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Some of the most interesting applications of nanotechnologies and nanoscience are certainly that applied in medicine: the nanoscale is the natural scale of all fundamental life processes, the scale at which diseases need to be met and conquered.
Among the disease that affects mankind, cancer is surely one of the worst ones.
This work is divided into two chapters.
Chapter I presents an introduction to the subject of the work, answering questions such as: "What is a tumor?", "What are its causes?", and so on; it also contains the hallmarks of cancer, as studied by D. Hanahan and Robert A. Weinberg/.
Another section presents the approaches used today to prevent, control and cure cancer: a brief analysis of the existing therapeutic and diagnostic technologies, together with the negative aspects related to the undesirable side effects they may cause on people.
The purpose of Chapter II is to understand what level has nanomedical research reached today, what are the therapeutic approaches that have just reached the clinic and what we could expect from tomorrow.
The first section deals with the evolution of cancer studies, from the substitution of old, static models of the disease with newer, more complex ones, to the hypothesis of future dynamic models capable of describing the disease in all its evolving properties.
The second section explores how medical methods have changed thanks to the innovations introduced by nanoscience and nanotechnology (from drug delivery to photodynamic therapy, from protein engineering to the introduction of quantum dots, and so on) and how these innovations work.
Every innovation will be treated separately to better understand its importance and to permit an effective comparison with the other ones.
Tumor: an Introduction
What is Tumor?
Tumor is a group of diseases characterized by uncontrolled growth and spread of abnormal cells, caused by both external factors (tobacco, chemicals, radiation, and infectious organisms) and internal factors (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism) that act together or in sequence to initiate or promote carcinogenesis.
The development of most tumors requires multiple steps that occur over many years, but usually they grow following a geometric law: at first the growth is very slow, and then it accelerates with the increasing of the tumorous mass. The critical size of the mass is about 1 cm3: when the tumor reaches this size, it begins to grow very quickly and it becomes detectable by medical examinations; at this step the first symptoms appear, but they are often ignored or underestimated: if the spread is not controlled, it can result in death.
In fact, a tumor may have different outcome, depending on the characteristics of mutated cells; in particular: it is called "cancer" when it presents infiltrating characteristics, it is composed by cells morphologically very different from the basic one and it often recurs after surgical resection; it is defined as "tumor" when it presents only expansive characteristics (thus causing pain from compression), a cellular morphology simile to that of the basic cell and a low recurrence rate after surgical excision; moreover, a tumor is defined "borderline" if it presents an intermediate behavior between tumor and cancer: the frequency of metastasis is generally very low and the course is slow. The branch of medicine which deals with the study of tumor is the "oncology".
New Cancer Cases and Deaths
One in eight deaths worldwide is due to cancer: cancer causes more deaths than AIDS, tuberculosis, and malaria combined. It is the second leading cause of death in economically developed countries (following heart diseases) and the third leading cause of death in developing countries (following heart diseases and diarrhoeal diseases). (Table 1).
Leading causes of death worldwide and in developing and developed countries -2001- (in thousands)
Cause of death
In 2007 there were more than 12 million new cancer cases worldwide, of which 5.4 million occurred in economically developed countries and 6.7 million in economically developing countries; the corresponding estimates for total cancer deaths in 2007 are 7.6 million (about 20,000 cancer deaths a day), 2.9 million in economically developed countries and 4.7 million in economically developing countries (figure 1).
The American Cancer Society estimates that in 2010 about 171,000 cancer deaths have been caused by tobacco use alone. In addition, approximately one-third (188,000) of the 569,490 cancer deaths expected to occur in 2010 are attributed to poor nutrition, physical inactivity, overweight, and obesity; 68,130 new cases of melanoma have been diagnosed in 2010 and more than 2 million basal cell and squamous cell skin cancers are diagnosed annually. Most skin cancer deaths are due to melanoma (8,700 deaths in 2010).
By 2050, the global burden is expected to grow to 27 million new cancer cases and 17.5 million cancer deaths simply due to the growth and aging of the population.
Trends in Cancer Incidence and Mortality
The burden of cancer is increasing in developing countries as childhood mortality and deaths from infectious diseases decline and more people live to older ages (in economically developed countries, 78% of all newly diagnosed cancer cases occur at age 55 and older, compared with 58% in developing countries). Further, as people in developing countries adopt western lifestyle behaviors, such as cigarette smoking, higher consumption of saturated fat and calorie-dense foods, and reduced physical activity, rates of cancers common in western countries will rise if preventive measures are not widely applied; on the other hand, several major cancers linked to chronic infectious conditions become less common as countries become economically developed. Nowadays, approximately 15% of all incident cancers worldwide are attributable to infections. This percentage is about three times higher in developing countries (26%) than in developed countries (8%) (figure 2).
Can Cancer be Prevented?
It is estimated that more than a half of all new cancers and cancer deaths worldwide are potentially preventable. Cancers related to tobacco use, heavy use of alcohol, and obesity are most effectively prevented through a combination of education and social policies; certain cancers that are related to infectious agents (hepatitis B - HBV, human immunodeficiency virus - HIV, human papilloma virus - HPV, and helicobacter pylori - H. pylori), could be prevented through vaccines, antibiotics, improved sanitation and education; some other cancers can be avoided by detection and removal of pre-cancerous lesions through regular screening examinations.
Early detection of cancer is important, as it provides a greater chance that treatment will be successful: screening and early treatment services have been proven to be effective in reducing the severity of disease and mortality, but they are not available in developing countries because of limited resources.
Interventions for Cancer Prevention and Control
A balanced approach to cancer control includes prevention, early detection and effective treatment. Successful national cancer control policies and programs raise awareness of cancer, reduce exposure to cancer risk factors, provide information and support for the adoption of healthy lifestyles, and increase the proportion of cancers detected early. For developing national strategies for the control of cancer, countries should consider the following four broad approaches:
The goal of primary prevention is to reduce or eliminate exposure to cancer-causing factors, which include modifiable factors related to tobacco use, nutrition, physical inactivity, occupational exposures, and chronic infections. Primary prevention offers the greatest public health potential and the most cost-effective long-term method of cancer control. Approaches to primary prevention include: immunization against, or treatment of, infectious agents that cause certain cancers; application of effective tobacco control measures; reduction of excessive alcohol consumption; maintenance of healthy body weight and physically active lifestyles; dietary intervention; sun/UV avoidance; reduction in occupational exposure to carcinogens; and pharmacological intervention.
Early Detection and Secondary Prevention
The main objective of early detection or secondary prevention through screening is to detect pre-cancerous changes or early stage cancers when they can be treated most effectively. Early detection is only valuable if it leads to timely diagnostic follow up and effective treatment.
There are two strategies for early detection:
1) opportunistic screening requested sporadically by a physician or an individual;
2) organized screening in which a defined population is contacted and invited to be screened at regular intervals.
Diagnosis and Treatment
Cancer diagnosis, including careful clinical and pathological assessments, is the first step to cancer management. Once a diagnosis is confirmed, it is necessary to determine cancer stage, where the main goals are to aid in the choice of therapy, to determine prognosis, and to standardize the design of research treatment protocols. The primary modalities of cancer treatment are surgery, chemotherapy, and radiotherapy; these may be used alone or in combination. There is increasing emphasis worldwide on the development of specialized cancer centers that apply evidence-based multimodal therapies, and provide rehabilitation and palliative care.
The most basic approach to palliative care for terminally ill cancer patients, especially in low-resource settings, involves using inexpensive oral analgesics, ranging from aspirin to opiates, depending on individual patients' needs, but unfortunately, sufficient supplies of opioid drugs for use in palliative care are often not available in developing countries because of regulatory or pricing obstacles, lack of knowledge, or false beliefs.
What are the Costs of Cancer?
In addition to the human toll of cancer, its financial cost is substantial: the direct costs include payments and resources used for treatment, as well as the costs of care and rehabilitation related to the illness; indirect costs include the loss of economic output due to days missed from work (morbidity costs) and premature death (mortality costs). There are also hidden costs of cancer, such as health insurance premiums and nonmedical expenses (transportation, child or elder care, housekeeping assistance, wigs, etc.).
However, data limitations do not allow estimating the worldwide economic costs of cancer; moreover, they are staggering, depending on the demographic evolution of the population.
Statistics, data and figures by Cancer Facts & Figures - 2010 
The Hallmarks of Cancer
D. Hanahan and Robert A. Weinberg supposed that the genotype of cancer cells is the manifestation of eight fundamental changes in cellular physiology (The hallmarks of cancer, The hallmarks of cancer - The next generation): self-sufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, reprogramming energy metabolism and avoiding immune destruction.
Each of these physiologic changes, new abilities acquired during tumor progression, represents the violation of an anti-cancer defense mechanism wired in normal tissues and cells.
The acquisition of these traits is made possible by two enabling characteristics: the development of genomic instability in cancer cells and the inflammation of pre-malignant and malignant lesions
Self-Sufficiency in Growth Signals
Normal cells need mitogenic growth signals to switch from quiescence to a proliferative state; cancer cells, on the contrary, show an extremely reduced dependence upon exogenous growth stimulation: they generate autonomously many of their own growth-signals, disrupting an homeostatic mechanism that operates to ensure a correct behavior of the different cells types within a tissue. Cancer cells can also switch the extracellular matrix receptors (the integrins) they express, favoring those who transmit pro-growth signals.
According to various evidence, it's likely that cell-to-cell growth signaling operates in the vast majority of human cancer, which are all composed by different types of cells that communicate through heterotypic signaling: cancer cells are successful if they succeed in inducing the nearby normal cells to release pro-growth signals.
Insensitivity to Antigrowth Signals
In normal tissues, multiple anti-proliferative signals operates to maintain cellular quiescence and tissues homeostasis; these signals can block proliferation through two different mechanism: cells can be forced to switch from the proliferative state to the quiescent one, or they can be induced to renounce permanently to their proliferative potential. Pre-cancerous cells must evade this signals if they want to survive.
At the molecular level, maybe all anti-proliferative signals are channeled through retinoblastoma protein (pRb), that blocks proliferation when in a hypophosphorylated state. Disruption of the pRb pathway renders cells insensitive to antigrowth factors.
Furthermore, cancer cells can turn off the expression of integrins, limiting anti-growth signals and favoring instead molecules that send pro-growth signals.
During apoptosis (programmed cell death), cellular membranes are destroyed, the cytosol is extruded, the nucleus is fragmented and the chromosomes are degraded: the dead cell is engulfed by nearby cells and it disappears.
The biopsy of different stages in human carcinogenesis shows that cancer cells acquire resistance against apoptosis, using different methods: the most important is surely the loss of the pro-apoptotic regulator p53, a tumor suppressor gene, with the consequent inactivation of its product, the p53 protein; this, in turn, causes the removal of a key component of the DNA damage sensor that induce apoptosis.
Limitless Replicative Potential
All cells carry an intrinsic program that limits their multiplication: normally, after they progress through a certain number of division, they stop growing, entering into a senescence state. However, some cells can bypass senescence, disabling some tumor-suppressor proteins, and can continue to replicate for additional generations, until they reach the crisis state. This state is characterized by massive cell death, chromosomes fusions and occasional appearances of a variant cell (1 out of 107) that acquires the capability of limitless replication (immortalization).
Many cancer cells seem to be immortalized: during tumor progression, pre-malignant cells exhaust allowed doublings and can develop their hallmarks capabilities only by reaching immortalization.
The counting device of cells generations is represented by the ends of chromosomes, telomeres: at the end of each cellular cycle, telomeric DNA loses 50-100 bp. The progressive shortening of telomeres eventually causes their inability to protect the end of chromosomal DNA, which hence participates in the fusion with the other chromosomal ends, leading to cells death.
On the contrary, almost all types of cancer maintain telomeres by upregulate expression of the telomerase enzyme or by starting recombination-based interchromosomal exchanges of sequence information.
Cell survival is based upon the oxygen and nutrients supplied by the vasculature: cells are obliged to reside within 100 Î¼m of a capillary blood vessel: at first, this closeness is ensured by the coordinated growth of vasculature and parenchyma, and then angiogenesis is regulated minutely.
Vascular endothelial growth factors (VEGF) and acidic and basic fibroblast growth factors (FGF1/2) initializes angiogenesis, while integrins signals contribute to this regulator balance.
In order to progress, incipient tumor must develop angiogenic ability, changing the balance between angiogenic inducers and inhibitors, often through alteration in gene transcription; however, some evidence suggests that different cells use diverse molecular strategies to activate angiogenesis, making research really difficult.
Tissue Invasion and Metastasis
During cancer progression, primary tumor masses produce pioneer cells that invade nearby tissues, where space and nutrients are not limiting, and base new settlement, the metastasis, that cause 90% of human cancer deaths. These metastasis arise as amalgams of cancer cells and normal supporting cells conscripted from the host tissue.
Invasion and metastasis are two exceedingly complex and closely connected processes, that use similar operational strategies, involving changes in the physical coupling of cells to their microenvironment and activation of extracellular proteases: different proteins involved in cell-to-environment tethering, such as cell-cell adhesion molecules (CAMs) and integrins, are altered in cells with invasive or metastatic abilities.
Reprogramming Energy Metabolism
Under aerobic conditions, normal cells process glucose, first to pyruvate via glycolysis in the cytosol and thereafter to CO2 in the mitochondria; under anaerobic conditions, glycolysis is favored and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria.
It seems that even in the presence of oxygen, cancer cells reprogram their glucose metabolism to promote glycolysis (aerobic glycolysis), by upregulating glucose transporter, maybe in order to facilitate macromolecules and organelles biosynthesis for assembling new cells.
Avoiding Immune Destruction
The theory of immune surveillance proposes that the immune system continuously monitors cells and tissues to recognize and eliminate incipient tumors: following this rationale, solid tumor that do appear have managed to avoid destruction.
In immunecompetent subjects, immunogenic cancer cells are routinely eliminated, leaving only weakly variants that can colonize both immunedeficient and immunecompetent hosts; on the contrary, if this type of cells grows in immunedeficient subjects, the immune system does not eliminate them, and if they are transplanted into syngeneic recipients, they are rejected when they confront, for the first time, the competent immune systems of their secondary hosts.
Recently, an increasing body of evidence suggests that the immune system operates as a barrier to tumor formation and progression, at least in some forms of non-virus induced cancer.
Nowadays it is clear that every neoplastic lesion contains immune cells at different densities. Historically, it was thought that these cells were an attempt to fight cancer, while by 2000 there are evidence that the tumor-associated inflammatory response paradoxically improves tumor genesis and progression, by providing bioactive molecules to the tumor microenvironment. Moreover, inflammatory cells can release chemicals, actively mutagenic for nearby cancer cells, accelerating their genetic evolution toward malignancy.
Genome Instability and Mutation
The acquisition of hallmark capabilities depends on how alterations in cancer cells genome proceed: mutant genotypes confer selective advantages to sub-clonal cells, leading to their dominance in local tissue environment.
During tumor progression, cancer cells often increase mutation rate by amplifying their sensibility to mutagenic agents or by disrupting the function of one or several components of the genomic maintenance machinery; among these, the most important one is TP53: it activates the retrieval of damaged DNA, blocks cell cycle and induces senescence or apoptosis if the damage is irreparable. Also the loss of telomeric DNA generates karyotypic disorder, depicting telomerase as an essential caretaker of genome integrity.
Importantly, the recurrence of specific aberrations at particular sites in the genome indicates that such sites harbor genes whose alteration favors neoplastic progression.
Figure 3 - The hallmarks of cancer and their therapeutic targeting.
How we Fight Cancer Today
Until now, different technologies have been used to treat cancer, all sharing various drawbacks, between which the most relevant are the side effects they cause on healty tissue :
Surgery is the oldest form of cancer treatment. Advances in surgical techniques have allowed surgeons to operate on a growing number of patients and have good outcomes. When a surgeon has to cut into the body to operate, it is called invasive surgery. Today, operations that involve less cutting and damage to nearby organs and tissues (less invasive surgery) often can be done to remove tumors while saving as much normal tissue and function as possible.
Surgery offers the greatest chance for cure for many types of cancer, especially those that have not spread to other parts of the body.
Surgery can be done for many reasons. Some types of surgery are very minor and may be called procedures, while others are much bigger operations.
The more common types of cancer surgeries are:
preventive-prophylactic surgery, to remove body tissue that is likely to become cancer, even though there are no signs of cancer at the time of the surgery;
diagnostic surgery, to get a tissue sample to identify the specifics of cancer;
staging surgery, to find out how much cancer there is and how far it has spread;
curative surgery, when a tumor is found in only one area, and it is likely that all of the tumor can be removed;
debulking-cytoreductive surgery, to remove some of the tumor when removing all of it would cause too much damage to an organ or nearby tissues;
palliative surgery, to treat problems caused by advanced cancer and to reduce patient's pain;
supportive surgery, to help with other types of treatment;
restorative-reconstructive surgery, to improve the way a person looks after major cancer surgery, or to restore the function of an organ or body part after surgery.
Chemotherapy is the use of strong drugs to treat cancer. There are more than 100 chemo drugs used today. Doctors choose certain types of drugs based on the stage of cancer growth. Chemo can be used for different reasons: to keep the cancer from spreading, to slow the cancer's growth, to kill cancer cells that may have spread to other parts of the body, to relieve symptoms caused by cancer or to cure it.
Chemo is often used to fight cancers that have spread to other parts of the body (metastasized), and it works to kill any cell that is growing fast, whether it's a cancer cell or not. So, some of the normal, healthy cells that grow quickly can be damaged. This can cause side effects, but some people have no side effects at all; for most people, side effects will go away in time after their treatment ends. How long that will take is different for each person. Some side effects can take longer to go away than others or they might not go away at all.
The most common ones are nausea and vomiting, hair loss, bone marrow changes, mouth and skin, memory or emotional changes, fertility problems, but they could be prevented or reduced in part.
Radiation therapy uses high-energy radiation to kill cancer cells by damaging their DNA, but it can also damage normal cells. Therefore, treatment must be carefully planned to minimize side effects.
The radiation used for cancer treatment may come from a machine outside the body, or it may come from radioactive material placed in the body near tumor cells or injected into the bloodstream.
A patient may receive radiation therapy before, during, or after surgery, depending on the type of cancer being treated. Some patients receive radiation therapy alone, and some receive radiation therapy in combination with chemotherapy.Computed Tomography Scanner
Linear Accelerator Used for External-beam Radiation Therapy
CT scans are often used in treatment planning for radiation therapy.
During CT scanning, pictures of the inside of the body are created by a computer linked to an x-ray machine.
Many types of external-beam radiation therapy areÂ delivered using a machine called a linear accelerator (also called a LINAC). A LINAC uses electricity to form a stream of fast-moving subatomic particles. This creates high-energy radiation that may be used to treat cancer.
Side effects vary from person to person and depend on the radiation dose and the part of the body being treated. The most common early side effects are fatigue (feeling tired) and skin changes. Other early side effects usually are hair loss and mouth problems.
Cryosurgery is a technique for freezing and killing abnormal cells using the extreme cold produced by liquid nitrogen or argon gas. It is used to treat some kinds of cancer and some precancerous or noncancerous conditions, and can be used both on the skin and inside the body, thanks to an instrument called "cryoprobe", which is guided through ultrasound (creating a picture called "sonogram") or MRI and placed in contact with the tumor. After cryosurgery, the frozen tissue thaws and is either naturally absorbed by the body (for internal tumors), or it dissolves and forms a scab (for external tumors).
Cryosurgery offers advantages over other methods of cancer treatment: it is less invasive than surgery, involving only a small incision or insertion of the cryoprobe through the skin. Consequently, pain, bleeding, and other complications of surgery are minimized. It is also less expensive than other treatments and requires shorter recovery time, but it has some side effects (although they may be less severe than those associated with surgery or radiation therapy) that depend on the location of the tumor. It can cause cramping, pain, or bleeding, or scarring and swelling; if nerves are damaged, loss of sensation may occur, and, rarely, it may cause a loss of pigmentation and loss of hair in the treated area.
Cryosurgery may offer an option for treating cancers that are considered inoperable or that do not respond to standard treatments. Furthermore, it can be used for patients who are not good candidates for conventional surgery because of their age or other medical conditions.
The major disadvantage of cryosurgery is the uncertainty surrounding its long-term effectiveness: additional studies are needed to determine the effectiveness of cryosurgery in controlling cancer and improving survival.
a Chance Against Cancer
The New Challenge of the 21st Century
Nowadays, the scientific and technological challenge is to move from models built from phenomenological description of cancer to network models derived from systems biology, and to transform them in a clinically relevant framework, following and understanding the evolution of the disease. To handle this challenge, both diagnostic and therapeutic technologies and strategies with fewer toxic side effects and more beneficial behavior have to be developed.
Many steps toward this goal have already been made: for example, few years ago we only used some drugs because they seemed to work, even if the mechanism was not well understood (and this often led to undesirable side effects), while today many proposed nanodrugs work by well-understood and very specific mechanisms, and this allows science to revolutionize its methods and its base concepts.
At first, the static model of cancer (figure 4-a) has been substituted by cancer pathways (figure 4-b), following the idea that a given type of cancer can be triggered by different genetic mutations, each leading to a different outcome; then, also this model has been recognized as limited, since it requires a prior knowledge that cancer exists (so it doesn't represent a good early detection strategy) and it assumes that a given cancer is homogeneous (which is almost certainly incorrect); nowadays, network models (figure 4-c) have been developed to account the real degree of interconnection among the various genes and proteins which formed the cancer pathways: using deep transcriptome analyses, together with focused proteomic investigations, network models allow scientists to understand the patho-physiology of disease progression at the molecular level and then to develop more informative diagnoses; finally, in the near future, the best cancer model will be the dynamic ones, and the evolving picture of cancer will change both diagnostically (thanks to multiparameter, inexpensive measurement and compu-tational technologies) and therapeutically (with the help of new nanotechnologies for drug encapsulation and delivery).
New Technologies Against Cancer:
Targeted Drug Delivery
Drug delivery can be achieved through three different methods:
Passive targeting is based upon extravasation of the nanoparticles at cancer site, where the microvasculature is leaky due to increased angiogenesis and to the presence of vasoactive permeability-enhancing factors.
Indeed, the majority of solid tumors exhibit a vascular pore cutoff size between 380 and 780 nm, while normal vasculature is impermeable to drug-associated carriers larger than 2 to 4 nm: this fact allows the increase of drug accumulation and local concentration in tumor sites, reducing drug distribution and toxicity to normal tissues.
The success of passive targeting depends upon the extent of time in which nanoparticles circulate in the blood: usually their opsonization by the mononuclear phagocytic system (MPS) limits their circulation half-lives, so their surfaces need to be modified to be "invisible" to MPS. This objective is achieved through PEGylation, a process in which a hydrophilic polymer such as polyethylene glycol (PEG) is covalently attached to the nanoparticles, masking them from the host's immune system thanks to its attributes of low degree immunogenicity and antigenicity. These modified nanoparticles have shown extended circulation half-lives of 45 hours in humans.
Active targeting is made possible by cancer overexpression of some epitopes or receptors used as targets, by coupling ligands that specifically bind to these receptors to long circulating nanoparticles carrying drugs, through covalent or non-covalent couplings.
These active targeting nanocarriers have different advantages over targeting ligand-drug conjugates: they can delivery larger payloads of therapeutic agent relative to number of ligand binding sites (increasing tumor to background ratio in imaging), and numerous ligand molecules can be attached to them (increasing probability of binding to target cells); moreover, the drug is not modified by the coupling with the ligand, since this coupling is established between ligand and nanocarriers; furthermore, active targeting enables more efficient distribution of the carriers in the tumor interstitium and reduces return of drug back to the circulation due to high intratumoral pressure; finally, ligand-nanocarrier conjugates can only extravasate at the disease site due to their size, but not normal vasculature, so the drugs cannot cause side effects because the ligand does not interact with the target epitopes of normal tissues.
Thus, active targeting can enhance the distribution of nanomedicine within the tumor interstitium, or it can be used to deliver drugs into resistant cancer cells.
Nanomedicines with a lower size range are favored in achieving long-circulation half-lives, due to reduced MPS uptake, and more efficient cellular uptake (increased internalization), by phagocytic or non-phagocytic cells or drug-resistant cancer cells.
Nanoscale Systems for Bioimaging and Detection
Nowadays, different imaging techniques (SPECT, PET, MRI, ultrasound, computed tomography, fluorescence microscopy) allow us to carry out in vivo imaging of nanoscale systems containing contrast agents and radiopharmaceutical for imaging: this first step in tumor analyses is fundamental for disease detection and for planning therapy and surgery.
The most common contrast agents carriers are enumerated below , .
Quantum Dots (QDs)
Semiconductor quantum dots (QDs) are nanoparticles or nanocrystals in the range of 1 to 10 nm, characterized by particular photophysical and photochemical properties: if excited at appropriate wavelengths, they emit light in different colors, depending on their size (quantum confinement - figure 5). They are usually composed of atoms from groups II-VI or III-V.
QDs are excellent reagents for in vivo imaging, thanks to their stability and their increased and multicolor fluorescence capability, appearing today as the most versatile technology for this kind of studies.
Indeed, compared to common fluorescent molecules, they have a better photostability, they transmit a brighter signal (with an high signal to noise ratio) and they can be used for long-term labeling of live cells. However, toxicity of QD is yet to be determined.
QDs can be directed to cell surface markers via conjugated antibodies and/or they can be internalized into the cells by endocytic uptake, following the cells for weeks.
In this way it is possible to optically codify live cells, by studying mixed cell populations with different-sized QDs, each emitting light of a different wavelength, or by tracking cellular extravasation characterizing metastasis.
Particular types of QDs are the "near-infrared fluorescent type II quantum dots": their emission spectrum is in the infrared, so they can detect and image objects much deeper into living tissue. They are particularly important in providing the surgeon with a real-time image of the cancer-affected organ during surgery, and can be used for confirmation that the operation has been complete if QDs fluorescence disappears in the concerned area. With these near-infrared particle deeper tumor can be visualized, eliminating the need for more invasive procedures.
QDs are also extremely useful for cancers detection and diagnosis, since they can home in on cancer targets and allows for the visualization of the tumors in vivo. To improve QDs biocompatibility, they can be coated with a copolymer containing multiple polyethylene glycol (PEG) molecules and monoclonal antibodies for recognition of tumor antigens. QD can be also associated with nanoscale systems such as phospholipid micelles and silicon nanospheres to improve their solubilization and reduce their accumulation in liver and bone.
Figure 4 - Solutions of differently sized quantum dots
Nowadays, magnetic nanoparticles such as colloidal iron oxide formulated with dextran are used as MRI contrast agents. Although these nanoparticles are toxic, since their internalization leads to membrane disruption, research is now trying to decrease internalization by coupling insulin on the iron oxide nanoparticle surface.
Dendrimers are polymeric complexes that comprise a series of well-defined branches around an inner core with sizes (1 to 10 nm) and physicochemical properties similar to macromolecules. However, in contrast to many traditional polymers, they have low polydispersity and are structurally well defined.
Dendrimers can be synthesized using two different approaches:
the convergent approach, for which the synthesis begins separately on different segments of the core at the periphery of the final molecule, and stops when these segments couple; each synthesized generation of dendrimer can be subsequently purified.
in the divergent approach, dendrimer is synthesized starting from the core, and then other successive generation are built; however, this method has a low yield, because of too many reactions conducted on a single molecules possessing a large number of equivalent reaction sites and also due to difficulties in purification of the excesses of reagent.
Gd MRI contrast agents based on small dendrimer are used to limit the prolonged retention and toxicity of larger dendrimer, and are excreted more quickly by the kidneys, allowing the visualization of vascular structures also thanks to little extravasation.
Liposome are uni- or multi-lamellar phospholipid spheres in the range of 30 nm to several micrometers, with properties depending upon their size, lipid composition, surface charge and method of preparation.
They are excellent carriers for a variety of radiopharmaceuticals and contrast agents. One of their positive feature is that if they are in the right nanosize range, the background signal caused by their agents distribution to normal tissues is absent, because they did not extravasate at the normal vasculature. Moreover, even 20 hours after injection, agents associated with sterically stabilized liposomes have exhibited good contrast enhancement in the tumor, since liposomes remains in the bloodstream until they accumulate in the tumor tissues.
Nanoscale Systems for Drug Delivery
As mentioned before, liposomes are excellent carriers for a variety of drugs and are being tested extensively for use in gene therapy protocols, such as the transfection of cells; particularly, for this purpose, synthetic pH-sensitive histidylated oligolysine can be added to a drug-liposome complex to aid the therapeutic gene in escaping from the endosome, that otherwise would degrade it. Importantly, their interaction with therapeutic agents is affected by lipid composition.
Moreover, liposomes circulation half-lives can be increased by modifying their surface with active targeting ligands, improving delivery of therapeutics to target cells.
Micelles are self-assemblies of amphiphiles that form supramolecular core-shell structure in the aqueous environment, due to hydrophobic interactions between amphiphilic molecules when their concentrations exceed the critical micelle concentration (CMC).
Nanosized micelles are generally smaller than 100 nm, and they can form delivery systems with reduced toxicity and high thermodynamic stability, composed by amphiphilic polymers that consist of a PEG and a low-molecular-weight hydrophobic core-forming block.
These micelles consists of regions with different polarity gradients, allowing their use for the solubilization of hydrophobic compounds of varying polarities without drug modification. Moreover, various evidences show that using these methods increase circulation half-life and tumor accumulation of drugs.
Micellar drug delivery systems can be divided into 4 classes: phospholipid micelles, pluronic micelles, poly(L-amino acid) micelles and polyester micelles, all sharing similar molecular architecture.
Figure 5 - Differences between liposomes and micelles
Nanoemulsions are isotropic liquid mixtures of oil and water stabilized with a surface active film composed by surfactant and co-surfactant, in which the dispersed phase droplets are in the nanosize range of typically 20 to 200 nm. They form upon simple mixing of the components, are thermodynamically and kinetically stable (unlike microemulsions) and optically transparent.
Depending on their structure, the rate of drug release they carry changes significantly:
oil-in-water (O/W) nanoemulsions contain >50 wt% water with strongly interacting oil droplets (5 to 14 nm), showing a slow release of hydrophobic drugs mainly solubilized in oil droplets, due to hindered diffusion, and a quick release of water-soluble drugs;
water-in-oil (W/O) systems contain <20 wt% water and present the reverse behavior;
systems containing between 20 and 50 wt% water are bi-continuous nanoemulsions: a relatively fast diffusion and release occur for both oil-soluble and water-soluble drugs.
Various experiments have shown that nanoemulsions have the ability to decrease toxicity of anticancer agents by increasing targeting to tumor sites.
Nanogels are mixture composed by flexible hydrophilic polymers in the nanosize scale, in which drug can be loaded spontaneously upon equilibration or swelling in water; these processes result in reduction of the solvent volume, that leads to gel collapse and formation of dense nanoparticles. Compared to existing solid nanoparticles, they have higher drug-loading capacities and simpler preparation methods, as described above.
Drug molecules can be associated with dendrimers in a variety of ways, for example by physically encapsulating drugs in the void spaces of the dendrimer interior by incubation or by forming dendrimer drug networks or prodrugs from a linkage of the drug to the dendrimer surface.
These molecules have also been extensively investigated for gene delivery, even if their toxicity and immunogenic potentials should be considered if they are applied for drug delivery.
Monoclonal antibodies are an essential weapon for the war against cancer: they can be used as imaging vehicles, for drug targeting, as drug carriers, and as drug itself.
Their mechanism of action operates at different levels and includes, singularly or in combination, interference with receptor function, complement-dependent cellular cytoxicity, receptor ligand binding competition, antibody-dependent - cell-mediated cytoxicity.
The "small interfering" RNAs, or siRNAs, are small double-stranded molecules that contain specific mRNAs complementary sequence, attractive as nanodrugs candidate for blocking the expression of cancer genes.
Poor nanoparticles uptake into targeted cancer cells or instability in the blood may require siRNA coupling with different nanoparticles containing a homing sequence to direct the complex to the tumor sites.
At the early stages of tumorigenesis the body can eliminate small tumors by itself, while with cancer progression, malignant cells develop mechanisms that blind the host to their presence.
Nowadays a new vaccines design is developed coupling antigens, that have low degree immunogenicity, with solid-core nanoshells of a narrowly defined size (40 nm to 50 nm), that act as adjuvant to boost the immune response against cancer.
Nanoshells are near-infrared-absorbing gold nanoparticles composed by a silica core surrounded by a thin gold metal shell, that heat up due to energy absorption if exposed to the appropriate wavelength of light.
Nanoshells can be attached to tumor-homing or -targeting molecules to increase their concentration to tumor site: when nanoparticles accumulate, the tumor is illuminated with a near-infrared diode laser, that cause the heating of nanoshells, with consequent thermal ablation of cancer tissues. This method is named "photodynamic therapy".
With some particular molecular dots, light can also be used to produce highly energetic oxygen molecules, that chemically react with cancer cells, destroying them.
Conclusions and Future Directions
Nowadays the fusion of Medicine and Nanothecnology is creating a new world in which all diseases FINIRE. Finire anche vecchie cure anticancro.
In the near future, this methods could be hopefully used to replace surgical resection of tumors or to reduce toxic side effects caused by chemotherapy.
What else can we expect from tomorrow?