Toward nanotechnology-based solutions for a particular disease: ovarian cancer as an example
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Joseph Youkhanna
Joseph Youkhanna received his Doctorate of Pharmacy degree in 2011 at MCPHS University. He obtained his undergraduate studies at Wayne State University in Detroit, MI. He worked closely with Dr. Reema Zeineldin for 1 year researching on teaching the expanding field of nanotechnology. Joseph is currently a staff pharmacist at Walgreens Pharmacy in Detroit, MI, USA.
Joan Syoufjy received her Bachelor Degree (BS) in Molecular Biology at the University of Michigan (US) in 2008. Then, she pursued her Doctor of Pharmacy degree (PharmD) at the MCPHS University where she started to work with Dr. Zeineldin to discover ways to incorporate methods of teaching Nanotechnology to PharmD students. Her interest in Nanotechnology provoked her to continue her education in Nuclear Pharmacy, which involves the preparation of radioactive medicine to help diagnose and treat specific diseases. She is currently employed with CVS/Pharmacy as a pharmacist in charge in Detroit, MI, USA.
Mary Rhorer received her Doctor of Pharmacy degree in May 2013 at MCPHS University in Worcester, MA, USA. Her research work with Dr. Zeineldin has focused on ovarian cancer therapy and nanotechnology. She is currently a clinical pharmacy resident in Albany, VA, Medical Center and she plans to specialize in Oncology Pharmacy.
Oyebola Abiodun Oladeinde received his “Laurea” degree in Chemistry in 2009 at Morgan State University. After graduation, he obtained a cancer research trainee award (CRTA) to join the Center for Cancer Research, Chemical Biology Laboratory at the National Cancer Institute, Frederick, MD, where he studied in the group of Dr. Larry Keefer (2009). In May 2013, he received his Doctor of Pharmacy degree at MCPHS University, where his research project involved the application of nanotechnology-based drug delivery against ovarian cancer resistant to current chemotherapy. He is currently a community pharmacist at Walgreens Pharmacy.
Reema Zeineldin received her PhD in Biomedical Sciences from the University of New Mexico (UNM) where her work focused on understanding the progression of ovarian cancer. During her postdoctoral training, she did research on biosensing in the Department of Chemical and Nuclear Engineering at UNM. She is currently an Associate Professor at MCPHS University teaching PharmD students and performing research that focuses on nano and bio integrations for biosensing and for the therapy of ovarian cancer.
Abstract
Recent nanotechnology research has been enhancing or creating new applications that have the potential to advance the diagnosis or therapy of diseases. These contributions to the field of nanomedicine have so far been focused on creating the new technologies rather than focusing on particular diseases in order to improve their outcomes. For the latter to occur, we recommend the following: (1) creation of interdisciplinary research funding that awards collaborations between biological, medical, clinical, and pharmaceutical scientists with their colleagues in engineering, physics, and chemistry, (2) increasing the training of bio- and medical students in the field of nanotechnology, and (3) focusing on specific diseases for creating nano-based solutions. In this review, we focus on ovarian cancer as an example of a disease that could benefit from advances in nanotechnology to enhance its understanding, diagnosis, and therapy. We also stress the need to train biological, medical, clinical, and pharmaceutical students in the field of nanotechnology with presenting results on such training in USA pharmacy schools.
1 Introduction
Research in the nanomedical field has been on the rise resulting in advances that are potentially useful for developing new diagnostic technologies and new therapies, but mostly, they are not focused toward particular diseases. Part of this problem is due to lack of training of personnel in the biomedical and health fields in the field of nanotechnology. Another reason for this problem is the lack of coordinated efforts that promote interdisciplinary collaborations that focus on disease-oriented nanosolutions.
The purpose of this review is to present the steps needed to move into practice the idea that nanotechnology should be disease-oriented (Figure 1). We present how nanotechnology can improve understanding, diagnosing, and treating a particular disease with using ovarian cancer as an example. We also evaluate the training of biomedical scientists and present potential solutions to enhance their participation in multidisciplinary research.
Schematic of steps needed for heading toward nanotechnology-based solutions for a particular disease.
2 Nanotechnology to improve understanding of ovarian cancer progression
Ovarian cancer is the leading cause of death from a gynecologic malignancy in the USA [1–3]. Ovarian cancer has always been thought to originate in the ovarian surface epithelium (OSE); however, recently, evidence points to either originating from the fimbria of fallopian tubes for high-serous-grade ovarian cancer or the OSE for low-grade invasive tumors [4–7]. The main problems of ovarian cancer’s poor prognosis have been its late diagnosis, when it has already metastasized to other organs, and relapse due to resistance to therapy. The first line chemotherapy for ovarian cancer is usually a combination of platinum- and taxane-based agents. However, resistance to both and, in particular, to platinum is common and is associated with relapse and recurrence of the disease. Some of these problems hindering eradicating ovarian cancer may be resolved if more nanotechnology efforts are directed toward understanding the mechanism of its progression, enhancing its early diagnosis, improving its therapy, and overcoming resistance. Recent developments in the nanotechnology field are helping us understand certain characteristics of ovarian cancer cells, such as variation of cells’ elasticity associated with sensitivity or resistance to therapy, affected cell-cell adhesions, and improving detection of ovarian cancer stem cells and circulating tumor cells. We will address each of these points separately and present how nanotechnology could improve our understanding of ovarian cancer progression and enhance its diagnosis and therapy.
2.1 Evaluate ovarian cancer origin and staging
Recently, it became clear that ovarian cancer may arise from either the fimbria of fallopian tubes or the OSE. High-grade serous ovarian carcinoma originates in the fimbria of fallopian tubes and is characterized by p53 inactivations [8–10]. In contrast, low-grade serous carcinomas seem to originate in the OSE or fallopian tubes and are characterized by mutations in K-RAS, B-RAF, and PTEN [8, 10–12].
The question to consider here is, can nanotechnology help identify for each patient the origin of her disease. The importance of answering this question is that it may help to determine the extent and the stage of the disease and potentially evaluate its response to therapy. In addition, this will facilitate better understanding of the mechanisms of ovarian cancer progression. To identify the origins of ovarian cancer, some efforts may be directed to create multimarker screening devices that are capable of evaluating simultaneously several markers of OSE or fallopian fimbria or even evaluate intracellular gene mutations or gene expression to understand the progression of the disease and potential response to therapy.
2.2 Probing ovarian cancer cells with atomic force microscopy for elastography
Certain nanotechnology applications may help us determine the changes in the mechanical properties of ovarian cancer cells during disease progression as they become more motile or resistant to chemotherapy. A variety of biophysical techniques such as membrane stretching, atomic force microscopy, optical traps, micropipette aspiration, particle tracking rheometry, magnetic twisting cytometry, optical tweezers, and various biophysical techniques in nanotechnology make use of ferromagnetic or superparamagnetic beads to attach to ovarian cancer cell receptors [13–18]. This allows for twisting and stretching of the cell, which provides a way to better understand the mechanical properties by which these cells progress.
A recent study evaluating cell stiffness using atomic force microscopy (AFM) found that invasive ovarian cancer cells are less stiff than the ones with lower invasive potential [19] or benign cells [20]. Also, they are more viscous than benign cells [20]. Furthermore, results showed that decreasing the organization of actin had a much greater effect on decreasing the elasticity and viscosity of a cell compared to decreasing the microtubule organization, the effect of which was insignificant [21]. It was concluded that the measurement of cell stiffness was a more sensitive measurement in determining the potential of cells to undergo metastasis when compared to examining the cell structure or epithelial characteristics (from determining the level of E-cadherin, cortical actin, and vimentin expression in certain ovarian cancer cells) [20, 21]. Stiffness measurements by AFM is helping better understand the mechanisms at work in tumor progression, at the physical and molecular level, thus, providing the clinical means that will determine the potential of cells to become metastatic. AFM was also used to differentiate between the nanomechanical properties of cisplatin-resistant and cisplatin-sensitive cells [22]. Only cisplatin-sensitive cells exhibited increased stiffness that was dose-dependent [22]. This research may help understand the mechanisms of drug resistance in relation to remodeling of the cell architecture.
2.3 Ovarian cancer specialized cells
There is evidence for the existence of certain rare cancer cells in ovarian cancer, including cancer stem cells (CSCs) and circulating tumor cells (CTCs) [23]. CSCs in ovarian cancers are heterogeneous and resistant to therapy and are capable of giving rise to similar cells or more differentiated ones [23–27]. CSC isolation and enrichment is based on expression of specific cell markers [24, 28]. Nanotechnology has the potential to improve our understanding of CSCs’ heterogeneity through cellular biomarkers screening, which may help resolve the origins of ovarian cancer whether it is OSE or fallopian fimbria. Furthermore, labeling CSCs with magnetic nanoparticles or quantum dots allows their in vivo tracking for the purpose of studying their migration and contribution to disease progression [29]. Another potential nanotechnology contribution could be targeting CSCs through their specific cell markers with nanocarriers loaded with cytotoxic agents. Potential targets within the CSCs could include the epigenetically modified regulatory elements or microRNAs [30].
The other type of rare cells is ovarian circulating tumor cells (CTCs), which are hard to detect. Nanotechnology could improve the detection of these cells; for example, recently, a novel microfluidic chip-based micro Hall made it possible to detect rare ovarian CTCs in the presence of immense numbers of blood cells and unbound reactants [31]. The magnetization properties and the bio-orthogonal chemistry of magnetic nanoparticles make it possible to detect biomarkers, epithelial cell adhesion molecule, and specific receptors of any individual cell [31]. The techniques and methods mentioned above provide a less expensive way in the diagnosis of rare cancer cells in clinical settings. Several microfluidic platforms or immunomagnetic particles employing recognition of CTCs’ markers have been created to detect or enrich for CTCs in cancers, and the reader is referred to a recent comprehensive review on this topic [32].
2.4 Other possibilities
Another nanotechnology contribution that may help study specific ovarian cancer cells from ascitic fluid is the ability to selectively remove them using magnetic nanoparticles [33, 34]. Nanotechnology may help understand ovarian cancer cell adhesions by using specific surface topographies that have nanoscale features or certain functional groups in order to evaluate interactions of ovarian cancer cells or ovarian CSCs with these surfaces, which may be designed to simulate mesothelial cells. For example, such surfaces that had immobilized E-cadherin or fibronectin on substrates have been used with other cell types [35], and they could easily be used with ovarian cancer cells. The value of this is to create simplified models with isolated molecules to understand interaction events that usually lead to adhesion of ovarian cancer cells to the mesothelial lining of the peritoneum, which precedes their invasion and metastasis.
3 Nanotechnology for ovarian cancer diagnosis
Late diagnosis of ovarian cancer is a serious problem as most women do not get diagnosed with the disease early enough to treat it. Instead, most are diagnosed when they are already at advanced stages (III or IV), when the disease has already spread to other organs. Early diagnosis of ovarian cancer will lead to immediate therapy and improved survival rate [1]. Nanotechnology could serve the early diagnosis of ovarian cancer by improving either screening of biomarkers or imaging techniques. Our purpose is to give a general overview on the possibilities where nanotechnology may enhance diagnosis of ovarian cancer; for more details, the readers are referred to our recent review on this topic [36].
3.1 Biomarker screening in ovarian cancer
Combining transvaginal sonography and serum marker CA125 (MUC16) has been the main modality studied so far for diagnosing ovarian cancer [1]. Recent advances in proteomics and genomics led to identification of additional diagnostic or prognostic biomarkers including genes, proteins, and metabolites [1, 37, 38]. Nanotechnology contribution to this area is mainly through creating new platforms to assess, simultaneously, hundreds of biomarkers in small volumes of samples. These platforms may include microfluidics or functionalized nanoparticles that adsorb to low abundance or low molecular weight biomarkers as summarized by Kim and coworkers [36].
3.2 Imaging of ovarian cancer
Recent improvements in existing imaging techniques are due to the use of nanomaterials in these techniques. An example of this is using in sonography lipid- or polymer-based microbubbles that contain contrast agents in what is referred to as contrast-enhanced ultrasound (CE US) [39–41]. The microbubbles may be targeted to specific cell markers such as vascular endothelial growth factor (VEGF) receptor, integrins, or P-selectin, which enables imaging at the vasculature or inflammation sites [42–47]. The half-life of the microbubbles is increased by functionalization with polyethylene glycol (PEGylation). CE US has been used in ovarian cancers to assess microvascular changes, which helps differentiate between benign and malignant cancers [48–50]. The advantages of this imaging technique include the early detection of neovascularities at metastatic sites and monitoring of the response to anti-angiogenic therapy in cancers [41, 51, 52].
Many nanomaterials have unique characteristics that enabled various modes of imaging including molecular and/or multimodal imaging in addition to enabling imaging techniques that were not previously in use. Molecular imaging techniques target particular cancer-associated cell markers either on the cell surface or intracellular markers such as intracellular signaling molecules or may even target gene expression [53–55]. Examples of such markers in ovarian cancer are folate receptor α and CA125. Multimodal or multiplexed imaging results from combining more than one imaging technique simultaneously for the early detection and to obtain information about the cancer localization and metastasis [56]. Moreover, multimodal imaging enables examining molecules within distinct cellular events simultaneously and in real time. Another advantage of nanoparticles is that they are multifunctional, so they can be functionalized with various moieties including targeting ligands, imaging agents, and more than one therapeutic agent. This characteristic of combing an imaging agent and a therapeutic agent allows for simultaneous diagnosis and therapy while following the patients’ response to therapy through imaging, which is referred to as theranostics.
Some examples of the newer deep-tissue imaging techniques that employ nanomaterials and that were not previously in use are surface-enhanced Raman spectroscopy (SERS)-based imaging and photoacoustic imaging (PAI). In SERS-based imaging, metallic nanoparticles such as gold and silver act as amplifiers to produce strong Raman spectrum [57, 58]. In PAI, carbon nanotubes and gold nanoshells are used [59–63] with non-ionizing near-infrared (NIR) light, which results in the generation of ultrasound waves that are collected and converted to electrical signals [63–67]. Furthermore, nanotechnology has been enhancing the sensitivity of magnetic resonance imaging (MRI) through the use of gadolinium-based nanoparticles or iron oxide nanoparticles as contrast agents [68, 69]. Using liposomes, micelles, or dendrimers as carriers of these contrast agents reduces the direct toxicity of contrast agents [70–79]. In addition, iron oxide has been used for molecular imaging to detect various cancer-specific cell markers such as folate receptor α, integrins, and transferrin receptor [68]. All the above improvements in imaging techniques are due to the unique optical characteristics of nanomaterials, and they could be employed for the diagnosis of ovarian cancer.
4 Nano-based ovarian cancer therapy
The treatment of ovarian cancer usually involves cytoreductive surgery followed by the standard first-line chemotherapeutic combination regimen of platinum- and taxane-based drugs [37, 80, 81]. Many ovarian cancer patients suffer from recurrence of ovarian cancer, and they become resistant to therapy and incurable [1–3, 37, 81]. Newer directions in ovarian cancer therapy may target the tumor microenvironment, e.g., use anti-angiogenic or immunomodulatory therapeutic agents [82–85]. Nanotechnology has the potential to enhance ovarian cancer therapy in many ways including enhancing intraperitoneal (IP) therapy, employing targeted nanocarriers, overcoming resistance, and introducing new modes of therapy as summarized in the following sections.
4.1 Nano has the potential to enhance IP therapy and reduce toxicity
Although IP therapy alone or in combination with intravenous (IV) therapy has better efficacy than IV therapy alone, the toxicities associated with it have been limiting its use in patients [86]. This is an area where nanotechnology could contribute through reducing toxicities of cytotoxic agents through being encapsulated within nanocarriers. Furthermore, recent studies demonstrate that IP administration of some nanocarriers resulted in their accumulation in the peritoneum including paclitaxel-loaded nanoparticles [87] and iron oxide nanoparticles [88]. This is a promising finding, but it may be nanoparticle-dependent.
4.2 Targeted nanocarrier therapies in ovarian cancer
The multifunctionality of nanocarriers makes them ideal for decorating with targeting moieties to ovarian cancer cells while at the same time being loaded with more than one therapeutic agent or even with therapeutic and imaging agents for theranostic value. The readers are referred to a recent review for more details on potential cell markers being targeted, such as VEGF, folate receptor α, mucins and other receptors in addition to presenting studies on the various types of nanocarriers being evaluated for this purpose [36].
4.3 Overcome resistance to chemotherapy in ovarian cancer
4.3.1 The mucin barrier
The presence of mucins (MUC) including CA 125 (MUC16) is a characteristic of epithelial ovarian cancers. Mucins are large extracellular proteins that carry oligosaccharide glycosylations serving to protect the cell and regulate the microenvironment at the cell surface. It has been determined that aberrant mucin expression occurs in ovarian tumors; the most notable being MUC1, MUC4, MUC5AC, MUC13, and MUC16 [89, 90]. Aside from screening purposes, mucins have been shown to form a physical barrier that hinders chemotherapeutics’ access to cells in many carcinomas, such as pancreatic and breast cancers [91, 92]. It appears that large penetration force is required for penetration of the tip of atomic force microscope for multidrug resistance ovarian cancer cells when compared to the same cells after inhibition of glycosylation that resulted in a reduced density of mucins [93]. This confirms that mucin forms a physical barrier to chemotherapy.
In ovarian cancer, specifically, mucins have been linked to peritoneal metastasis through the interaction with mesothelin on the peritoneal lining as well as inhibiting the normal immunological response of natural killer (NK) cells that results in lysis of ovarian cancer cells, thus, leading to tumor progression [94–96]. Treatment of ovarian cancer by targeting the mucin barrier could improve the chemotherapeutic response of cancerous tumor cells. It was suggested that nanotechnology may be incorporated into this type of treatment by coupling anti-mucin radiolabeled antibodies with liposomes and other nanoparticles to improve the response in treating resistant tumor cells through increased tumor uptake and chemotherapy retention [90]. Moreover, nanotechnology could improve the penetration of the mucin barrier if nanoparticles are loaded with enzymes that specifically digest mucins or interfere with their gene expression.
4.3.2 Spheroids penetration
Ovarian cancers usually shed cells in the form of single cells or multicellular aggregates (MCAs) or what is referred to as spheroids. These spheroids may attach to the mesothelial lining of the peritoneum to initiate secondary tumors in adjacent organs [97–99]. They are resistant to radiation- and chemotherapy and contribute to relapse in treatment [99–102]. Improved penetration of these spheroids has been recently reported using carbon nanotubes [103]. This finding shows great promise for carbon nanotubes, or perhaps rod-shaped nanomaterials, in improved uptake and penetration by these aggregated cells, which could potentially enhance their response to therapy and which remains to be explored further.
4.4 New modes of therapy and other possibilities
Newer modes of therapy are emerging due to special characteristics of nanomaterials. For example, photodynamic therapy uses a selective wavelength of light to irradiate targeted photosensitizing nanomaterials that have been administered locally or systemically. The form of radiation most commonly used to heat the nanoparticles is NIR tuned to a wavelength between 650 and 900 nm [104]. When irradiated, the nanomaterials absorb the radiation, generating heat and causing apoptosis of the cells that have internalized the nanomaterials. This form of cell killing is commonly referred to as photothermal ablation. Among the nanomaterials that have been studied and proven to be effective photosensitizers are gold nanoparticles and carbon nanotubes [105–109]. These nanomaterials, along with magnetic nanoparticles that have photo- or magnetothermal characteristics, could be useful in combining imaging with ablation therapy to monitor responses to individualized therapies.
Additional new strategies for improved ovarian cancer therapy may employ enzyme-triggered drug release where enzymes within the tumor environment may hydrolyze the nanocarrier to trigger drug release at the tumor site [110]. In the case of ovarian cancer, phospholipases and metalloproteases that exist at the cancer microenvironment [111–113] could be employed for such a mechanism of drug release.
5 Training bio- and medical specialists in the field of nanotechnology
We presented above the possibilities where nanotechnology could improve research and therapy of a disease using ovarian cancer as an example. There is a great need to move from trying new nanotechnologies with cell systems or animal models that happen to be available to researchers to doing research that is more focused on particular diseases. For that purpose, interdisciplinary collaborations are needed between engineers, physicists, and chemist with their colleagues in the bio/medical/clinical and pharmaceutical sciences. However, for this to actually happen, the latter scientists must be trained in the field so that they can shift their research from focusing on evaluating toxicities of nanomaterials into nanotechnology-based research that focuses on finding solutions for specific diseases.
Currently, education and training of a new generation of nanotechnology-trained personnel with various specializations does not seem to meet the future workforce needs within the United States, Europe, or the world [114–116]. Since the emergence of nanotechnology, there has been an emphasis on the importance of educating students studying engineering, physics, chemistry, and material science on the topic to provide the labor force that is needed to push forth industrial advancement [114, 117, 118]. In contrast, educating students within the biological, medical, pharmaceutical, clinical, or health science fields on the topic has been lagging or even hardly mentioned in literature.
Currently, the vision of education on nanotechnology focuses on using degrees in traditional disciplines and adding an option for a minor, concentration, or certificate in nanotechnology [115]. These programs attract mainly nonbiology and nonmedical students because they are offered by nonbio- or nonmedical departments such as chemistry, physics, or engineering departments. Recently, Duncan and Gasper (2011) critically evaluated the clinical relevance of preclinical and clinical studies in the field of nanotechnology [119]. One of their conclusions was that although nanotechnology has great potential in contributing to nano-based therapies and diagnostics, such successful disease-specific contributions may be possible through interdisciplinary collaborations [119]. This translates to collaborations not only between engineers, physicists, and chemists but also with biological, biomedical, clinical, and pharmaceutical scientists.
We sent a survey to pharmacy schools within the United States to evaluate if the topic of nanotechnology is taught to pharmaceutical science graduate students and to Doctor of Pharmacy (PharmD) students. The survey instrument consisted of six questions regarding nanotechnology (Table 1) and was approved by the authors’ Institutional Review Board (IRB) with an exempt designation. Forty-three (43.4% response rate) pharmacy schools responded to the survey (Table 1). Several pharmacy schools (20 out of 43) volunteered unsolicited information about which courses taught a section on nanotechnology.
Responses of surveyed pharmacy schools.a
| Question | Response (%) | NRc | p-Valued | |||
|---|---|---|---|---|---|---|
| Yes | No | N/Ab | ||||
| PharmD curriculum | ||||||
| 1. | Is nanotechnology taught as a stand-alone course to PharmD students, e.g., an elective? | 4 (9.3%) | 39 (90.7%) | 0 | 0 | <0.001 |
| 2. | Is nanotechnology included as a topic as part of other offered courses? | 29 (67.4%) | 14 (32.6%) | 0 | 0 | 0.022 |
| 3. | Do PharmD students get a brief exposure to the topic of nanotechnology? | 33 (76.7%) | 9 (20.9%) | 1 (2.3%) | 0 | <0.001 |
| Graduate curriculum | ||||||
| 1. | Is nanotechnology taught as a stand-alone course to graduate students, e.g., an elective? | 9 (20.9%) | 14 (32.6%) | 17 (39.5%)e | 3 (7.0%) | 0.297 |
| 2. | Is nanotechnology included as a topic as part of other offered courses? | 20 (46.5%) | 4 (9.3%) | 16 (37.2%)e | 3 (7.0%) | 0.001 |
| 3. | Do graduate students get a brief exposure to the topic of nanotechnology? | 22 (51.2%) | 2 (4.7%) | 16 (37.2%)e | 3 (7.0%) | <0.001 |
aThis survey was sent via email to 99 pharmacy schools throughout the USA that were affiliated with the American Association of Colleges of Pharmacy (AACP) in 2011 and that had the Dean’s contact information readily available through each school’s website.
bN/A, not applicable. Several Pharmacy schools responded with “not applicable” when answering the questions in relation to graduate program because these schools do not have a graduate program.
cNR, no response.
dp-Value from χ2-test for each question (null hypothesis: yes=no).
eSeveral of the responding pharmacy schools answered N/A (not applicable) to the survey as 16 schools do not offer a graduate program in pharmaceutical sciences.
As shown in Table 1, only four (9.3%) pharmacy schools offer a stand-alone elective course on nanotechnology to PharmD students. On the other hand, 29 (67.4%) schools offer the topic as part of another course. Nonetheless, those 29 schools were among 33 schools that indicated that students had only a brief exposure to the topic. According to the extra information volunteered by responding schools, when this topic is taught as part of another course, that course is either a core course like pharmaceutics or biopharmaceutics or an elective such as advanced or novel drug delivery systems, biotechnology, or pharmacogenomics. Several schools volunteered information that such teaching is at an introductory level and is for part of a lecture or two rather than a stand-alone topic.
Among the schools that offer graduate studies (27 schools), we found that 81.5% (22 out of 27 schools) offer a brief exposure to the topic of nanotechnology, while 7.4% (2 out of 27 schools) do not. Only 33% of the schools with graduate programs (9 out of 27) offer the topic as a stand-alone graduate course. Table 1 shows the detailed responses of pharmacy schools regarding the graduate curricula. The number of schools that offered to graduate students a stand-alone course on nanotechnology was not statistically different from those that did not.
In addition, we evaluated the association between groups (PharmD curriculum and graduate curriculum) and the outcomes (yes and no answers) by forming a 2×2 contingency tables for each question (Table 2). We found that only for question 1, on a stand-alone course, the p-value was <0.005 indicating that stand-alone courses on nanotechnology seem to be more prevalent in pharmaceutical science graduate programs rather than PharmD programs.
Contingency tables comparing the responses for PharmD with graduate student curricula.
| PharmD curriculum | Graduate curriculum | p-Valuea | |
|---|---|---|---|
| Question 1 responses | |||
| Yes | 4 | 9 | 0.008 |
| No | 39 | 14 | |
| Question 2 responses | |||
| Yes | 29 | 20 | 0.250 |
| No | 14 | 4 | |
| Question 3 responses | |||
| Yes | 33 | 22 | 0.303 |
| No | 9 | 2 | |
ap-Value from Fisher’s exact test for each question (null hypothesis: yes for PharmD=yes for graduate).
Overall, this survey demonstrated that most pharmacy schools do not have an established stand-alone course of education in the field of nanotechnology. On the other hand, ~77% of the responding schools indicated that PharmD students get exposed briefly to the topic within one to two lectures. Our findings for the graduate program also showed that one-third of pharmacy schools have a stand-alone course, while the majority teaches it as part of another course or teach it briefly. This survey demonstrates that there is more inclination for the graduate program than the PharmD program to teach nanotechnology as a stand-alone topic. This may be explained by the involvement of graduate students in research contributing to nano-based pharmaceuticals. On the other hand, 77% of the schools that graduate pharmacists with a PharmD degree only briefly expose their students to the topic of nanotechnology. Around 20% in 2007 (predicted 50% in 2020) pursue clinical residencies [120] where they interact with patients while being consulted on treatments and/or design of clinical trials. This subgroup represents clinicians who lack sufficient training in the field of nanobiotechnology and who could benefit from such training in order to be involved in multidisciplinary collaborations for disease-specific nanosolutions. We suspect that similar limited nanotechnology-educational trends exist among other bio, medical, and clinical fields worldwide; although we are not aware of studies that evaluate this.
6 Summary and future directions
There is a need to create interdisciplinary collaborative opportunities to direct the field of nanotechnology into a direction of research that is disease-oriented rather than material-oriented and, thus, accelerate specific disease needed solutions. Currently, there is a deficit in providing training funding for bio- and medical students (majors: biology, medicine, pharmacy, dentistry, optometry, imaging) at BS, MS, and doctoral levels. A real need for funding exists at the postbaccalaureate level for training basic and clinical scientists who may collaborate with their colleagues in other fields to advance the disease-focused nanotechnologies for the purpose of curing diseases. Funding for this purpose could be set specifically for setting up and for attending nanotechnology courses, virtual labs, wet labs, and summer internships. Furthermore, there is a current deficiency in the training of biological and medical scientists in the field of nanotechnology. Thus, funding is needed to train the future trainers possibly through summer internships or workshops. In addition, in order to promote interdisciplinary collaborations, then, funding for nano-solutions for specific diseases may be needed. Reviewers of these grants ought to be a combination of disease and nano specialists.
About the authors
Joseph Youkhanna received his Doctorate of Pharmacy degree in 2011 at MCPHS University. He obtained his undergraduate studies at Wayne State University in Detroit, MI. He worked closely with Dr. Reema Zeineldin for 1 year researching on teaching the expanding field of nanotechnology. Joseph is currently a staff pharmacist at Walgreens Pharmacy in Detroit, MI, USA.
Joan Syoufjy received her Bachelor Degree (BS) in Molecular Biology at the University of Michigan (US) in 2008. Then, she pursued her Doctor of Pharmacy degree (PharmD) at the MCPHS University where she started to work with Dr. Zeineldin to discover ways to incorporate methods of teaching Nanotechnology to PharmD students. Her interest in Nanotechnology provoked her to continue her education in Nuclear Pharmacy, which involves the preparation of radioactive medicine to help diagnose and treat specific diseases. She is currently employed with CVS/Pharmacy as a pharmacist in charge in Detroit, MI, USA.
Mary Rhorer received her Doctor of Pharmacy degree in May 2013 at MCPHS University in Worcester, MA, USA. Her research work with Dr. Zeineldin has focused on ovarian cancer therapy and nanotechnology. She is currently a clinical pharmacy resident in Albany, VA, Medical Center and she plans to specialize in Oncology Pharmacy.
Oyebola Abiodun Oladeinde received his “Laurea” degree in Chemistry in 2009 at Morgan State University. After graduation, he obtained a cancer research trainee award (CRTA) to join the Center for Cancer Research, Chemical Biology Laboratory at the National Cancer Institute, Frederick, MD, where he studied in the group of Dr. Larry Keefer (2009). In May 2013, he received his Doctor of Pharmacy degree at MCPHS University, where his research project involved the application of nanotechnology-based drug delivery against ovarian cancer resistant to current chemotherapy. He is currently a community pharmacist at Walgreens Pharmacy.
Reema Zeineldin received her PhD in Biomedical Sciences from the University of New Mexico (UNM) where her work focused on understanding the progression of ovarian cancer. During her postdoctoral training, she did research on biosensing in the Department of Chemical and Nuclear Engineering at UNM. She is currently an Associate Professor at MCPHS University teaching PharmD students and performing research that focuses on nano and bio integrations for biosensing and for the therapy of ovarian cancer.
Funding for this work was provided by the MCPHS University.
References
[1] Das PM, Bast RC, Jr. Early detection of ovarian cancer. Biomark. Med. 2008, 2, 291–303.Search in Google Scholar
[2] Markman M. Pharmaceutical management of ovarian cancer: current status. Drugs 2008, 68, 771–789.10.2165/00003495-200868060-00004Search in Google Scholar
[3] Jayde V, White K, Blomfield P. Symptoms and diagnostic delay in ovarian cancer: a summary of the literature. Contemp. Nurse 2009 Dec-2010, 34, 55–65.10.5172/conu.2009.34.1.055Search in Google Scholar
[4] Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J. Clin. Oncol. 2008, 26, 5284–5293.Search in Google Scholar
[5] Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J. Pathol. 2007, 211, 26–35.Search in Google Scholar
[6] Dubeau L. The cell of origin of ovarian epithelial tumours. Lancet Oncol. 2008, 9, 1191–1197.10.1016/S1470-2045(08)70308-5Search in Google Scholar
[7] Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J. Pathol. 2001, 195, 451–456.Search in Google Scholar
[8] Shih IM, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am. J. Pathol. 2004, 164, 1511–1518.Search in Google Scholar
[9] Singer G, Stöhr R, Cope L, Dehari R, Hartmann A, Cao DF, Wang TL, Kurman RJ, Shih IeM. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am. J. Surg. Pathol. 2005, 29, 218–224.Search in Google Scholar
[10] Landen CN, Jr, Birrer MJ, Sood AK. Early events in the pathogenesis of epithelial ovarian cancer. J. Clin. Oncol. 2008, 26, 995–1005.Search in Google Scholar
[11] Ho CL, Kurman RJ, Dehari R, Wang TL, Shih Ie M. Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res. 2004, 64, 6915–6918.Search in Google Scholar
[12] Vang R, Shih Ie M, Kurman RJ. Fallopian tube precursors of ovarian low- and high-grade serous neoplasms. Histopathology 2013, 62, 44–58.10.1111/his.12046Search in Google Scholar PubMed
[13] Kumar S, Weaver VM. Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev. 2009, 28, 113–127.Search in Google Scholar
[14] Bao G, Suresh S. Cell and molecular mechanics of biological materials. Nat. Mater. 2003, 2, 715–725.Search in Google Scholar
[15] Huang H, Kamm RD, Lee RT. Cell mechanics and mechanotransduction: pathways, probes, and physiology. Am. J. Physiol. 2004, 287, C1–11.Search in Google Scholar
[16] Tim O’Brien E, Cribb J, Marshburn D, Taylor RM, 2nd, Superfine R. Chapter 16: Magnetic manipulation for force measurements in cell biology. Methods Cell Biol. 2008, 89, 433–450.Search in Google Scholar
[17] Wirtz D. Particle-tracking microrheology of living cells: principles and applications. Ann. Rev. Biophys. 2009, 38, 301–326.10.1146/annurev.biophys.050708.133724Search in Google Scholar PubMed
[18] Overby DR, Matthews BD, Alsberg E, Ingber DE. Novel dynamic rheological behavior of individual focal adhesions measured within single cells using electromagnetic pulling cytometry. Acta. Biomater. 2005, 1, 295–303.Search in Google Scholar
[19] Swaminathan V, Mythreye K, O’Brien ET, Berchuck A, Blobe GC, Superfine R. Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Cancer Res. 2011, 71, 5075–5080.Search in Google Scholar
[20] Ketene AN, Schmelz EM, Roberts PC, Agah M. The effects of cancer progression on the viscoelasticity of ovarian cell cytoskeleton structures. Nanomedicine 2012, 8, 93–102.10.1016/j.nano.2011.05.012Search in Google Scholar PubMed
[21] Ketene AN, Roberts PC, Shea AA, Schmelz EM, Agah M. Actin filaments play a primary role for structural integrity and viscoelastic response in cells. Integr. Biol. (Camb) 2012, 4, 540–549.10.1039/c2ib00168cSearch in Google Scholar PubMed
[22] Sharma S, Santiskulvong C, Bentolila LA, Rao J, Dorigo O, Gimzewski JK. Correlative nanomechanical profiling with super-resolution F-actin imaging reveals novel insights into mechanisms of cisplatin resistance in ovarian cancer cells. Nanomedicine 2012, 8, 757–766.10.1016/j.nano.2011.09.015Search in Google Scholar PubMed
[23] Foster R, Buckanovich RJ, Rueda BR. Ovarian cancer stem cells: working towards the root of stemness. Cancer Lett. In press.Search in Google Scholar
[24] Bapat SA. Human ovarian cancer stem cells. Reproduction (Cambridge, England) 2010, 140, 33–41.10.1530/REP-09-0389Search in Google Scholar PubMed
[25] Fong MY, Kakar SS. The role of cancer stem cells and the side population in epithelial ovarian cancer. Histol. Histopathol. 2010, 25, 113–120.Search in Google Scholar
[26] Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc. Natl. Acad. Sci. USA 2006, 103, 11154–11159.10.1073/pnas.0603672103Search in Google Scholar PubMed PubMed Central
[27] Alvero AB, Chen R, Fu HH, Montagna M, Schwartz PE, Rutherford T, Silasi DA, Steffensen KD, Waldstrom M, Visintin I, Mor G. Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle (Georgetown, Tex) 2009, 8, 158–166.10.4161/cc.8.1.7533Search in Google Scholar PubMed PubMed Central
[28] Berry NB, Bapat SA. Ovarian cancer plasticity and epigenomics in the acquisition of a stem-like phenotype. J. Ovarian Res. 2008, 1, 8.Search in Google Scholar
[29] Ferreira L, Karp JM, Nobre L, Langer R. New opportunities: the use of nanotechnologies to manipulate and track stem cells. Cell Stem. Cell 2008, 3, 136–146.10.1016/j.stem.2008.07.020Search in Google Scholar PubMed
[30] Murphy SK. Targeting ovarian cancer-initiating cells. Anticancer Agents Med. Chem. 2010, 10, 157–163.10.2174/187152010790909272Search in Google Scholar PubMed
[31] Issadore D, Chung J, Shao H, Liong M, Ghazani AA, Castro CM, Weissleder R, Lee H. Ultrasensitive clinical enumeration of rare cells ex vivo using a micro-hall detector. Sci. Transl. Med. 2012, 4, 141ra92.Search in Google Scholar
[32] Parkinson DR, Dracopoli N, Petty BG, Compton C, Cristofanilli M, Deisseroth A, Hayes DF, Kapke G, Kumar P, Lee JSh, Liu MC, McCormack R, Mikulski S, Nagahara L, Pantel K, Pearson-White S, Punnoose EA, Roadcap LT, Schade AE, Scher HI, Sigman CC, Kelloff GJ. Considerations in the development of circulating tumor cell technology for clinical use. J. Transl. Med. 2012, 10, 138.Search in Google Scholar
[33] Scarberry KE, Dickerson EB, Zhang ZJ, Benigno BB, McDonald JF. Selective removal of ovarian cancer cells from human ascites fluid using magnetic nanoparticles. Nanomedicine 2010, 6, 399–408.10.1016/j.nano.2009.11.003Search in Google Scholar PubMed
[34] Scarberry KE, Mezencev R, McDonald JF. Targeted removal of migratory tumor cells by functionalized magnetic nanoparticles impedes metastasis and tumor progression. Nanomedicine (London, England) 2011, 6, 69–78.10.2217/nnm.10.103Search in Google Scholar PubMed
[35] Silvestre J, Kenis PJ, Leckband DE. Cadherin and integrin regulation of epithelial cell migration. Langmuir 2009, 25, 10092–10099.10.1021/la901109eSearch in Google Scholar PubMed PubMed Central
[36] Kim PS, Djazayeri S, Zeineldin R. Novel nanotechnology approaches to diagnosis and therapy of ovarian cancer. Gynecol. Oncol. 2011, 120, 393–403.Search in Google Scholar
[37] Williams TI, Toups KL, Saggese DA, Kalli KR, Cliby WA, Muddiman DC. Epithelial ovarian cancer: disease etiology, treatment, detection, and investigational gene, metabolite, and protein biomarkers. J. Proteome. Res. 2007, 6, 2936–2962.Search in Google Scholar
[38] Kulasingam V, Pavlou MP, Diamandis EP. Integrating high-throughput technologies in the quest for effective biomarkers for ovarian cancer. Nat. Rev. 2010, 10, 371–378.Search in Google Scholar
[39] Frinking PJ, Bouakaz A, Kirkhorn J, Ten Cate FJ, de Jong N. Ultrasound contrast imaging: current and new potential methods. Ultrasound Med. Biol. 2000, 26, 965–975.Search in Google Scholar
[40] Calliada F, Campani R, Bottinelli O, Bozzini A, Sommaruga MG. Ultrasound contrast agents: basic principles. Eur. J. Radiol. 1998, 27, S157–S160.Search in Google Scholar
[41] Kiessling F, Bzyl J, Fokong S, Siepmann M, Schmitz G, Palmowski M. Targeted ultrasound imaging of cancer: an emerging technology on its way to clinics. Curr. Pharm. Des. 2012, 18, 2184–2199.Search in Google Scholar
[42] Warram JM, Sorace AG, Saini R, Umphrey HR, Zinn KR, Hoyt K. A triple-targeted ultrasound contrast agent provides improved localization to tumor vasculature. J. Ultrasound Med. 2011, 30, 921–931.Search in Google Scholar
[43] Deshpande N, Ren Y, Foygel K, Rosenberg J, Willmann JK. Tumor angiogenic marker expression levels during tumor growth: longitudinal assessment with molecularly targeted microbubbles and US imaging. Radiology 2011, 258, 804–811.10.1148/radiol.10101079Search in Google Scholar PubMed PubMed Central
[44] Eisenbrey JR, Forsberg F. Contrast-enhanced ultrasound for molecular imaging of angiogenesis. Eur. J. Nucl. Med. Mol. Imaging 2010, 37, S138–S146.10.1007/s00259-010-1449-6Search in Google Scholar PubMed
[45] Willmann JK, Cheng Z, Davis C, Lutz AM, Schipper ML, Nielsen CH, Gambhir SS. Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice. Radiology 2008, 249, 212–219.10.1148/radiol.2491072050Search in Google Scholar PubMed PubMed Central
[46] Saini R, Warram JM, Sorace AG, Umphrey H, Zinn KR, Hoyt K. Model system using controlled receptor expression for evaluating targeted ultrasound contrast agents. Ultrasound Med. Biol. 2011, 37, 1306–1313.Search in Google Scholar
[47] Klibanov AL, Rychak JJ, Yang WC, Alikhani S, Li B, Acton S, Lindner JR, Ley K, Kaul S. Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow. Contrast Media Mol. Imaging 2006, 1, 259–266.10.1002/cmmi.113Search in Google Scholar PubMed
[48] Fleischer AC, Lyshchik A, Jones HW, Jr., Crispens M, Loveless M, Andreotti RF, Williams PK, Fishman DA. Contrast-enhanced transvaginal sonography of benign versus malignant ovarian masses: preliminary findings. J. Ultrasound Med. 2008, 27, 1011–1018; quiz 9–21.Search in Google Scholar
[49] Fleischer AC, Lyshchik A, Jones HW, 3rd, Crispens MA, Andreotti RF, Williams PK, Fishman DA. Diagnostic parameters to differentiate benign from malignant ovarian masses with contrast-enhanced transvaginal sonography. J. Ultrasound Med. 2009, 28, 1273–1280.Search in Google Scholar
[50] Fleischer AC, Lyshchik A, Andreotti RF, Hwang M, Jones HW, Fishman DA. Advances in sonographic detection of ovarian cancer: depiction of tumor neovascularity with microbubbles. AJR. Am. J. Roentgenol. 2010, 194, 343–348.Search in Google Scholar
[51] Wilson SR, Burns PN. Microbubble-enhanced US in body imaging: what role? Radiology 2010, 257, 24–39.10.1148/radiol.10091210Search in Google Scholar PubMed
[52] Cavalieri F, Zhou M, Ashokkumar M. The design of multifunctional microbubbles for ultrasound image-guided cancer therapy. Curr. Top. Med. Chem. 2010, 10, 1198–1210.Search in Google Scholar
[53] Kircher MF, Hricak H, Larson SM. Molecular imaging for personalized cancer care. Mol. Oncol. 2012, 6, 182–195.Search in Google Scholar
[54] Bhang HE, Pomper MG. Cancer imaging: gene transcription-based imaging and therapeutic systems. Int. J. Biochem. Cell Biol. 2012, 44, 684–689.Search in Google Scholar
[55] Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003, 17, 545–580.Search in Google Scholar
[56] Kobayashi H, Longmire MR, Ogawa M, Choyke PL, Kawamoto S. Multiplexed imaging in cancer diagnosis: applications and future advances. Lancet Oncol. 2010, 11, 589–595.Search in Google Scholar
[57] Brus L. Noble metal nanocrystals: plasmon electron transfer photochemistry and single-molecule Raman spectroscopy. Acc. Chem. Res. 2008, 41, 1742–1749.10.1021/ar800121rSearch in Google Scholar PubMed
[58] Thakor AS, Jokerst J, Zavaleta C, Massoud TF, Gambhir SS. Gold nanoparticles: a revival in precious metal administration to patients. Nano Lett. 2011, 11, 4029–4036.Search in Google Scholar
[59] Zavaleta C, de la Zerda A, Liu Z, Keren S, Cheng Z, Schipper M, Chen X, Dai H, Gambhir SS. Noninvasive Raman spectroscopy in living mice for evaluation of tumor targeting with carbon nanotubes. Nano Lett. 2008, 8, 2800–2805.Search in Google Scholar
[60] Pramanik M, Swierczewska M, Green D, Sitharaman B, Wang LV. Single-walled carbon nanotubes as a multimodal-thermoacoustic and photoacoustic-contrast agent. J. Biomed Opt. 2009, 14, 034018.Search in Google Scholar
[61] Akers WJ, Kim C, Berezin M, Guo K, Fuhrhop R, Lanza GM, Fischer GM, Daltrozzo E, Zumbusch A, Cai X, Wang LV, Achilefu S. Noninvasive photoacoustic and fluorescence sentinel lymph node identification using dye-loaded perfluorocarbon nanoparticles. ACS Nano 2011, 5, 173–182.10.1021/nn102274qSearch in Google Scholar PubMed PubMed Central
[62] Pan D, Pramanik M, Wickline SA, Wang LV, Lanza GM. Recent advances in colloidal gold nanobeacons for molecular photoacoustic imaging. Contrast media Mol. Imaging 2011, 6, 378–388.10.1002/cmmi.449Search in Google Scholar PubMed
[63] Doane TL, Burda C. The unique role of nanoparticles in nanomedicine: imaging, drug delivery and therapy. Chem. Soc. Rev. 2012, 41, 2885–2911.Search in Google Scholar
[64] Solomon M, Liu Y, Berezin MY, Achilefu S. Optical imaging in cancer research: basic principles, tumor detection, and therapeutic monitoring. Med. Princ. Pract. 2011, 20, 397–415.Search in Google Scholar
[65] Kim C, Favazza C, Wang LV. In vivo photoacoustic tomography of chemicals: high-resolution functional and molecular optical imaging at new depths. Chem. Rev. 2010, 110, 2756–2782.Search in Google Scholar
[66] Emelianov SY, Li PC, O’Donnell M. Photoacoustics for molecular imaging and therapy. Phys. Today 2009, 62, 34–39.10.1063/1.3141939Search in Google Scholar PubMed PubMed Central
[67] Ntziachristos V. Going deeper than microscopy: the optical imaging frontier in biology. Nat. Methods 2010, 7, 603–614.10.1038/nmeth.1483Search in Google Scholar PubMed
[68] Rosen JE, Chan L, Shieh DB, Gu FX. Iron oxide nanoparticles for targeted cancer imaging and diagnostics. Nanomedicine 2012, 8, 275–290.10.1016/j.nano.2011.08.017Search in Google Scholar PubMed
[69] Aime S, Castelli DD, Crich SG, Gianolio E, Terreno E. Pushing the sensitivity envelope of lanthanide-based magnetic resonance imaging (MRI) contrast agents for molecular imaging applications. Acc. Chem. Res. 2009, 42, 822–831.Search in Google Scholar
[70] Liu Y, Zhang N. Gadolinium loaded nanoparticles in theranostic magnetic resonance imaging. Biomaterials 2012, 33, 5363–5375.10.1016/j.biomaterials.2012.03.084Search in Google Scholar PubMed
[71] Kobayashi H, Brechbiel MW. Nano-sized MRI contrast agents with dendrimer cores. Adv. Drug Deliv. Rev. 2005, 57, 2271–2286.Search in Google Scholar
[72] Torchilin VP. Polymeric contrast agents for medical imaging. Curr. Pharm. Biotechnol. 2000, 1, 183–215.10.2174/1389201003378960Search in Google Scholar PubMed
[73] Erdogan S, Medarova ZO, Roby A, Moore A, Torchilin VP. Enhanced tumor MR imaging with gadolinium-loaded polychelating polymer-containing tumor-targeted liposomes. J. Magn. Reson. Imaging 2008, 27, 574–580.10.1002/jmri.21202Search in Google Scholar PubMed
[74] Erdogan S, Roby A, Sawant R, Hurley J, Torchilin VP. Gadolinium-loaded polychelating polymer-containing cancer cell-specific immunoliposomes. J. Liposome Res. 2006, 16, 45–55.Search in Google Scholar
[75] Kozlowska D, Foran P, MacMahon P, Shelly MJ, Eustace S, O’Kennedy R. Molecular and magnetic resonance imaging: The value of immunoliposomes. Adv. Drug Deliv. Rev. 2009, 61, 1402–11.Search in Google Scholar
[76] Peng XH, Qian X, Mao H, Wang AY, Chen ZG, Nie S, Shin DM. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy. Int. J. Nanomed. 2008, 3, 311–321.Search in Google Scholar
[77] Torchilin VP. Multifunctional nanocarriers. Adv. Drug Deliv. Rev. 2012, 64, 302–315.10.1016/j.addr.2012.09.031Search in Google Scholar
[78] Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (London, England) 2008, 3, 703–717.10.2217/17435889.3.5.703Search in Google Scholar PubMed PubMed Central
[79] Mody VV, Nounou MI, Bikram M. Novel nanomedicine-based MRI contrast agents for gynecological malignancies. Adv. Drug Deliv. Rev. 2009, 61, 795–807.Search in Google Scholar
[80] Metzger-Filho O, Moulin C, D’Hondt V. First-line systemic treatment of ovarian cancer: a critical review of available evidence and expectations for future directions. Curr. Opin. Oncol. 2010, 22, 513–520.Search in Google Scholar
[81] Gubbels JA, Claussen N, Kapur AK, Connor JP, Patankar MS. The detection, treatment, and biology of epithelial ovarian cancer. J. Ovarian Res. 2010, 3, 8.Search in Google Scholar
[82] Gomez-Raposo C, Mendiola M, Barriuso J, Casado E, Hardisson D, Redondo A. Angiogenesis and ovarian cancer. Clin. Transl. Oncol. 2009, 11, 564–571.Search in Google Scholar
[83] Gomez-Raposo C, Mendiola M, Barriuso J, Hardisson D, Redondo A. From targeted therapy in ovarian cancer to personalizing therapy for ovarian cancer. Expert Opin. Investig. Drugs 2011, 20, 591–594.10.1517/13543784.2011.571202Search in Google Scholar PubMed
[84] O’Malley DM, Richardson DL, Rheaume PS, Salani R, Eisenhauer EL, McCann GA, Fowler JM, Copeland LJ, Cohn DE, Backes FJ. Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer. Gynecol. Oncol. 2011, 121, 269–272.Search in Google Scholar
[85] Vaughan S, Coward JI, Bast RC, Jr., Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR. Rethinking ovarian cancer: recommendations for improving outcomes. Nat. Rev. 2011, 11, 719–725.Search in Google Scholar
[86] Liu J, Matulonis UA. New advances in ovarian cancer. Oncology (Williston Park, NY) 2010, 24, 721–728.Search in Google Scholar
[87] Colson YL, Liu R, Southard EB, Schulz MD, Wade JE, Griset AP, Zubris KA, Padera RF, Grinstaff MW. The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis. Biomaterials 2011, 32, 832–840.10.1016/j.biomaterials.2010.09.059Search in Google Scholar PubMed
[88] Toraya-Brown S, Sheen MR, Baird JR, Barry S, Demidenko E, Turk MJ, Hoopes PJ, Conejo-Garcia JR, Fiering S. Phagocytes mediate targeting of iron oxide nanoparticles to tumors for cancer therapy. Integr. Biol. (Camb) 2012, 5, 159–171.10.1039/c2ib20180aSearch in Google Scholar PubMed PubMed Central
[89] Singh AP, Senapati S, Ponnusamy MP, Jain M, Lele SM, Davis JS, Remmenga S, Batra SK. Clinical potential of mucins in diagnosis, prognosis, and therapy of ovarian cancer. Lancet Oncol. 2008, 9, 1076–1085.Search in Google Scholar
[90] Chauhan SC, Kumar D, Jaggi M. Mucins in ovarian cancer diagnosis and therapy. J. Ovarian Res. 2009, 2, 21.Search in Google Scholar
[91] Kalra AV, Campbell RB. Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain. Br. J. Cancer 2007, 97, 910–918.10.1038/sj.bjc.6603972Search in Google Scholar PubMed PubMed Central
[92] Nagy P, Friedländer E, Tanner M, Kapanen AI, Carraway KL, Isola J, Jovin TM. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res. 2005, 65, 473–482.Search in Google Scholar
[93] Wang X, Shah AA, Campbell RB, Wan K. Glycoprotein mucin molecular brush on cancer cell surface acting as mechanical barrier against drug delivery. Appl. Phys. Lett. 2010, 97, 263703.Search in Google Scholar
[94] Belisle JA, Gubbels JA, Raphael CA, Migneault M, Rancourt C, Connor JP, Patankar MS. Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125). Immunology 2007, 122, 418–429.10.1111/j.1365-2567.2007.02660.xSearch in Google Scholar PubMed PubMed Central
[95] Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho M, Bera TK, Connor J, Sathyanarayana BK, Lee B, Pastan I, Patankar MS. Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol. Cancer 2006, 5, 50.10.1186/1476-4598-5-50Search in Google Scholar PubMed PubMed Central
[96] Gubbels JA, Felder M, Horibata S, Belisle JA, Kapur A, Holden H, Petrie S, Migneault M, Rancourt C, Connor JP, Patankar MS. MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells. Mol. Cancer 2010, 9, 11.10.1186/1476-4598-9-11Search in Google Scholar PubMed PubMed Central
[97] Hudson LG, Zeineldin R, Stack MS. Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression. Clin. Exp. Metastasis 2008, 25, 643–655.10.1007/s10585-008-9171-5Search in Google Scholar PubMed PubMed Central
[98] Lengyel E. Ovarian cancer development and metastasis. Am. J. Pathol. 2010, 177, 3.Search in Google Scholar
[99] Shield K, Ackland ML, Ahmed N, Rice GE. Multicellular spheroids in ovarian cancer metastases: biology and pathology. Gynecol. Oncol. 2009, 113, 143–148.Search in Google Scholar
[100] Filippovich IV, Sorokina NI, Robillard N, Chatal JF. Radiation-induced apoptosis in human ovarian carcinoma cells growing as a monolayer and as multicell spheroids. Int. J. Cancer 1997, 72, 851–859.10.1002/(SICI)1097-0215(19970904)72:5<851::AID-IJC23>3.0.CO;2-ASearch in Google Scholar
[101] Makhija S, Taylor DD, Gibb RK, Gercel-Taylor C. Taxol-induced bcl-2 phosphorylation in ovarian cancer cell monolayer and spheroids. Int. J. Oncol. 1999, 14, 515–521.Search in Google Scholar
[102] Bardies M, Thedrez P, Gestin JF, Marcille BM, Guerreau D, Faivre-Chauvet A, Mahe M, Sai-Maurel C, Chatal J-F. Use of multi-cell spheroids of ovarian carcinoma as an intraperitoneal radio-immunotherapy model: uptake, retention kinetics and dosimetric evaluation. Int. J. Cancer 1992, 50, 984–991.10.1002/ijc.2910500627Search in Google Scholar
[103] Bhirde AA, Liu G, Jin A, Iglesias-Bartolome R, Sousa AA, Leapman RD, Gutkind JS, Lee S, Chen X. Combining portable Raman probes with nanotubes for theranostic applications. Theranostics 2011, 1, 310–321.10.7150/thno/v01p0310Search in Google Scholar
[104] Conde J, Rosa J, Lima JC, Baptista PV. Nanophotonics for molecular diagnostics and therapy applications. Int. J. Photoenergy 2012:ID 619530.10.1155/2012/619530Search in Google Scholar
[105] Huang X, El-Sayed IH, Qian W, El-Sayed MA. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J. Am. Chem. Soc. 2006, 128, 2115–2120.Search in Google Scholar
[106] Kirui DK, Rey DA, Batt CA. Gold hybrid nanoparticles for targeted phototherapy and cancer imaging. Nanotechnology 2010, 21, 105105.10.1088/0957-4484/21/10/105105Search in Google Scholar
[107] Kang B, Yu D, Dai Y, Chang S, Chen D, Ding Y. Cancer-cell targeting and photoacoustic therapy using carbon nanotubes as “bomb” agents. Small 2009, 5, 1292–1301.10.1002/smll.200801820Search in Google Scholar
[108] Gannon CJ, Cherukuri P, Yakobson BI, Cognet L, Kanzius JS, Kittrell C, Weisman RB, Pasquali M, Schmidt HK, Smalley RE, Curley SA. Carbon nanotube-enhanced thermal destruction of cancer cells in a noninvasive radiofrequency field. Cancer 2007, 110, 2654–2665.10.1002/cncr.23155Search in Google Scholar
[109] Kam NW, O’Connell M, Wisdom JA, Dai H. Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. Proc. Natl. Acad. Sci. USA 2005, 102, 11600–11605.10.1073/pnas.0502680102Search in Google Scholar
[110] Andresen TL, Thompson DH, Kaasgaard T. Enzyme-triggered nanomedicine: drug release strategies in cancer therapy. Mol. Membr. Biol. 2010, 27, 353–363.Search in Google Scholar
[111] Cai Q, Zhao Z, Antalis C, Yan L, Del Priore G, Hamed AH, Stehman FB, Schilder JM, Xu Y. Elevated and secreted phospholipase A(2) activities as new potential therapeutic targets in human epithelial ovarian cancer. FASEB J. 2012, 26, 3306–3320.Search in Google Scholar
[112] Hu X, Li D, Zhang W, Zhou J, Tang B, Li L. Matrix metalloproteinase-9 expression correlates with prognosis and involved in ovarian cancer cell invasion. Arch. Gynecol. Obstet. 2012, 286, 1537–1543.Search in Google Scholar
[113] Ghosh S, Wu Y, Stack MS. Ovarian cancer-associated proteinases. Cancer Treatment Res. 2002, 107, 331–351.Search in Google Scholar
[114] Roco MC. Converging science and technology at the nanoscale: opportunities for education and training. Nat. Biotechnol. 2003, 21, 1247–1249.Search in Google Scholar
[115] Thayer AM. Filling nanotech jobs. Chem. Eng. News 2010, 88, 10–16.10.1021/cen-v088n029.p010Search in Google Scholar
[116] Malsch I. Nano-education from a European perspective. J. Phys. Conf. Ser. 2008, 100, 032001.10.1088/1742-6596/100/3/032001Search in Google Scholar
[117] Uddin M, Chowdhury AR. Integration of nanotechnology into the undergraduate engineering curriculum. Int. Conf. Eng. Ed. 2001, Session 8B26, 6–9.Search in Google Scholar
[118] Foley ET, Hersam MC. Assessing the need for nanotechnology education reform in the United States. Nanotechnol. Law Bus. 2006, 3, 467–484.Search in Google Scholar
[119] Duncan R, Gaspar R. Nanomedicine(s) under the microscope. Mol. Pharm. 2011, 8, 2101–2141.Search in Google Scholar
[120] Johnson TJ. Pharmacist work force in 2020: implications of requiring residency training for practice. Am. J. Health-Syst. Pharm. 2008, 65, 166–170.10.2146/ajhp070231Search in Google Scholar PubMed
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- Editorial
- Biomedical nanotechnologies
- Reviews
- Imaging modalities using magnetic nanoparticles – overview of the developments in recent years
- Magnetic nanoparticles for cancer therapy
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- Collagen/silica nanocomposites and hybrids for bone tissue engineering
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Articles in the same Issue
- Masthead
- Masthead
- Graphical abstracts
- In this issue
- Editorial
- Biomedical nanotechnologies
- Reviews
- Imaging modalities using magnetic nanoparticles – overview of the developments in recent years
- Magnetic nanoparticles for cancer therapy
- Nanotechnologies in tissue engineering
- Collagen/silica nanocomposites and hybrids for bone tissue engineering
- Nanomedicine in diagnostics and therapy of cardiovascular diseases: beyond atherosclerotic plaque imaging
- Toward nanotechnology-based solutions for a particular disease: ovarian cancer as an example
