: 257-296.

[6] Halperin EC. Particle therapy and treatment of cancer. The Lancet Oncology 2006; 7: 676- 685.

[7] Stauffer PR and Goldberg SN. Introduction: Thermal ablation therapy. International Journal of Hyperthermia 2004; 20: 671-677.

[8] Timmerman RD, Bizekis CS, Pass HI, Fong Y, Dupuy DE, Dawson LA and Lu D. Local Surgical, Ablative, and Radiation Treatment of Metasta- ses. CA Cancer J Clin 2009; 59: 145-170.

[9] Gannon WE. Combination Chemotherapy With or Without Microwave Thermotherapy Before Surgery in Treating Women With Locally Ad- vanced Breast Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (Md): National Library of Medicine (US). 2000-[2011]. Available from http://clinicaltrials.gov/show/NCT00036985 NLM identifier: NCT00036985.

[10] Gannon WE. Microwave Thermotherapy in Treating Women With Stage I or Stage II Breast Cancer. In: ClinicalTrials.gov[Internet]. Be- thesda (Md): National Library of Medicine (US). 2000-[2011]. Available from http:// clinicaltrials.gov/show/NCT00036998 NLM identifier: NCT00036998.

[11] ClinicalTrials.gov[Internet]. Bethesda (Md): Na- tional Library of Medicine (US). 2000-[2011]. Available from http://www.clinicaltrials.gov/ ct2/results?term=ablation+cancer

[12] Shinohara K. Thermal ablation of prostate dis- eases: advantages and limitations. Interna- tional Journal of Hyperthermia 2004; 20: 679- 697.

[13] Manthe RL, Foy SP, Krishnamurthy N, Sharma B and Labhasetwar V. Tumor Ablation and Nanotechnology. Molecular Pharmaceutics 2010; 7: 1880-1898.

[14] Moroz P, Jones SK and Gray BN. Magnetically mediated hyperthermia: current status and future directions. International Journal of Hy- perthermia 2002; 18: 267-284.

[15] Raghav G, Kyle A, Joel S, Franz S, Greg V, John B and John CB. Adjuvant Approaches to En- hance Cryosurgery. Journal of Biomechanical Engineering 2009; 131: 074003.

[16] Littrup PJ, Jallad B, Chandiwala-Mody P, D'Agostini M, Adam BA and Bouwman D. Cryotherapy for breast cancer: a feasibility study without excision. J Vasc Interv Radiol 2009; 20: 1329-1341.

[17] Tatli S, Acar M, Tuncali K, Morrison PR and Silverman S. Percutaneous cryoablation tech- niques and clinical applications. Diagn Interv Radiol 2010; 16: 90-95.

[18] Wang H, Littrup PJ, Duan Y, Zhang Y, Feng H and Nie Z. Thoracic masses treated with percu- taneous cryotherapy: initial experience with more than 200 procedures. Radiology 2005; 235: 289-298.

[19] Emily SD, Jennifer GM and Jennifer LW.

Nanoparticles for Thermal Cancer Therapy. Journal of Biomechanical Engineering 2009; 131: 074001.

[20] Kong G, Braun RD and Dewhirst MW. Hyper- thermia enables tumor-specific nanoparticle delivery: Effect of particle size. Cancer Re- search 2000; 60: 4440-4445.

[21] Issels RD. Hyperthermia adds to chemotherapy. European Journal of Cancer 2008; 44: 2546- 2554.

[22] Mir LM and Rubinsky B. Treatment of cancer with cryochemotherapy. British Journal of Can- cer 2002; 86: 1658-1660.

[23] Ahmed M and Goldberg SN. Combination ra- diofrequency thermal ablation and adjuvant IV liposomal doxorubicin increases tissue coagula- tion and intratumoural drug accumulation. In- ternational Journal of Hyperthermia 2004; 20: 781-802.

[24] Clarke DM, Baust JM, Van Buskirk RG and Baust JG. Addition of anticancer agents en- hances freezing-induced prostate cancer cell death: implications of mitochondrial involve- ment. Cryobiology 2004; 49: 45-61.

[25] Yuan F, Zhou W, Zhang J, Zhang Z, Zou C, Huang L, Zhang Y and Dai Z. Anticancer drugs are synergistic with freezing in induction of apoptosis in HCC cells. Cryobiology 2008; 57: 60-65.

[26] Ikekawa S, Ishihara K, Tanaka S and Ikeda S. Basic studies of cryochemotherapy in a murine tumor system. Cryobiology 1985; 22: 477-483.

[27] Forest V, Peoc'h M, Campos L, Guyotat D and Vergnon JM. Benefit of a combined treatment of cryotherapy and chemotherapy on tumour growth and late cryo-induced angiogenesis in a non-small-cell lung cancer model. Lung Cancer 2006; 54: 79-86.

[28] Clarke DM, Baust JM, Van Buskirk RG and Baust JG. Chemo-cryo combination therapy: an adjunctive model for the treatment of prostate cancer. Cryobiology 2001; 42: 274-285.

[29] Forest V, Peoc'h M, Campos L, Guyotat D and Vergnon JM. Effects of cryotherapy or chemo- therapy on apoptosis in a non-small-cell lung cancer xenografted into SCID mice. Cryobiology 2005; 50: 29-37.

[30] Ahmed M, Monsky WE, Girnun G, Lukyanov A, D’Ippolito G, Kruskal JB, Stuart KE, Torchilin VP and Goldberg SN. Radiofrequency Thermal Ablation Sharply Increases Intratumoral Lipo- somal Doxorubicin Accumulation and Tumor Coagulation. Cancer Research 2003; 63: 6327- 6333.

[31] Monsky WL, Kruskal JB, Lukyanov AN, Girnun GD, Ahmed M, Gazelle GS, Huertas JC, Stuart KE, Torchilin VP and Goldberg SN. Radio- frequency Ablation Increases Intratumoral Lipo- somal Doxorubicin Accumulation in a Rat Breast Tumor Model1. Radiology 2002; 224: 823-829.

[32] Han B, Iftekhar A and Bischof JC. Improved

Nanotechnology in energy-based therapies

516 Am J Cancer Res 2011;1(4):508-520

cryosurgery by use of thermophysical and in- flammatory adjuvants. Technol Cancer Res Treat 2004; 3: 103-111.

[33] Kawaguchi Y, Sugiyama Y and Saji S. [Cryoimmunological therapy with local injection of OK-432 against advance or recurrent breast cancer]. Gan To Kagaku Ryoho 2003; 30: 1583 -1586.

[34] Han B, Swanlund DJ and Bischof JC. Cryoinjury of MCF-7 human breast cancer cells and inhibi- tion of post-thaw recovery using TNF-alpha. Technol Cancer Res Treat 2007; 6: 625-634.

[35] Chao BH, He X and Bischof JC. Pre-treatment inflammation induced by TNF-alpha augments cryosurgical injury on human prostate cancer. Cryobiology 2004; 49: 10-27.

[36] Sugiyama Y, Saji S, Miya K, Kunieda K, Takao H, Kawaguchi Y, Kimura A, Honda S and Matsui K. [Therapeutic effect of multimodal therapy, such as cryosurgery, locoregional immunother- apy and systemic chemotherapy against far advanced breast cancer]. Gan To Kagaku Ryoho 2001; 28: 1616-1619.

[37] Jiang J, Goel R, Iftekhar MA, Visaria R, Belcher JD, Vercellotti GM and Bischof JC. Tumor necro- sis factor-alpha-induced accentuation in cryoin- jury: mechanisms in vitro and in vivo. Mol Can- cer Ther 2008; 7: 2547-2555.

[38] Salloum M, Ma R and Zhu L. Enhancement in treatment planning for magnetic nanoparticle hyperthermia: Optimization of the heat absorp- tion pattern. International Journal of Hyperther- mia 2009; 25: 309-321.

[39] Ray PC, Yu HT and Fu PP. Toxicity and Environ- mental Risks of Nanomaterials: Challenges and Future Needs. Journal of Environmental Sci- ence and Health Part C-Environmental Carcino- genesis & Ecotoxicology Reviews 2009; 27: 1- 35.

[40] Minchinton AI and Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer 2006; 6: 583- 592.

[41] Vasir JK and Labhasetwar V. Biodegradable nanoparticles for cytosolic delivery of therapeu- tics. Adv Drug Deliv Rev 2007; 59: 718-728.

[42] Kumar MNVR. Nano and microparticles as con- trolled drug delivery devices. J Pharm Pharm Sci 2000; 3: 234-258.

[43] Vinogradov SV, Bronich TK and Kabanov AV. Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. Adv Drug Deliv Rev 2002; 54: 135-147.

[44] Tanaka T, Decuzzi P, Cristofanilli M, Sakamoto JH, Tasciotti E, Robertson FM and Ferrari M. Nanotechnology for breast cancer therapy. Biomed Microdevices 2009; 11: 49-63.

[45] Breunig M, Bauer S and Goepferich A. Polymers and nanoparticles: intelligent tools for intracel- lular targeting? Eur J Pharm Biopharm 2008; 68: 112-128.

[46] Thurber GM, Schmidt MM and Wittrup KD. Anti- body tumor penetration: transport opposed by

systemic and antigen-mediated clearance. Adv Drug Deliv Rev 2008; 60: 1421-1434.

[47] Kostarelos K, Emfietzoglou D, Papakostas A, Yang WH, Ballangrud A and Sgouros G. Binding and interstitial penetration of liposomes within avascular tumor spheroids. Int J Cancer 2004; 112: 713-721.

[48] Zagaynova EV, Shirmanova MV, Kirillin MY, Khlebtsov BN, Orlova AG, Balalaeva IV, Sirot- kina MA, Bugrova ML, Agrba PD and Kamensky VA. Contrasting properties of gold nanoparticles for optical coherence tomography: phantom, in vivo studies and Monte Carlo simulation. Phys Med Biol 2008; 53: 4995-5009.

[49] Nuttens VE, Wera AC, Bouchat V and Lucas S. Determination of biological vector characteris- tics and nanoparticle dimensions for radioim- munotherapy with radioactive nanoparticles. Appl Radiat Isot 2008; 66: 168-172.

[50] Needham D and Dewhirst MW. The develop- ment and testing of a new temperature- sensitive drug delivery system for the treatment of solid tumors. Adv Drug Deliv Rev 2001; 53: 285-305.

[51] Kostarelos K, Emfietzoglou D, Papakostas A, Yang WH, Ballangrud AM and Sgouros G. Engi- neering lipid vesicles of enhanced intratumoral transport capabilities: correlating liposome characteristics with penetration into human prostate tumor spheroids. J Liposome Res 2005; 15: 15-27.

[52] Wu NZ, Klitzman B, Rosner G, Needham D and Dewhirst MW. Measurement of material ex- travasation in microvascular networks using fluorescence video-microscopy. Microvasc Res 1993; 46: 231-253.

[53] Yuan F, Leunig M, Berk DA and Jain RK. Mi- crovascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice. Microvasc Res 1993; 45: 269-289.

[54] Weinstein JN, Eger RR, Covell DG, Black CD, Mulshine J, Carrasquillo JA, Larson SM and Keenan AM. The pharmacology of monoclonal antibodies. Ann N Y Acad Sci 1987; 507: 199- 210.

[55] Jung S, Patzelt A, Otberg N, Thiede G, Sterry W and Lademann J. Strategy of topical vaccina- tion with nanoparticles. J Biomed Opt 2009; 14: 021001.

[56] Thiesen B and Jordan A. Clinical applications of magnetic nanoparticles for hyperthermia. Inter- national Journal of Hyperthermia 2008; 24: 467-474.

[57] Jordan A. Hyperthermia classic commentary: 'Inductive heating of ferrimagnetic particles and magnetic fluids: Physical evaluation of their potential for hyperthermia' by Andreas Jordan et al., International Journal of Hyperthermia, 1993;9:51-68. International Journal of Hyper- thermia 2009; 25: 512-516.

Nanotechnology in energy-based therapies

517 Am J Cancer Res 2011;1(4):508-520

[58] Kappiyoor R, Liangruksa M, Ganguly R and Puri IK. The effects of magnetic nanoparticle proper- ties on magnetic fluid hyperthermia. Journal of Applied Physics 2010; 108: -.

[59] Matsumura Y and Maeda H. A New Concept for Macromolecular Therapeutics in Cancer- Chemotherapy - Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Research 1986; 46: 6387-6392.

[60] Wang X, Yang L, Chen Z and Shin DM. Applica- tion of Nanotechnology in Cancer Therapy and Imaging. CA Cancer J Clin 2008; 58: 97-110.

[61] Dreher MR and Chilkoti A. Toward a Systems Engineering Approach to Cancer Drug Delivery. Journal of the National Cancer Institute 2007; 99: 983-985.

[62] Glazer ES and Curley SA. Radiofrequency Field- Induced Thermal Cytotoxicity in Cancer Cells Treated With Fluorescent Nanoparticles. Can- cer 2010; 116: 3285-3293.

[63] Kikumori T, Kobayashi T, Sawaki M and Imai T. Anti-cancer effect of hyperthermia on breast cancer by magnetite nanoparticle-loaded anti- HER2 immunoliposomes. Breast Cancer Re- search and Treatment 2009; 113: 435-441.

[64] Carpin LB, Bickford LR, Agollah G, Yu TK, Schiff R, Li Y and Drezek RA. Immunoconjugated gold nanoshell-mediated photothermal ablation of trastuzumab-resistant breast cancer cells. Breast Cancer Research and Treatment 2011; 125: 27-34.

[65] Glazer ES, Zhu CH, Massey KL, Thompson CS, Kaluarachchi WD, Hamir AN and Curley SA. Noninvasive Radiofrequency Field Destruction of Pancreatic Adenocarcinoma Xenografts Treated with Targeted Gold Nanoparticles. Clini- cal Cancer Research 2010; 16: 5712-5721.

[66] Van Meir EG, Hadjipanayis CG, Norden AD, Shu H-K, Wen PY and Olson JJ. Exciting New Ad- vances in Neuro-Oncology: The Avenue to a Cure for Malignant Glioma. CA Cancer J Clin 60: 166-193.

[67] Jensen SS, Andresen TL, Davidsen J, Høyrup P, Shnyder SD, Bibby MC, Gill JH and Jørgensen K. Secretory phospholipase A2 as a tumor-specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer etherlipids. Molecular Cancer Therapeutics 2004; 3: 1451-1458.

[68] Cheng R, Feng F, Meng F, Deng C, Feijen J and Zhong Z. Glutathione-responsive nano-vehicles as a promising platform for targeted intracellu- lar drug and gene delivery. Journal of Controlled Release In Press, Uncorrected Proof:

[69] Kenny GD, Kamaly N, Kalber TL, Brody LP, Sa- huri M, Shamsaei E, Miller AD and Bell JD. Novel multifunctional nanoparticle mediates siRNA tumour delivery, visualisation and thera- peutic tumour reduction in vivo. Journal of Con- trolled Release 149: 111-116.

[70] Collins RE and Cheng XD. Structural and bio-

chemical advances in mammalian RNAi. Jour- nal of Cellular Biochemistry 2006; 99: 1251- 1266.

[71] Hannon GJ. RNA interference. Nature 2002; 418: 244-251.

[72] Bernards R. Exploring the uses of RNAi - Gene knockdown and the Nobel Prize. New England Journal of Medicine 2006; 355: 2391-2393.

[73] Bumcrot D, Manoharan M, Koteliansky V and Sah DWY. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nature Chemi- cal Biology 2006; 2: 711-719.

[74] Fire A, Xu SQ, Montgomery MK, Kostas SA, Driver SE and Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391: 806-811.

[75] Gilmore IR, Fox SP, Hollins AJ and Akhtar S. Delivery Strategies for siRNA-mediated Gene Silencing. Current Drug Delivery 2006; 3: 147- 155.

[76] Li CX, Parker A, Menocal E, Xiang SL, Borodyansky L and Fruehauf JH. Delivery of RNA interference. Cell Cycle 2006; 5: 2103- 2109.

[77] Gilmore IR, Fox SP, Hollins AJ, Muhammad SB and Akhtar S. The design and exogenous deliv- ery of siRNA for post-transcriptional gene si- lencing. Journal of Drug Targeting 2004; 12: 315-340.

[78] Graham FL and Vandereb AJ. New Technique for Assay of Infectivity of Human Adenovirus 5 DNA. Virology 1973; 52: 456-467.

[79] Maitra A. Calcium phosphate nanoparticles: second-generation nonviral vectors in gene therapy. Expert Review of Molecular Diagnos- tics 2005; 5: 893-905.

[80] Jordan M, Schallhorn A and Wurm FM. Trans- fecting Mammalian Cells: Optimization of Criti- cal Parameters Affecting Calcium-Phosphate Precipitate Formation. Nucleic Acids Research 1996; 24: 596-601.

[81] Minko T, Kopecková P and Kopecek J. Prelimi- nary evaluation of caspases-dependent apop- tosis signaling pathways of free and HPMA co- polymer-bound doxorubicin in human ovarian carcinoma cells. Journal of Controlled Release 2001; 71: 227-237.

[82] Garbuzenko OB, Saad M, Betigeri S, Zhang M, Vetcher AA, Soldatenkov VA, Reimer DC, Poz- harov VP and Minko T. Intratracheal Versus Intravenous Liposomal Delivery of siRNA, An- tisense Oligonucleotides and Anticancer Drug. Pharmaceutical Research 2009; 26: 382-394.

[83] Lee SH, Kim SH and Park TG. Intracellular siRNA delivery system using polyelectrolyte complex micelles prepared from VEGF siRNA- PEG conjugate and cationic fusogenic peptide. Biochemical and Biophysical Research Commu- nications 2007; 357: 511-516.

[84] Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME and Triche TJ. Sequence-specific knock-

Nanotechnology in energy-based therapies

518 Am J Cancer Res 2011;1(4):508-520

down of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sar- coma. Cancer Research 2005; 65: 8984-8992.

[85] Urban-Klein B, Werth S, Abuharbeid S, Czubayko F and Aigner A. RNAi-mediated gene- targeting through systemic application of poly- ethylenimine (PEI)-complexed siRNA in vivo. Gene Therapy 2005; 12: 461-466.

[86] Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey RK, Racie T, Rajeev KG, Rohl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Manoha- ran M and Vornlocher HP. Therapeutic silenc- ing of an endogenous gene by systemic ad- ministration of modified siRNAs. Nature 2004; 432: 173-178.

[87] Sorensen DR, Leirdal M and Sioud M. Gene silencing by systemic delivery of synthetic siRNAs in adult mice. Journal of Molecular Biology 2003; 327: 761-766.

[88] Cao N, Cheng D, Zou S, Ai H, Gao J and Shuai X. The synergistic effect of hierarchical assem- blies of siRNA and chemotherapeutic drugs co -delivered into hepatic cancer cells. Biomate- rials 32: 2222-2232.

[89] Elbakry A, Zaky A, Liebkl R, Rachel R, Goepferich A and Breunig M. Layer-by-Layer Assembled Gold Nanoparticles for siRNA De- livery. Nano Letters 2009; 9: 2059-2064.

[90] Bhavsar MD and Amiji MM. Gastrointestinal distribution and in vivo gene transfection stud- ies with nanoparticles-in-microsphere oral system (NiMOS). Journal of Controlled Release 2007; 119: 339-348.

[91] Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R and Cheresh DA. Tumor regression by targeted gene delivery to the neovasculature. Science 2002; 296: 2404- 2407.

[92] Pardridge WM. Intravenous, non-viral RNAi gene therapy of brain cancer. Expert Opinion on Biological Therapy 2004; 4: 1103-1113.

[93] Kim B, Tang QQ, Biswas PS, Xu J, Schiffelers RM, Xie FY, Ansari AM, Scaria PV, Woodle MC, Lu P and Rouse BT. Inhibition of ocular angio- genesis by siRNA targeting vascular endothe- lial growth factor pathway genes - Therapeutic strategy for herpetic stromal keratitis. Ameri- can Journal of Pathology 2004; 165: 2177- 2185.

[94] Toub N, Bertrand JR, Tamaddon A, Elhamess H, Hillaireau H, Maksimenko A, Maccario J, Malvy C, Fattal E and Couvreur P. Efficacy of siRNA nanocapsules targeted against the EWS -Fli1 oncogene in Ewing sarcoma. Pharmaceu- tical Research 2006; 23: 892-900.

[95] Kortylewski M, Swiderski P, Herrmann A, Wang L, Kowolik C, Kujawski M, Lee H, Scuto A, Liu Y, Yang CM, Deng JH, Soifer HS,

Raubitschek A, Forman S, Rossi JJ, Pardoll DM, Jove R and Yu H. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 ago- nist enhances antitumor immune responses. Nature Biotechnology 2009; 27: 925-U988.

[96] MacDiarmid JA, Amaro-Mugridge NB, Madrid- Weiss J, Sedliarou I, Wetzel S, Kochar K, Brahmbhatt VN, Phillips L, Pattison ST, Petti C, Stillman B, Graham RM and Brahmbhatt H. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nature Biotechnology 2009; 27: 643-U697.

[97] Hollins AJ, Omidi Y, Benter IF and Akhtar S. Toxicogenomics of drug delivery systems: Ex- ploiting delivery system-induced changes in target gene expression to enhance siRNA ac- tivity. Journal of Drug Targeting 2007; 15: 83- 88.

[98] Fedorov Y, Anderson EM, Birmingham A, Rey- nolds A, Karpilow J, Robinson K, Leake D, Marshall WS and Khvorova A. Off-target ef- fects by siRNA can induce toxic phenotype. Rna-a Publication of the Rna Society 2006; 12: 1188-1196.

[99] Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G and Linsley PS. Expression profiling reveals off- target gene regulation by RNAi. Nature Bio- technology 2003; 21: 635-637.

[100] Liu TY, Hu SH, Liu KH, Shaiu RS, Liu DM and Chen SY. Instantaneous Drug Delivery of Mag- netic/Thermally Sensitive Nanospheres by a High-Frequency Magnetic Field. Langmuir 2008; 24: 13306-13311.

[101] Liu TY, Liu KH, Liu DM, Chen SY and Chen IW. Temperature-Sensitive Nanocapsules for Con- trolled Drug Release Caused by Magnetically Triggered Structural Disruption. Advanced Functional Materials 2009; 19: 616-623.

[102] Wells J, Sen A and Hui SW. Localized delivery to CT-26 tumors in mice using thermosensitive liposomes. International Journal of Pharma- ceutics 2003; 261: 105-114.

[103] Lee SH, Choi SH, Kim SH and Park TG. Ther- mally sensitive cationic polymer nanocapsules for specific cytosolic delivery and efficient gene silencing of siRNA: Swelling induced physical disruption of endosome by cold shock. Journal of Controlled Release 2008; 125: 25-32.

[104] Choi SH, Lee SH and Park TG. Temperature- sensitive pluronic/poly(ethylenimine) nano- capsules for thermally triggered disruption of intracellular endosomal compartment. Bio- macromolecules 2006; 7: 1864-1870.

[105] Dromi S, Frenkel V, Luk A, Traughber B, Ang- stadt M, Bur M, Poff J, Xie JW, Libutti SK, Li KCP and Wood BJ. Pulsed-high intensity fo- cused ultrasound and low temperature sensi- tive liposomes for enhanced targeted drug delivery and antitumor effect. Clinical Cancer

Nanotechnology in energy-based therapies

519 Am J Cancer Res 2011;1(4):508-520

Research 2007; 13: 2722-2727. [106] Frenkel V, Etherington A, Greene M, Quijano J,

Xie JW, Hunter F, Dromi S and Li KCP. Delivery of liposomal doxorubicin (Doxil) in a breast cancer tumor model: Investigation of potential enhancement by pulsed-high intensity focused ultrasound exposure. Academic Radiology 2006; 13: 469-479.

[107] Ahmed M, Liu ZJ, Lukyanov AN, Signoretti S, Horkan C, Monsky WL, Torchilin VP and Gold- berg SN. Combination radiofrequency ablation with intratumoral liposomal doxorubicin: Effect on drug accumulation and coagulation in mul- tiple tissues and tumor types in animals. Radi- ology 2005; 235: 469-477.

[108] Steinberg Y, Schroeder A, Talmon Y, Schmidt J, Khalfin RL, Cohen Y, Devoisselle JM, Begu S and Avnir D. Triggered release of aqueous content from liposome-derived sol-gel nano- capsules. Langmuir 2007; 23: 12024-12031.

[109] Kong G, Anyarambhatla G, Petros WP, Braun RD, Colvin OM, Needham D and Dewhirst MW. Efficacy of Liposomes and Hyperthermia in a Human Tumor Xenograft Model: Importance of Triggered Drug Release. Cancer Research 2000; 60: 6950-6957.

[110] Needham D, Anyarambhatla G, Kong G and Dewhirst MW. A New Temperature-sensitive Liposome for Use with Mild Hyperthermia: Characterization and Testing in a Human Tu- mor Xenograft Model. Cancer Research 2000; 60: 1197-1201.

[111] Hauck ML, LaRue SM, Petros WP, Poulson JM, Yu D, Spasojevic I, Pruitt AF, Klein A, Case B, Thrall DE, Needham D and Dewhirst MW. Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Sponta- neous Canine Tumors. Clinical Cancer Re- search 2006; 12: 4004-4010.

[112] Ponce AM, Viglianti BL, Yu D, Yarmolenko PS, Michelich CR, Woo J, Bally MB and Dewhirst MW. Magnetic Resonance Imaging of Tem- perature-Sensitive Liposome Release: Drug Dose Painting and Antitumor Effects. Journal of the National Cancer Institute 2007; 99: 53- 63.

[113] Yuh EL, Shulman SG, Mehta SA, Xie J, Chen L, Frenkel V, Bednarski MD and Li KCP. Delivery of Systemic Chemotherapeutic Agent to Tu- mors by Using Focused Ultrasound: Study in a Murine Model1. Radiology 2005; 234: 431- 437.

[114] Lindner LH, Eichhorn ME, Eibl H, Teichert N, Schmitt-Sody M, Issels RD and Dellian M. Novel Temperature-Sensitive Liposomes with Prolonged Circulation Time. Clinical Cancer Research 2004; 10: 2168-2178.

[115] Park J-H, von Maltzahn G, Xu MJ, Fogal V, Ko- tamraju VR, Ruoslahti E, Bhatia SN and Sailor MJ. Cooperative nanomaterial system to sensi- tize, target, and treat tumors. Proceedings of the National Academy of Sciences 107: 981-

986. [116] Chen Q, Tong S, Dewhirst MW and Yuan F.

Targeting tumor microvessels using doxorubi- cin encapsulated in a novel thermosensitive liposome. Molecular Cancer Therapeutics 2004; 3: 1311-1317.

[117] Wood B. Heat Activated Liposomal Doxorubi- cin and Radiofrequency Ablation in Treating Patients With Primary or Metastatic Liver Tu- mors. In: ClinicalTrials.gov[Internet]. Bethesda (Md): National Library of Medicine (US). 2000- [ 2 0 1 1 ] . A v a i l a b l e f r o m h t t p : / / clinicaltrials.gov/show/NCT00093444 NLM identifier: NCT00093444.

[118] Van Doren C. Liposomal Doxorubicin and ther- mal therapy in treating patients with prostate cancer. In: ClinicalTrials.gov[Internet]. Be- thesda (Md): National Library of Medicine (US). 2000-[2011]. Available from http:// clinicaltrials.gov/show/NCT00061867 NLM identifier: NCT00061867.

[119] Poon RT and Lencioni R. Phase 3 Study of ThermoDox With Radiofrequency Ablation (RFA) in Treatment of Hepatocellular Carci- noma (HCC). In: ClinicalTrials.gov[Internet]. Bethesda (Md): National Library of Medicine (US). 2000-[2011]. Available from http:// clinicaltrials.gov/show/NCT00617981 NLM identifier: NCT00617981.

[120] Borys N. A Study of ThermoDox™ in Combina- tion With Radiofrequency Ablation (RFA) in Primary and Metastatic Tumors of the Liver. In: ClinicalTrials.gov[Internet]. Bethesda (Md): National Library of Medicine (US). 2000- [ 2 0 1 1 ] . A v a i l a b l e f r o m h t t p : / / clinicaltrials.gov/show/NCT00441376 NLM identifier: NCT00441376.

[121] Borys N. Phase 1/2 Study of ThermoDox With Approved Hyperthermia in Treatment of Breast Cancer Recurrence at the Chest Wall (DIGNITY). In: ClinicalTrials.gov[Internet]. Be- thesda (Md): National Library of Medicine (US). 2000-[2011]. Available from http:// clinicaltrials.gov/show/NCT00826085 NLM identifier: NCT00826085.

[122] Yoshida M, Watanabe Y, Sato M, Maehara T, Aono H, Naohara T, Hirazawa H, Horiuchi A, Yukumi S, Sato K, Nakagawa H, Yamamoto Y, Sugishita H and Kawachi K. Feasibility of chemohyperthermia with docetaxel-embedded magnetoliposomes as minimally invasive local treatment for cancer. International Journal of Cancer 2010; 126: 1955-1965.

[123] Li FR, Yan WH, Guo YH, Qi H and Zhou HX. Preparation of carboplatin-Fe@C-loaded chito- san nanoparticles and study on hyperthermia combined with pharmacotherapy for liver can- cer. International Journal of Hyperthermia 2009; 25: 383-391.

[124] Tai LA, Tsai PJ, Wang YC, Wang YJ, Lo LW and Yang CS. Thermosensitive liposomes entrap- ping iron oxide nanoparticles for controllable

Nanotechnology in energy-based therapies

520 Am J Cancer Res 2011;1(4):508-520

drug release. Nanotechnology 2009; 20: -. [125] Jain TK, Reddy MK, Morales MA, Leslie-

Pelecky DL and Labhasetwar V. Biodistribu- tion, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Molecu- lar Pharmaceutics 2008; 5: 316-327.

[126] Jain TK, Richey J, Strand M, Leslie-Pelecky DL, Flask CA and Labhasetwar V. Magnetic nanoparticles with dual functional properties: Drug delivery and magnetic resonance imag- ing. Biomaterials 2008; 29: 4012-4021.

[127] Jain TK, Morales MA, Sahoo SK, Leslie-Pelecky DL and Labhasetwar V. Iron oxide nanoparti- cles for sustained delivery of anticancer agents. Molecular Pharmaceutics 2005; 2: 194-205.

[128] Jain TK, Foy SP, Erokwu B, Dimitrijevic S, Flask CA and Labhasetwar V. Magnetic resonance imaging of multifunctional pluronic stabilized iron-oxide nanoparticles in tumor-bearing mice. Biomaterials 2009; 30: 6748-6756.

[129] Zou P, Yu Y, Wang YA, Zhong Y, Welton A, Gal- baÌ n C, Wang S and Sun D. Superparamag- netic Iron Oxide Nanotheranostics for Tar- geted Cancer Cell Imaging and pH-Dependent Intracellular Drug Release. Molecular Pharma- ceutics 7: 1974-1984.

[130] Pedro RN, Thekke-Adiyat T, Goel R, Shenoi M, Slaton J, Schmechel S, Bischof J and Ander- son JK. Use of Tumor Necrosis Factor-alpha- coated Gold Nanoparticles to Enhance Radiof- requency Ablation in a Translational Model of Renal Tumors. Urology 2010; 76: 494-498.

[131] Goel R, Shah N, Visaria R, Paciotti GF and Bischof JC. Biodistribution of TNF-alpha- coated gold nanoparticles in an in vivo model system. Nanomedicine 2009; 4: 401-410.

[132] Visaria R, Bischof JC, Loren M, Williams B, Ebbini E, Paciotti G and Griffin R. Nanothera- peutics for enhancing thermal therapy of can- cer. International Journal of Hyperthermia 2007; 23: 501-511.

[133] Ito A, Honda H and Kobayashi T. Cancer immu- notherapy based on intracellular hyperthermia using magnetite nanoparticles: a novel con- cept of "heat-controlled necrosis" with heat shock protein expression. Cancer Immunology Immunotherapy 2006; 55: 320-328.

[134] Goel R, Swanlund D, Coed J, Paciotti GF and Bischof JC. Article on TNF-alpha-based accen- tuation in cryoinjury (vol 6, pg 2039, 2007). Molecular Cancer Therapeutics 2007; 6: 2383-2383.

[135] Goel R, Swanlund D, Coad J, Paciotti GF and Bischof JC. TNF-alpha-based accentuation in cryoinjury - dose, delivery, and response. Mo- lecular Cancer Therapeutics 2007; 6: 2039- 2047.

[136] Tsai TL, Shieh DB, Yeh CS, Tzeng Y, Htet K, Chuang KS, Hwu JR and Su WC. The down regulation of target genes by photo activated DNA nanoscissors. Biomaterials 2010; 31: 6545-6554.

[137] Conde J, de la Fuente JM and Baptista PV. In vitro transcription and translation inhibition via DNA functionalized gold nanoparticles. Nanotechnology 2010; 21: -.

[138] Csaki A, Garwe F, Steinbruck A, Maubach G, Festag G, Weise A, Riemann I, Konig K and Fritzsche W. A parallel approach for subwave- length molecular surgery using gene-specific positioned metal nanoparticles as laser light antennas. Nano Letters 2007; 7: 247-253.

[139] Hamad-Schifferli K, Schwartz JJ, Santos AT, Zhang SG and Jacobson JM. Remote elec- tronic control of DNA hybridization through inductive coupling to an attached metal nanocrystal antenna. Nature 2002; 415: 152- 155.

[140] Chisholm EJ, Vassaux G, Martin-Duque P, Chevre R, Lambert O, Pitard B, Merron A, Weeks M, Burnet J, Peerlinck I, Dai M-S, Alusi G, Mather SJ, Bolton K, Uchegbu IF, Schatzlein AG and Baril P. Cancer-Specific Transgene Expression Mediated by Systemic Injection of Nanoparticles. Cancer Research 2009; 69: 2655-2662.

[141] Pettersson E, Lundeberg J and Ahmadian A. Generations of sequencing technologies. Ge- nomics 2009; 93: 105-111.

[142] Zhang WJ, Rong JH, Wang Q and He XM. The encapsulation and intracellular delivery of trehalose using a thermally responsive nano- capsule. Nanotechnology 2009; 20: -.

[143] Zhang WJ, Gilstrap K, Wu LY, Bahadur KCR, Moss MA, Wang QA, Lu XB and He XM. Synthe- sis and Characterization of Thermally Respon- sive Pluronic F127-Chitosan Nanocapsules for Controlled Release and Intracellular Delivery of Small Molecules. Acs Nano 2010; 4: 6747- 6759.

[144] Maier-Hauff K, Ulrich F, Nestler D, Niehoff H, Wust P, Thiesen B, Orawa H, Budach V and Jordan A. Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. Journal of Neuro- Oncology 1-8.