Nanotechnologyis the science that deals with the
processes that occur at molecular level and of nanolength scale size.
the...
The uncontrolled growth can cause problems in one
or more of the following ways:
-spreading into normal tissues nearby.
-c...
Tumors can be benign or malignant:
Benign tumors are not cancer:
Benign tumors are rarely life-threatening.
Generally, ben...
Normally, cells grow and divide to form new cells as the
body needs them. When cells grow old, they die, and
new cells tak...
Malignant tumors often can be removed, but sometimes
they grow back.
Cells from malignant tumors can invade and damage
nea...
Cancer
The small size of nanoparticles endows them with
properties that can be very useful in oncology,
particularly in im...
downside, however, is that quantum dots are usually
made of quite toxic elements.
Another nanoproperty, high surface area ...
diagnosis of cancer in the early stages from a few
drops of a patient's blood.
The basic point to use drug delivery is bas...
molecules that are next to them (like tumors). This
therapy is appealing for many reasons. It does not
leave a “toxic trai...
Mucous membranes and glands, such as salivary
glands and tear glands, are sensitive to radiation and
some chemotherapy med...
another cancer. The secondary cancer usually arises
months, or more likely even years after the initial
treatment. Both ch...
can cause permanent damage to the testes that
produce the sperm as well as the sperm. Radiation to
the area of the testes ...
Nanotechnology
will allow the reduction of screening tools which
means that many tests can be run on a single device.
This...
pinpoint the changes in the genetics of cancer.
Nanowires can be coated with a probe such as an
antibody that binds to a t...
Cantilevers
Nanoscale cantilevers are built using
semiconductor lithographic techniques.
1
These
can be coated with molecu...
• Types of Nanoparticles as Drug Delivery
•
• Systems
• Nanoparticles can consist of a number of
materials, including poly...
improve the pharmacokinetics and
pharmacodynamics of associated drugs.1 To date,
liposome-based formulations of several an...
preferential accumulation of liposomes in tumor
tissues. One strategy to achieve tumor-specific
targeting is to conjugate ...
• Targeted Delivery of Therapeutic Nanoparticles
• Passive Targeting
• Passive targeting takes advantage of the inherent
s...
usually of 10-fold or greater, can be achieved when a
drug is delivered by a nanoparticle rather than as a
free drug.88 Ho...
specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala-
Gly-Gln) was efficiently and specifically cleaved by
MMP-2.90 When cer...
• An alternative strategy to overcome these
limitations is to conjugate a targeting ligand or an
antibody to nanoparticles...
outcomes underline the importance of polymer-drug
design
• Choice of Target Receptor. Selection of the
appropriate recepto...
• Choice of Targeting Ligand. One of the greatest
challenges to the design of nanoparticles that can
selectively and succe...
targeted therapies. Whole mAbs have 2 binding
domains showing high binding avidity. The Fc
domain of the mAb can induce co...
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Nanotechnology

  1. 1. Nanotechnologyis the science that deals with the processes that occur at molecular level and of nanolength scale size. there are three step in the world of measurements the first step is the meter, the second step is micron (world of cells) and the last step is nanometer (smaller than the cell). ‘Pharmaceutical nanotechnology’embraces applications of nanoscience to pharmacy as nanomaterials, and as devices like drug delivery, diagnostic, imaging and biosensor. Uses of Nanotechnology: 1-Diagnosis and treatment of cancer According to the US National Cancer Institute (OTIR, 2006) “Nanotechnology will change the very foundations of cancer diagnosis, treatment, and prevention”. We have already seen how nanotechnology, an extremely wide and versatile field, can affect many of its composing disciplines in amazingly innovative and unpredictable ways. Q- what is cancer ? Cancer is a disease caused by normal cells changing them so that they grow in an uncontrolled way.
  2. 2. The uncontrolled growth can cause problems in one or more of the following ways: -spreading into normal tissues nearby. -causing pressure on other body structure. -spreading to other parts of the body through the lymphatic system or blood stream. The word cancerwas first applied to the disease by Hippocrates (460–370 B.C.), the Greek philosopher, who used the words carcinosand carcinomato refer to non-ulcer forming and ulcer forming tumors. The words refer to a crab, probably due to the external appearance of cancerous tumors, which have branch-like projections that resemble the claws of a crab. Understanding Cancer Cancer begins in cells, the building blocks that form tissues. Tissues make up the organs of the body. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place. Sometimes, this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. These extra cells can form a mass of tissue called a growth or tumor.
  3. 3. Tumors can be benign or malignant: Benign tumors are not cancer: Benign tumors are rarely life-threatening. Generally, benign tumors can be removed, and they usually do not grow back. Cells from benign tumors do not invade the tissues around them. Cells from benign tumors do not spread to other parts of the body. Malignant tumors are cancer: Malignant tumors are generally more serious than benign tumors. They may be life-threatening. Malignant tumors often can be removed, but sometimes they grow back. Cells from malignant tumors can invade and damage nearby tissues and organs. Cells from malignant tumors can spread (metastasize) to other parts of the body. Cancer cells spread by breaking away from the original (primary) tumor and entering the bloodstream or lymphatic system. The cells can invade other organs, forming new tumors that damage these organs. The spread of cancer is called metastasis. Understanding Cancer Cancer begins in cells, the building blocks that form tissues. Tissues make up the organs of the body.
  4. 4. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place. Sometimes, this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. These extra cells can form a mass of tissue called a growth ortumor. Tumors can be benign or malignant: Benign tumors are not cancer: Benign tumors are rarely life-threatening. Generally, benign tumors can be removed, and they usually do not grow back. Cells from benign tumors do not invade the tissues around them. Cells from benign tumors do not spread to other parts of the body. Malignant tumors are cancer: Malignant tumors are generally more serious than benign tumors. They may be life-threatening.
  5. 5. Malignant tumors often can be removed, but sometimes they grow back. Cells from malignant tumors can invade and damage nearby tissues and organs. Cells from malignant tumors can spread (metastasize) to other parts of the body. Cancer cells spread by breaking away from the original (primary) tumor and entering the bloodstream or lymphatic system. The cells can invade other organs, forming new tumors that damage these organs. The spread of cancer is called metastasis. A schematic illustration showing how nanoparticles or other cancer drugs might be used to treat cancer.
  6. 6. Cancer The small size of nanoparticles endows them with properties that can be very useful in oncology, particularly in imaging. Quantum dots (nanoparticles with quantum confinement properties, such as size- tunable light emission), when used in conjunction with MRI (magnetic resonance imaging), can produce exceptional images of tumor sites. These nanoparticles are much brighter than organic dyes and only need one light source for excitation. This means that the use of fluorescent quantum dots could produce a higher contrast image and at a lower cost than today's organic dyes used as contrast media. The
  7. 7. downside, however, is that quantum dots are usually made of quite toxic elements. Another nanoproperty, high surface area to volume ratio, allows many functional groups to be attached to a nanoparticle, which can seek out and bind to certain tumor cells. Additionally, the small size of nanoparticles (10 to 100 nanometers), allows them to preferentially accumulate at tumor sites (because tumors lack an effective lymphatic drainage system). A very exciting research question is how to make these imaging nanoparticles do more things for cancer. For instance, is it possible to manufacture multifunctional nanoparticles that would detect, image, and then proceed to treat a tumor? This question is under vigorous investigation; the answer to which could shape the future of cancer treatment> promising new cancer treatment that may one day replace radiation and chemotherapy is edging closer to human trials. Kanzius RF therapy attaches microscopic nanoparticles to cancer cells and then "cooks" tumors inside the body with radio waves that heat only the nanoparticles and the adjacent (cancerous) cells. Sensor test chips containing thousands of nanowires, able to detect proteins and other biomarkers left behind by cancer cells, could enable the detection and
  8. 8. diagnosis of cancer in the early stages from a few drops of a patient's blood. The basic point to use drug delivery is based upon three facts: a) efficient encapsulation of the drugs, b) successful delivery of said drugs to the targeted region of the body, and c) successful release of that drug there. Researchers at Rice University under Prof. Jennifer West, have demonstrated the use of 120 nm diameter nanoshells coated with gold to kill cancer tumors in mice. The nanoshells can be targeted to bond to cancerous cells by conjugating antibodies or peptides to the nanoshell surface. By irradiating the area of the tumor with an infrared laser, which passes through flesh without heating it, the gold is heated sufficiently to cause death to the cancer cells.] Nanoparticles of cadmium selenide (quantum dots) glow when exposed to ultraviolet light. When injected, they seep into cancer tumors. The surgeon can see the glowing tumor, and use it as a guide for more accurate tumor removal. In photodynamic therapy, a particle is placed within the body and is illuminated with light from the outside. The light gets absorbed by the particle and if the particle is metal, energy from the light will heat the particle and surrounding tissue. Light may also be used to produce high energy oxygen molecules which will chemically react with and destroy most organic
  9. 9. molecules that are next to them (like tumors). This therapy is appealing for many reasons. It does not leave a “toxic trail” of reactive molecules throughout the body (chemotherapy) because it is directed where only the light is shined and the particles exist. Photodynamic therapy has potential for a noninvasive procedure for dealing with diseases, growth and tumors. Chemotherapy is the delivery of drugs to treat disease, most commonly cancer, and radiation therapy is the use of high energy ionizing radiation to inhibit the division and growth of cells (usually cancer cells). Both of these therapy options are highly effective in treating many types of cancers; however they can also affect the normal healthy cells in the body, inducing unwanted side effects. Most of the side effects from chemotherapy and radiation subside when treatments end, but there are some that can be long-term. Dryness
  10. 10. Mucous membranes and glands, such as salivary glands and tear glands, are sensitive to radiation and some chemotherapy medications. Radiation therapy to the head and neck region can induce xerostomia (dry mouth) and xerophthalmia (dry eyes). Radiation can also affect the sweat glands, causing them to stop working and making temperature regulation difficult. These conditions may be long-term and do affect the patient’s overall quality of life. Hair Loss Hair follicles contain rapidly growing and dividing cells making them susceptible to damage from both chemotherapy and radiation therapy. This damage causes hair loss, which is usually temporary. Chemotherapy can cause hair loss over all of your body, but radiation only causes hair loss to the localized area where it was administered. Depending on the medication and the level of radiation, the damage to the hair follicle can be extensive enough to induce permanent hair loss . Secondary Tumors A secondary tumor is the formation of a new and unrelated cancer as a result of the treatment of
  11. 11. another cancer. The secondary cancer usually arises months, or more likely even years after the initial treatment. Both chemotherapy and radiation are known carcinogens, meaning they can cause cancer. The risk of secondary tumors is usually so low that the benefits of the treatment outweigh the risks, but your doctor will continue to monitor your overall health, even after treatments have ended Hearing Loss Chemotherapy medications, especially cis-platin, can cause tinnitus, which is a ringing sensation in your ears. There is no specific treatment for tinnitus, so it can lead to hearing loss. Radiation therapy administered to the brain can cause damage to the inner ear, resulting in hearing loss as well. Infertility The cells of the reproductive system for both men and women are rapidly dividing cells, making them vulnerable to damage from both chemotherapy and radiation therapy. For men, chemotherapy treatments
  12. 12. can cause permanent damage to the testes that produce the sperm as well as the sperm. Radiation to the area of the testes reduces the number and functionality of the present sperm. High doses of radiation can induce long-term effects. In both cases you may want to consult your doctor about freezing some of your sperm to ensure your ability to father children in the future. Chemotherapy can cause permanent damage to the ovaries, which are responsible for producing hormones essential to fertility. Radiation therapy to the pelvis region can cause women to experience signs of menopause, which may be long-term if the radiation dose is high Improved Diagnostics Nanodevices can provide rapid and sensitive detection of cancer-related molecules by enabling scientists to detect molecular changes even when they occur only in a small percentage of cells. This would allow early detection of cancer – a critical step in improving cancer treatment.
  13. 13. Nanotechnology will allow the reduction of screening tools which means that many tests can be run on a single device. This makes cancer screening faster and more cost- efficient. Nanowires Nanowires by nature have incredible properties of selectivity and specificity. Nanowires can be engineered to sense and pick up molecular markers of cancer cells. By laying down nanowires across a microfluidic channel and allowing cells or particles to flow through it. The wires can detect the presence of genes and relay the information via electrical connections to doctors and researchers. This technology can help
  14. 14. pinpoint the changes in the genetics of cancer. Nanowires can be coated with a probe such as an antibody that binds to a target protein. Proteins that bind to the antibody will change the nanowire’s electrical conductance and this can be Particles flow through microfluidic channel measured by a detector. 2 Jim Heath, a nanotechnology researcher at California Institute of Technology has designed a nanowire detector. Each nanowire bears a different antibody or oligonucleotide, a short stretch of DNA that can be used to recognize specific RNA sequences. They have begun testing the chip on proteins secreted by cancer cells. 2 Carbon nanotubes are also being used to make DNA biosensors. This uses self-assembled carbon nanotubes and probe DNA oligonucleotides immobilized by covalent binding to the nanotubes. When hybridization between the probe and the target DNA sequence occurs, the change is noted in the voltammetirc peak of an indicator. 3 The DNA biosensors being developed are more efficient and more selective than current detection methods.
  15. 15. Cantilevers Nanoscale cantilevers are built using semiconductor lithographic techniques. 1 These can be coated with molecules (like antibodies) capable of binding to specific molecules that only cancer cells secrete. When the target molecule binds to the antibody on the cantilever, a physical property of the cantilever changes and the change can be detected. Researchers can study the binding real time and the information may also allow quantitative analysis. The nanometer- sized cantilevers are extremely sensitive and can detect single molecules of DNA or protein. Thus providing fast and sensitive detection methods for cancer related molecules.
  16. 16. • Types of Nanoparticles as Drug Delivery • • Systems • Nanoparticles can consist of a number of materials, including polymers, metals, and ceramics. Based on their manufacturing methods and materials used, these particles can adopt diverse shapes and sizes with distinct properties. Many types of nanoparticles are under various stages of development as drug delivery systems, including liposomes and other lipid-based carriers (such as lipid emulsions and lipid-drug complexes), polymer-drug conjugates, polymer microspheres, micelles, and various ligand-targeted products (such as immunoconjugates0 • Liposomes and Other Lipid-based Nanoparticles • Liposomes are self-assembling, spherical, closed colloidal structures composed of • lipid bilayers that surround a central aqueous space. Liposomes are the most studied formulation of nanoparticle for drug delivery (). Several types of anticancer drugs have been developed as lipid-based systems by using a variety of preparation methods. Liposomal formulations have shown an ability to
  17. 17. improve the pharmacokinetics and pharmacodynamics of associated drugs.1 To date, liposome-based formulations of several anticancer agents (Stealth liposomal doxorubicin [Doxil], liposomal doxorubicin [Myocet], and liposomal daunorubicin [DaunoXome]) have been approved for the treatment of metastatic breast cancer and Kaposi's sarcoma.2 • First generation liposomes have an unmodified phospholipid surface that can attract plasma proteins, which in turn trigger recognition and uptake of the liposomes by the mononuclear phagocytic system (MPS), which is synonymous with the reticuloendothelial system,1 resulting in their rapid clearance from the circulation. This property impedes the distribution of liposomes and their associated drug to solid tumors or other non-MPS sites of drug action. Second generation liposomal drugs are being developed in an effort to evade MPS recognition and subsequent clearance. Surface-modified liposomes (Stealth) have hydrophilic carbohydrates or polymers, which usually are lipid derivatives of polyethylene glycol (PEG) grafted to the liposome surfaceWhile this surface modification has solved the problem of fast clearance from the circulation, yielding liposomes with a significantly increased half-life in the blood, the challenge remains to attain
  18. 18. preferential accumulation of liposomes in tumor tissues. One strategy to achieve tumor-specific targeting is to conjugate a targeting moiety on the outer surface of the lipid bilayer of the liposome that selectively delivers drug to the desired site of action. For example, an immunoliposome has antibodies or antibody fragments conjugated on its outer surface, usually at the terminus of PEG. Several studies have documented improved therapeutic efficacy of immunoliposomes targeted to internalizing antigens or receptors compared with that of nontargeted liposomes. An in vitro study of a liposome formulation of doxorubicin (DOX) targeted to the internalizing antigen CD44 on B16F10 melanoma cells showed enhanced intracellular drug uptake from the targeted liposomes when compared with the free form of DOX. The enhanced uptake was correlated with enhanced cell killing efficacy. A liposomal formulation of cisplatin that lacked efficacy demonstrated encouraging therapeutic results when delivered in an immunoliposome targeted to an internalizing antigen. Recently, promising results were reported from a Phase I clinical study that evaluated the effect of MCC-465, a PEGylated liposomal formulation containing DOX targeted with an F(ab')2 fragment of a human mAb named GAH, in patients with metastatic stomach cancer
  19. 19. • Targeted Delivery of Therapeutic Nanoparticles • Passive Targeting • Passive targeting takes advantage of the inherent size of nanoparticles and the unique properties of tumor vasculature, such as the enhanced permeability and retention (EPR) effect and the tumor microenvironment.79,80,81–82 This approach can effectively enhance drug bioavailability and efficacy. • EPR Effect. Angiogenesis is crucial to tumor progression. Angiogenic blood vessels in tumor tissues, unlike those in normal tissues, have gaps as large as 600 to 800 nm between adjacent endothelial cells.18,83 This defective vascular architecture coupled with poor lymphatic drainage induces the EPR effect,83,84,85–86 which allows nanoparticles to extravasate through these gaps into extravascular spaces and accumulate inside tumor tissues87 (Figure 1). Dramatic increases in tumor drug accumulation,
  20. 20. usually of 10-fold or greater, can be achieved when a drug is delivered by a nanoparticle rather than as a free drug.88 However, the localization of nanoparticles within the tumor is not homogeneous. The factors that result in high concentrations of nanoparticles in one part of the tumor tissue but not in other parts are not well understood yet.89 In general, the accumulation of nanoparticles in tumors depends on factors including the size, surface characteristics, and circulation half-life of the nanoparticle and the degree of angiogenesis of the tumor. Usually, less nanoparticle accumulation is seen in preangiogenic or necrotic tumors.18 • Tumor Microenvironment. Hyperproliferative cancer cells have profound effects on their surrounding microenvironment. Tumors must adapt to use glycolysis (hypoxic metabolism) to obtain extra energy, resulting in an acidic microenvironment.81 In addition, cancer cells overexpress and release some enzymes that are crucial to tumor migration, invasion, and metastasis, including matrix metalloproteinases (MMPs).82 Tumor-activated prodrug therapy is an example of passive targeting that takes advantage of this characteristic of the tumor-associated microenvironment. A nanoparticle conjugating an albumin-bound form of DOX with an MMP-2–
  21. 21. specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala- Gly-Gln) was efficiently and specifically cleaved by MMP-2.90 When certain pH-sensitive molecules are incorporated into liposomes, drugs can be specifically released from the complexes by a change in pH.91 The pH-sensitive liposomes are stable at physiologic conditions (pH 7.2), but degraded in tumor- associated acidic areas. Likewise, thermolabile liposomes are expected to be activated by the local hyperthermic microenvironment.92 • Active Targeting • The polymeric nanoparticles that have been tested clinically so far have mostly lacked a targeting moiety and instead rely mainly on the EPR effect of tumors, the tumor microenvironment, and tumor angiogenesis to promote some tumor-selective delivery of nanoparticles to tumor tissues. However, these drug delivery systems using a binary structure conjugate inevitably have intrinsic limitations to the degree of targeting specificity they can achieve. In the case of the EPR effect, while poor lymphatic drainage on the one hand helps the extravasated drugs to be enriched in the tumor interstitium, on the other hand, it induces drug outflow from the cells as a result of higher osmotic pressure in the interstitium, which eventually leads to drug redistribution in some portions of the cancer tissue.93
  22. 22. • An alternative strategy to overcome these limitations is to conjugate a targeting ligand or an antibody to nanoparticles. By incorporating a targeting molecule that specifically binds an antigen or receptor that is either uniquely expressed or overexpressed on the tumor cell surface, the ligand- targeted approach is expected to selectively deliver drugs to tumor tissues with greater efficiency (Figure 2). Such targeted nanoparticles may constitute the next generation of polymeric nanoparticle drug delivery systems. Indeed, several targeted polymeric nanoparticles are currently undergoing preclinical studies.65,77,94,95–96 One of these, HPMA copolymer-DOX-galactosamine (PK2, FCE28069), has progressed to a clinical trial. In this nanoparticle, galactosamine moieties bind to the asialoglycoprotein receptor on hepatocytes.65,76 In a Phase I/II study, this targeted nanoparticle showed 12- to 50-fold greater accumulation than the free DOX in hepatocellular carcinoma tissue. Antitumor activity was observed in patients with primary hepatocellular carcinoma in this study.65,76 These promising early clinical results suggest the potential of targeted polymeric nanoparticles as anticancer drug delivery systems. Lessons have also been learned from many of the early clinical studies. For example, the failure of HPMA conjugates of paclitaxel and camptothecin in Phase I clinical trials was reported. Such negative
  23. 23. outcomes underline the importance of polymer-drug design • Choice of Target Receptor. Selection of the appropriate receptor or antigen on cancer cells is crucial for the optimal design of targeted nanoparticles. The ideal targets are those that are abundantly and uniquely expressed on tumor cells, but have negligible or low expression on normal cells. The targeted antigen or receptor should also have a high density on the surface of the target tumor cells. Whether the targeted nanoconjugate can be internalized after binding to the target cell is another important criterion in the selection of proper targeting ligands. In the case of an antibody or other ligand that cannot trigger the internalization process, the drug can enter cells through simple diffusion or other transport system after being released from the targeted conjugate at or near the cell surface. However, drug released outside the cell may disperse or redistribute to the surrounding normal tissues rather than exclusively to the cancer cells. In vitro and in vivo comparisons using internalizing or noninternalizing ligands have shown that the intracellular concentration of drug is much higher when the drug is released from nanoparticles in the cytoplasm after internalization.43,98
  24. 24. • Choice of Targeting Ligand. One of the greatest challenges to the design of nanoparticles that can selectively and successfully transport drug to cancerous tissues is the choice of targeting agent(s). This strategy also relies on the ability of the targeting agent or ligand to bind the tumor cell surface in an appropriate manner to trigger receptor-mediated endocytosis. The therapeutic agent will thereby be delivered to the interior of the cancer cell.85 A variety of tumor-targeting ligands, such as antibodies, growth factors, or cytokines, have been used to facilitate the uptake of carriers into target cells.90,92,99,100,101,102,103,104,105,106–107 • Ligands targeting cell-surface receptors can be natural materials like folate and growth factors, which have the advantages of lower molecular weight and lower immunogenicity than antibodies. However, some ligands, such as folate that is supplied by food, show naturally high concentrations in the human body and may compete with the nanoparticle- conjugated ligand for binding to the receptor, effectively reducing the intracellular concentration of delivered drug. Recent advances in molecular biology and genetic engineering allow modified antibodies to be used as targeting moieties in an active-targeting approach. MAbs or antibody fragments (such as antigen-binding fragments or single-chain variable fragments) are the most frequently used ligands for
  25. 25. targeted therapies. Whole mAbs have 2 binding domains showing high binding avidity. The Fc domain of the mAb can induce complement-mediated cytotoxicity and antibody-dependent, cell-mediated cytotoxicity, leading to additional cell-killing effect. On the other hand, the Fc domain also initiates an immune response and can be rapidly eliminated in the circulation, resulting in decreased accumulation of targeted nanoparticles into cancer cells.13 Compared with whole mAbs, the use of antibody fragments as a targeting moiety can reduce immunogenicity and improve the pharmacokinetic profiles of nanoparticles.1 For example, liposomes coupled with mAb fragments instead of whole antibodies showed decreased clearance rates and increased circulation half-lives, allowing the liposomes sufficient time to be distributed and bind to the targeted cells.1,39 This strategy improved the therapeutic efficacy of immunoliposomal DOX targeted against CD19 on human B lymphoma cells in animal models

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