Prostrate Cancer I

Men with prostate cancer, the most common cancer diagnosed in the US, are faced with making the difficult decision of choosing among different treatment options ranging from watchful waiting to chemotherapy, radiation therapy, or surgery. Some patients, however, because of age or other health issues, cannot tolerate existing therapies. In addition, current therapies are often accompanied by serious side effects that impact on the quality of life. Often these side effects are the result of damage to healthy tissues that are in close proximity to the prostate. Furthermore, many existing therapies treat the symptoms, but do not affect a permanent cure. Thus, there is a need for an improved therapy that is more effective, safer, and can be tolerated by more patients than existing treatments.

The utility of a cationic poly(b-amino ester)polymer, C32, for delivering DNA encoding a diphtheria toxin suicide gene (DT-A) to subcutaneous tumors derived from human prostate cancer cells in mice, resulting in tumor growth suppression. This study, as well as others, suggests the potential therapeutic value of targeting suicide gene expression to the enlarged prostate and to prostate tumor cells.

To further explore this potential, in this study, we used nanoparticles to deliver DT-A to normal prostate and prostate tumors in mice. In contrast to the earlier xenograft studies, this study tests efficacy of this potential therapy to kill cells within the prostate microenvironment. One advantage of suicide DNA-based therapy, as compared to other therapies, is that, in addition to delivering DNA to a specific site, cell-specific promoters can be used to regulate gene expression, resulting in the death of targeted cell populations, and the preservation of healthy tissue that is in close proximity to the targeted cells. In this study, a prostate-specific modified human PSA promoter, PSEBC [7], is used to regulate DT-A expression. The extensive apoptosis observed in prostate epithelial cells and prostate tumors, but not in surrounding tissues, following local injection of nanoparticle-delivered PSA/DT-A DNA suggests that this strategy may have application in the treatment of and prostate cancer.

Nanovectors

Intravascularly injectable nanovectors are a class of nanotechnological devices used in cancer. Their envisioned use is for the in vivo, non-invasive  visualization of molecular markers of early stages of disease; the targeted delivery of therapeutic agents, with a concurrent, substantial reduction of deleterious side effects; and the interception and containment of lesions before they reach the lethal or even the malignant phenotype, with minimal or no concurrent loss of quality of life.

Liposomes are the simplest form of a nanovector that use the overexpression of fenestrations in cancer neovasculature to increase drug concentration at tumour sites. They are only the first in an ever-growing number of nanovectors under development for novel, more efficacious drug-delivery modalities. Liposome-encapsulated formulations of doxorubicin were approved 10 years ago for the treatment of Kaposi’s sarcoma, and are now used to treat breast cancer and refractory ovarian cancer.

Nanovectors in general have at least a tripartite constitution, featuring a core constituent material, a therapeutic and/or imaging payload, and biological surface modifiers, which enhance the biodistribution and tumour targeting of the nanoparticle dispersion (as seen in the figure). The figure shows the final stage of the intravenous journey with the arrival of a nanocarrier which is about 100 times smaller than a strand of hair and its payload of anti-cancer medication.

A major clinical advantage sought by the use of nanovectors over simple immunotargeted drugs is the specific delivery of large amounts of therapeutic or imaging agents per targeting biorecognition event. Targeting methods that have been investigated range from covalently linked antibodies to mechanisms based on the size and physical properties of the nanovector. Nanovectors are designed to reduce the clearance time of small peptide drugs, provide protection of active agents from enzymatic or environmental degradation, and avoid obstacles such as protective exclusion by the blood–brain barrier or the vascular endothelium or osmotic pressure states in cancer lesions to the targeting of the active moiety. The exclusion or the augmented osmotic pressure can result in outward convection of the therapeutic moiety and nanoparticle sequestration by the Reticulo-Endothelial System (RES).

The nanovectors act as carriers for the therapeutic and imaging payloads, or their constituent materials might also possess image-enhancement properties, such as in the case for iron oxide for MRI, and semiconductor nanocrystals or quantum dots for optical imaging.

Many polymer-based vectors have been investigated and seem most promising for clinical translation. For instance, dendrimers are self-assembling synthetic polymers with exquisitely tunable nanoscale dimensions, which were recently used for the MRI of the lymphatic drainage in a mouse model of breast cancer. This indicates that dendimer-based contrast agents might be

used to non-invasively detect cancer cells in the lymph nodes in patients, to provide early signals of disease, or information about patterns

of metastatic spread.

Silicon and silica are emerging as interesting candidate materials for injectable nanovectors. Porosified silicon is biodegradable, with kinetics that are much more rapid (minutes to hours) than those of biodegradable polymers (weeks to months), and therefore release drugs with previously unattainable

time profiles.

Metal-based nanovectors include nanoshells, which comprise a gold layer over a silica core. The thickness of the gold layer can be precisely tuned, so that the nanoshell can be selectively activated through tissue irradiation with near-infrared light to perform localized therapeutic thermal ablation.

Thus the nanovectors can be used as highly selective, externally activated therapeutic agents. It is estimated that several thousand different nanovector types have been reported in the literature. Just a minute fraction of their potential uses against cancer have been explored, yet these offer technological foundations for meeting the fundamental cancer nanotechnology challenges.

Nanotechnology: Anti-Cancer Therapy For Breast Cancer – Part 3

A fine tuning between size, shape and surface physico-chemical properties can lead to a precise control of the particulate behavior in terms of margination dynamics, vascular adhesion and internalization, and mathematical modeling can lead to define Design Maps, which can help predict particle behavior and drive particle development. These study clearly suggests that the geometry of the delivery carriers is one of critical determinant for their behavior in the circulation. In conclusion, it is evident that anti-cancer therapy certainly needs a breakthrough to eradicate cancer related death. Nanotechnology is one of the growing fields in medical science with a promise to address long standing clinical issues. There are an overwhelming number of distinct nanoparticles that have been developed which vary with respect to many properties, such as particle size, shape, charge, surface modification, and drug payload/therapeutic effect. The future challenges in the successful clinical applications of nanotechnology based drug delivery are not the lack of novel technologies, it is rather the need to identify favorable physio-chemical properties that will allow injectable nanovectors to overcome multiple barriers.

Nanotechnology: Anti-Cancer Therapy For Breast Cancer – Part 2

While basic and clinical science have revealed and identified multiple problems that cause a reduction of therapeutic efficacy of systemic chemo and immunotherapy for breast cancer, numerous new nanotechnology-based drug delivery platforms have been tested to address these unmet clinical problems. Though nanomedicine holds great promise, there are still multiple challenges in order to bring this novel technology to the clinic. In particular, controlling the biodistribution of nanoparticulates in vivo and the avoidance of biological barriers are two of the most important challenges. The third generation of particulate systems can help in addressing these challenges. The main advantage of these over the previous generations relies on their modularity: each stage is dedicated to a specific function and can be rationally designed to execute that specific function with superior performances. For a multi-stage third generation particulate, the 1st stage particulate is designed to navigate into the circulatory system, avoid or limit the recognition from the cells of the immune system and accumulate with higher percentage in the organs of interest; whereas the 2nd stage particulates, loaded within the 1st stage, are designed to diffuse within the organ of interest, interact specifically with the target cells and release their payload. Clearly the functions of the two particulates are different and their geometrical and physico-chemical properties should be different so that the 1st stage could be optimally designed for vascular targeting, whereas the 2nd stage would be optimally designed for extravascular targeting. Obviously the whole delivery process can be broken down into more steps (specific functions), meaning more stages, leading to fully multiple stage particulate systems.

The work of Decuzzi and Ferrari over the past years has shown how the behavior of particulate systems can be fine tuned not only by tailoring their surface physico-chemical properties (decoration with ligand molecules; polymeric coating with PEG) but also controlling their geometrical properties, as size and shape. These three engineering parameters (size, shape and physico-chemistry) play a crucial role in particulate (i) transport within the circulation and in the tissue; (ii) recognition of vascular and extravascular targets; (iii) interaction with target cells and cells of the immune system; and can be tailored during the fabrication and synthesis process with great accuracy. Particles with nonspherical shapes have been shown to drift laterally towards the vessel walls in capillary flows, mimicking the behavior of platelets, and by doing so the likelihood of recognition of specific biological targets in the vasculature can be significantly increased. Non-spherical particles have been shown to adhere more strongly to the vessel walls under flow, and in particular for oblate spheroidal particles it has been estimated an increased of about 50 times in the deliverable payload compared to classical spherical particles with the same strength of adhesion. Nonspherical particles have been also shown to resist more internalization, so that can adhere to cells of the vessel wall without being internalized while releasing their payloads.

Nanotechnology: Anti-Cancer Therapy For Breast Cancer

Application of nanotechnology to medical science has been emerging as a new field of interdisciplinary research among medicine, biology, toxicology, pharmacology, chemistry, material science, engineering, and mathematics, and is expected to bring a major breakthrough to address unsolved medical issues. The delivery strategy of these vectors is based on enhanced permeation and retention (EPR) effect ; the circulating vector accumulates in the tumor mass over time because it is sufficiently small (<300 nm) to extravasate by crossing passively the fenestrations in the diseased vasculature (passive targeting). In addition to liposomal doxorubicin, albumin-bound paclitaxel (Abraxane ®) is another example of an EPR based nanovector application for breast cancer chemotherapy.

Paclitaxel is highly hydrophobic and dissolved in cremophor to prevent paclitaxel precipitation. However, according to Liebmancn et al. 1993, cremophor-associated toxicities are severe (hypersensitivity reaction and neurotoxicity) and challenge the application of paclitaxel. Albumin-bound paclitaxel was developed to improve the solubility of paclitaxel. This formulation improves the toxicity profile of conventional paclitaxel therapy formulated with cremophor (Nyman et al. 2005). These vectors are not specifically targeted against any molecule expressed on the tumor cells or the endothelium and have been classified as ‘first generation’ vectors [6] . The ‘second generation’ of therapeutic nanovectors evolved to be able to recognize and target specific biological molecules on the surface of the cancer cells (active targeting). Such application will promise to improve therapeutic window to delivery higher concentration to diseased lesion, while reducing life-threatening systemic cytotoxicity. This can be achieved by chemical coupling of high affinity ligand, such as Arg–Gly–Asp (RGD), folate, prostate specific membrane antigen , on the surface of the nanoparticles, and it facilitates the interaction of nanoparticles and cancer cells, resulting in a dramatic improvement of the biodistribution of nanoparticles compared to the non-targeted first generation nanovectors. We are currently developing a ‘third generation’ of nanovectors , which relies on a multi-stage strategy and is characterized as a carrier for nanoparticles and a higher level of multi-functional integration. Biodegradable mesoporous silicon microparticles (1st stage) can be loaded with one or multiple types of nanoparticles (2nd stage) containing different types of payloads, both for therapy and imaging (Figure 2). The 1st stage particle is designed to navigate within the circulatory system and to recognize specifically the diseased endothelium through a judicious (mathematically driven) choice of its geometrical (size, shape) and surface physico-chemical properties. The 2nd stage nanoparticles within the pores of the 1st stage, are released towards the tumor mass from the site of vascular adhesion (tumor endothelium) as the 1st stage degrades over time. The 2nd stage nanoparticles are sufficiently small (<20 nm) to easily cross the inter-endothelial junctions and diffuse within the extravascular compartment. The delivery strategy of the third generation vectors does not rely on the EPR effect, in that the 1st stage particles are directed towards the vascular endothelium and the 2nd stage particles pass the fenestrations. The modularity of the third generation vectors presents a powerful tool to address multiple unmet medical issues, with a focus of development of multifunctional and multimodal therapies.

Breast Cancer

The global incidence and mortality of breast cancer remains high despite extraordinary progress
in understanding the molecular mechanisms underlying carcinogenesis, tumor promotion, and
the establishment of molecular targeted therapies. Worldwide, 1,301,867 new cases of breast
cancer were diagnosed, 464,854 deaths were caused by breast cancer, and more than 4.4 million
women were diagnosed with breast cancer in 2007. The estimated national number of newly
diagnosed cases in the United States in 2008 is 182,460 with an expected death toll of 40,480
(Jemal et al. 2007). Since 1990, there has been an overall increase in breast cancer incidence
rates of about 1.5% annually.
Breast cancer detection involves examination (self, clinical) and radiography (Mammography,
Positron Emission Tomography (PET), MRI) followed by invasive biopsy for the histological
confirmation of invasive disease. The development of mammography has greatly increased the
likelihood of early detection of breast cancer, and randomized clinical trials have demonstrated
a 30% reduction in breast cancer mortality in women age 50–69, who are screened annually
with mammography (Elwood et al. 1993; Kerlikowske 1997). Although early detection of breast
cancer by mammography is associated with less invasive surgical procedures and may increase
survival, the 5-year survival rate of metastatic breast cancer (stage IV) is still below 15%
(www.cancer.org). Thus, the development of effective therapies against invasive breast cancer
and particularly highly metastatic disease still remains a significant priority. The treatment
of primary breast cancer has mainly relied upon initial surgical intervention (lumpectomy, or
partial/total mastectomy) followed by radiation and various forms of systemic adjuvant therapy
including cytotoxic chemotherapy, hormonal therapy, and most recently immunotherapy (e.g.
trastuzumab).
Generally, breast tumors are categorized into four different stages based upon their size, location,
and evidence of metastasis. Treatment options are also determined by the stage, hormone and
human epidermal growth factor receptor 2 (HER-2/neu) status of breast tumors. Over the past
30 years, many novel drugs have been developed for controlling breast cancer growth, and these
drugs have shown significant clinical benefits in some cases of breast cancer. Approximately
65% of breast tumors demonstrate hormone receptor positivity and therefore the most
common breast cancer therapies today are hormonal therapies (e.g. selective estrogen receptor
modulators (SERMs), and aromatase inhibitors). Additional therapies include chemotherapy (e.g.
anthracyclines and taxanes), often used in combinations and immunotherapies (e.g. trastuzumab).

Nanotechnology in Cancer

In an ideal scenario, the onset of the transformational processes leading towards malignancy would be detected early, as a matter of routine screening, by non-invasive means such as proteomic pattern analysis from blood samples, or the in vivo imaging of molecular profiles and evolving lesion contours. The biology of the host and the disease would be accurately determined, and dictate choices for targeting and barrier-avoiding strategies for an intervention plan. Transforming cellular populations would be eradicated or contained, without collateral effects on healthy tissues, in a routine that could be repeated many times. Treatment efficacy would be monitored in real time. Therapeutics would be supplanted by personalized prevention. If fully integrated with the established cancer research enterprise, nanotechnology might help this vision become reality. Nanotechnology concerns the study of devices that are themselves or have essential components in the 1–1,000 nm dimensional range (from a few atoms to subcellular size). Cancer nanotechnology has two main subfields of nanotechnology are nanovectors (administration of targeted therapeutic) and imaging moieties.

As nanotechnological applications in the field of medical science have expanded rapidly towards multiple directions in the past 10 years, the definition of nanotechnology has been broadened. There are four ingredients are necessary to identify a nanotechnology tool:

• the characteristic size of the device has to be nano
• the device has to be man-made
• the device has to exhibit properties that only arise because of the nanoscopic dimensions
• the peculiar behavior of the device has to be predictable through the construction of appropriate mathematical models.

Many different types of nano-delivery systems with different materials and physio-chemical properties have been developed for application to different diseases. Most well studied among these are liposomes, polymer-based platforms, dendrimers, gold nanoshells, nanocrystal, carbon-60 fullerenes, silicon- and silica-based nanoparticle and super paramagnetic nanoparticulates. An excellent example that nanotechnology has already achieved in the field of medicine is liposomal drug delivery. Several different formulations of liposomal doxorubicin have successfully been used in the clinic for the treatment of breast, ovarian, and Kaposi sarcoma (Di Paolo 2004).

Various liposomal doxorubicin formulations were developed in an effort to improve the therapeutic index of the conventional doxorubicin chemotherapy while maintaining its anti-tumor activity. For example, the efficacy of three liposomal doxorubicins are currently being used: liposomal daunorubicin (DaunoXome), liposomal doxorubicin (D-99, Myocet™), and pegylated liposomal doxorubicin (Doxil) marketed and distributed in the U.S. and Caelyx® distributed outside the U.S.). Generally, these agents exhibit efficacies comparable to those of conventional doxorubicin, except with better safety profiles and less cardiotoxicity.

Side Effects of Conventional Therapies

Most tumors, including breast cancer, are treated with a combination chemotherapy strategy with the common addition of biological agents that demonstrate synergistic or additive effects by multiple mechanisms. Even though chemo and adjuvant therapies have proven their efficacy, side effects associated with these therapies are serious and sometimes even lives threatening. The known side effects of chemotherapy are caused by the cell killing effect of such agents. This derives from the fundamental phenomenon that available cytotoxic agents are not selective in their activity, and therefore non-specifically damage normal replicating cells in the bone marrow, gastrointestinal epithelia, and hair follicles. For example, acute toxicities associated with conventional doxorubicin include myelosuppression, nausea, vomiting, mucositis, and alopecia. The most serious, conventional doxorubicin induced toxicity is irreversible congestive heart failure (Von Hoff et al. 1979). Tamoxifen is also associated with serious side effects and complications including an increased risk for endometrial cancer by 2.4 times in women aged 50 years or older (Fisher et al. 2005) and thromboembolic disease by 1.9 times (Cuzick et al. 2003).

Targeted therapies showed significantly positive effect as evidenced by multiple clinical studies, however, even these targeted therapies caused serious side effects. Trastuzumab alone or in combination with chemotherapy may cause serious heart problems including ventricular dysfunction and congestive heart failure in addition to common flu-like symptoms (Slamon et al. 2001). Therefore, the development of a novel treatment strategy including selective delivery of cytotoxic agents to tumor mass for the treatment of advanced breast cancer is critical to improving the therapeutic index and efficacy/toxicity balances.

Cancer Therapies Overview

Cancer Therapies

Some conventional anti–cancer therapies include Immunotherapy, Hormone Therapy and Chemotherapy along with surgery.

Surgery:

Certain types of cancer are treated most effectively by simply removing the tumor surgically. Surgery is the oldest form of treating cancer and can also have an important role in diagnosing and staging of cancer. Surgery is done for many reasons, often to accomplish one or more of these goals: preventative (prophylactic), diagnostic, staging, curative , cytoreductive, palliative, supportive  and reconstructive surgery.

Immunotherapy:

Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient’s immune system to attack the malignant tumor cells that are responsible for the disease. This can be either through immunization of the patient, in which case the patient’s own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient’s immune system is recruited to destroy tumor cells by the therapeutic antibodies.

Since the immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self, many kinds of tumor cells that arise as a result of the onset of cancer are more or less tolerated by the patient’s own immune system since the tumor cells are essentially the patient’s own cells that are growing, dividing and spreading without proper regulatory control.In spite of this fact, however, many kinds of tumor cells display unusual antigens that are either inappropriate for the cell type and/or its environment, or are only normally present during the organisms’ development (e.g. fetal antigens). Examples of such antigens include the glycosphingolipid GD2, a disialoganglioside that is normally only expressed at a significant level on the outer surface membranes of neuronal cells, where its exposure to the immune system is limited by the blood-brain barrier. GD2 is expressed on the surfaces of a wide range of tumor cells including neuroblastoma, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas and other soft tissue sarcomas. GD2 is thus a convenient tumor-specific target for immunotherapies. Other kinds of tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signal transduction pathways that cause the unregulated growth and division of the tumor cell. e.g. ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of breast cancer tumor cells.

Hormone therapy

This can be used to target specific hormones in males for prostrate cancer and breast cancer in women. Hormone therapy, also known as androgen deprivation therapy, is the use of drugs or surgery to decrease the production of male hormones, or androgens, in order to stop or limit the growth of prostate cancer. Prostate cancer is hormone-sensitive or hormone-dependent, meaning that prostate cancer growth depends on androgens, particularly testosterone. The goal of hormone therapy is to dramatically reduce testosterone levels in the blood, thus slowing the rate of prostate cancer cell growth. Hormone therapy is the primary treatment for prostate cancer that has spread beyond the prostate gland to distant sites, including lymph nodes, bone and other organs.

With breast cancer, the female hormones estrogen and progesterone can promote the growth of some breast cancer cells. So in these patients, hormone therapy is given to block the body’s naturally occurring estrogen and fight the cancer’s growth. There are two types of hormone therapy for breast cancer: drugs that inhibit estrogen and progesterone from promoting breast cancer cell growth  and those used to turn off the production of hormones from the ovaries. Hormone therapy for cancer treatment stops hormones from getting to cancer cells.

Systemic Chemotherapy

Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells by impeding their growth and reproduction. These drugs often are called “anticancer” drugs. Chemotherapy drugs are given intravenously, by injection or by mouth. Chemotherapy is often used alone, or in conjunction with radiation therapy or surgery. Most of the patients can be treated with immune or hormone therapy, however, the remaining 10–15% of (breast) cancers comprise a “receptor-negative’ or “triplenegative”category defined by the absence of expression of the receptor proteins. The triple negative breast cancer is highly proliferative and aggressive with poor prognosis due to a lack of specific treatment guidelines, and therefore, triple-negative breast cancers are managed with standard chemotherapy .Unfortunately, such treatment is associated with high rates of local and systemic recurrence. The combination docetaxel/capecitabine has shown survival advantages when compared to single agent docetaxel suggesting that the combination regimen may show a superior benefit.

What is Oncology?

Oncology is the branch of medicine concerned with the study, diagnosis, treatment, and prevention of malignant neoplasm (cancer), where a group of cells display uncontrolled division, invasion (adjacent tissues), and metastasis (spread to other locations via lymph or blood). These features differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, e.g. leukemia, don’t. Cancer may affect people at all ages, even fetuses, but the risk for most varieties increases with age. Cancer causes about 13% of all deaths; 7.6 million people die from this disease in the world, annually [1].

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or congenital. Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against apoptosis, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are then inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Cancer can be classified by the cell type (therefore the tissue) presumed to be the origin. Examples of general categories include:

• Carcinoma: Malignant tumors derived from epithelial cells; including breast, prostate, lung and colon cancer
• Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells
• Lymphoma and leukemia: Malignancies derived from hematopoietic cells
• Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull)
• Blastoma: resembles an immature or embryonic tissue

Diagnosis of this disease usually requires the histological examination of a tissue biopsy specimen; most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, the cancer is usually treated with a combination of surgery, chemotherapy etc. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.